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Sample records for non-obese diabetic mice

  1. Multiple mechanisms involved in diabetes protection by lipopolysaccharide in non-obese diabetic mice

    SciTech Connect

    Wang, Jun; Cao, Hui; Wang, Hongjie; Yin, Guoxiao; Du, Jiao; Xia, Fei; Lu, Jingli; Xiang, Ming

    2015-06-15

    Toll-like receptor 4 (TLR4) activation has been proposed to be important for islet cell inflammation and eventually β cell loss in the course of type 1 diabetes (T1D) development. However, according to the “hygiene hypothesis”, bacterial endotoxin lipopolysaccharide (LPS), an agonist on TLR4, inhibits T1D progression. Here we investigated possible mechanisms for the protective effect of LPS on T1D development in non-obese diabetic (NOD) mice. We found that LPS administration to NOD mice during the prediabetic state neither prevented nor reversed insulitis, but delayed the onset and decreased the incidence of diabetes, and that a multiple-injection protocol is more effective than a single LPS intervention. Further, LPS administration suppressed spleen T lymphocyte proliferation, increased the generation of CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T cells (Tregs), reduced the synthesis of strong Th1 proinflammatory cytokines, and downregulated TLR4 and its downstream MyD88-dependent signaling pathway. Most importantly, multiple injections of LPS induced a potential tolerogenic dendritic cell (DC) subset with low TLR4 expression without influencing the DC phenotype. Explanting DCs from repeated LPS-treated NOD mice into NOD/SCID diabetic mice conferred sustained protective effects against the progression of diabetes in the recipients. Overall, these results suggest that multiple mechanisms are involved in the protective effects of LPS against the development of diabetes in NOD diabetic mice. These include Treg induction, down-regulation of TLR4 and its downstream MyD88-dependent signaling pathway, and the emergence of a potential tolerogenic DC subset. - Highlights: • Administration of lipopolysaccharide (LPS) prevented type 1 diabetes in NOD mice. • Downregulating TLR4 level and MyD88-dependent pathway contributed to protection of LPS. • LPS administration also hampered DC maturation and promoted Treg differentiation.

  2. Epigallocatechin gallate delays the onset of type 1 diabetes in spontaneous non-obese diabetic mice.

    PubMed

    Fu, Zhuo; Zhen, Wei; Yuskavage, Julia; Liu, Dongmin

    2011-04-01

    Type 1 diabetes (T1D) results from the autoimmune-mediated destruction of pancreatic β-cells, leading to deficiency of insulin production. Successful islet transplantation can normalise hyperglycaemia in T1D patients; however, the limited availability of the islets, loss of islet cell mass through apoptosis after islet isolation and potential autoimmune destruction of the transplanted islets prevent the widespread use of this procedure. Therefore, the search for novel and cost-effective agents that can prevent or treat T1D is extremely important to decrease the burden of morbidity from this disease. In the present study, we discovered that ( - )-epigallocatechin gallate (EGCG, 0·05 % in drinking-water), the primary polyphenolic component in green tea, effectively delayed the onset of T1D in non-obese diabetic (NOD) mice. At 32 weeks of age, eight (66·7 %) out of twelve mice in the control group developed diabetes, whereas only three (25 %) out of twelve mice in the EGCG-treated group became diabetic (P < 0·05). Consistently, mice supplemented with EGCG had significantly higher plasma insulin levels and survival rate but lower glycosylated Hb concentrations compared with the control animals. EGCG had no significant effects on food or water intake and body weight in mice, suggesting that the glucose-lowering effect was not due to an alteration in these parameters. While EGCG did not modulate insulitis, it elevated the circulating anti-inflammatory cytokine IL-10 level in NOD mice. These findings demonstrate that EGCG may be a novel, plant-derived compound capable of reducing the risk of T1D. PMID:21144096

  3. The Gut Microbiota Modulates Glycaemic Control and Serum Metabolite Profiles in Non-Obese Diabetic Mice

    PubMed Central

    Greiner, Thomas U.; Hyötyläinen, Tuulia; Knip, Mikael; Bäckhed, Fredrik; Orešič, Matej

    2014-01-01

    Islet autoimmunity in children who later progress to type 1 diabetes is preceded by dysregulated serum metabolite profiles, but the origin of these metabolic changes is unknown. The gut microbiota affects host metabolism and changes in its composition contribute to several immune-mediated diseases; however, it is not known whether the gut microbiota is involved in the early metabolic disturbances in progression to type 1 diabetes. We rederived non-obese diabetic (NOD) mice as germ free to explore the potential role of the gut microbiota in the development of diabetic autoimmunity and to directly investigate whether the metabolic profiles associated with the development of type 1 diabetes can be modulated by the gut microbiota. The absence of a gut microbiota in NOD mice did not affect the overall diabetes incidence but resulted in increased insulitis and levels of interferon gamma and interleukin 12; these changes were counterbalanced by improved peripheral glucose metabolism. Furthermore, we observed a markedly increased variation in blood glucose levels in the absence of a microbiota in NOD mice that did not progress to diabetes. Additionally, germ-free NOD mice had a metabolite profile similar to that of pre-diabetic children. Our data suggest that germ-free NOD mice have reduced glycaemic control and dysregulated immunologic and metabolic responses. PMID:25390735

  4. Non-obese diabetic mice rapidly develop dramatic sympathetic neuritic dystrophy: a new experimental model of diabetic autonomic neuropathy.

    PubMed

    Schmidt, Robert E; Dorsey, Denise A; Beaudet, Lucie N; Frederick, Kathy E; Parvin, Curtis A; Plurad, Santiago B; Levisetti, Matteo G

    2003-11-01

    To address the pathogenesis of diabetic autonomic neuropathy, we have examined the sympathetic nervous system in non-obese diabetic (NOD) and streptozotocin (STZ)-induced diabetic mice, two models of type 1 diabetes, and the db/db mouse, a model of type 2 diabetes. After only 3 to 5 weeks of diabetes, NOD mice developed markedly swollen axons and dendrites ("neuritic dystrophy") in the prevertebral superior mesenteric and celiac ganglia (SMG-CG), similar to the pathology described in diabetic STZ- and BBW-rat and man. Comparable changes failed to develop in the superior cervical ganglia of the NOD mouse or in the SMG-CG of non-diabetic NOD siblings. STZ-induced diabetic mice develop identical changes, although at a much slower pace and to a lesser degree than NOD mice. NOD-SCID mice, which are genetically identical to NOD mice except for the absence of T and B cells, do not develop diabetes or neuropathology comparable to diabetic NOD mice. However, STZ-treated NOD-SCID mice develop severe neuritic dystrophy, evidence against an exclusively autoimmune pathogenesis for autonomic neuropathy in this model. Chronically diabetic type 2 db/db mice fail to develop neuritic dystrophy, suggesting that hyperglycemia alone may not be the critical and sufficient element. The NOD mouse appears to be a valuable model of diabetic sympathetic autonomic neuropathy with unambiguous, rapidly developing neuropathology which corresponds closely to the characteristic pathology of other rodent models and man. PMID:14578206

  5. Non-obese diabetic mice rapidly develop dramatic sympathetic neuritic dystrophy: a new experimental model of diabetic autonomic neuropathy.

    PubMed

    Schmidt, Robert E; Dorsey, Denise A; Beaudet, Lucie N; Frederick, Kathy E; Parvin, Curtis A; Plurad, Santiago B; Levisetti, Matteo G

    2003-11-01

    To address the pathogenesis of diabetic autonomic neuropathy, we have examined the sympathetic nervous system in non-obese diabetic (NOD) and streptozotocin (STZ)-induced diabetic mice, two models of type 1 diabetes, and the db/db mouse, a model of type 2 diabetes. After only 3 to 5 weeks of diabetes, NOD mice developed markedly swollen axons and dendrites ("neuritic dystrophy") in the prevertebral superior mesenteric and celiac ganglia (SMG-CG), similar to the pathology described in diabetic STZ- and BBW-rat and man. Comparable changes failed to develop in the superior cervical ganglia of the NOD mouse or in the SMG-CG of non-diabetic NOD siblings. STZ-induced diabetic mice develop identical changes, although at a much slower pace and to a lesser degree than NOD mice. NOD-SCID mice, which are genetically identical to NOD mice except for the absence of T and B cells, do not develop diabetes or neuropathology comparable to diabetic NOD mice. However, STZ-treated NOD-SCID mice develop severe neuritic dystrophy, evidence against an exclusively autoimmune pathogenesis for autonomic neuropathy in this model. Chronically diabetic type 2 db/db mice fail to develop neuritic dystrophy, suggesting that hyperglycemia alone may not be the critical and sufficient element. The NOD mouse appears to be a valuable model of diabetic sympathetic autonomic neuropathy with unambiguous, rapidly developing neuropathology which corresponds closely to the characteristic pathology of other rodent models and man.

  6. Protective effect of berberine on serum glucose levels in non-obese diabetic mice.

    PubMed

    Chueh, Wei-Han; Lin, Jin-Yuarn

    2012-03-01

    Among the active components in traditional anti-diabetic herbal plants, berberine which is an isoquinoline alkaloid exhibits promising potential for its potent anti-inflammatory and hypoglycemic effects. However, the berberine effect on serum glucose levels in type 1 diabetes (T1D) subjects still remains unknown. This study investigated berberine's effects on serum glucose levels using non-obese diabetic (NOD) mice that spontaneously develop T1D. The NOD mice were randomly divided into four groups, administered water with 50, 150, and 500 mg berberine/kg bw, respectively, through 14 weeks. ICR mice were also selected as a species control group to compare with the NOD mice. Changes in body weight, oral glucose challenge, and serum glucose levels were determined to identify the protective effect of berberine on T1D. After the 14-week oral supplementation, berberine decreased fasting serum glucose levels in NOD mice close to the levels in normal ICR mice in a dose dependent manner. Serum berberine levels showed a significantly (P<0.05) negative and non-linear correlation with fasting glucose levels in berberine-administered NOD mice. Our results suggested that berberine supplemented at appropriate doses for 14 weeks did not cause toxic side effects, but improved hyperglycemia in NOD mice.

  7. Changes in the Growth Hormone-IGF-I Axis in Non-obese Diabetic Mice

    PubMed Central

    Segev, Yael; Eshet, Rina; Flyvbjerg, Allan; Phillip, Moshe

    2000-01-01

    We investigated the changes in GH-IGF-I axis in non-obese diabetic (NOD)-mice, a model of insulin dependent diabetes mellitus. Diabetic female NOD mice and their age- and sex-matched controls were sacrificed at 4, 14, 21 and 30 days (30d DM) after the onset of glycosuria. Serum GH levels increased and serum IGF-I levels decreased in the 30d DM group (182 ± 32% and 45 ± 24% of age-matched controls respectively, p < 0.05). Another group (30d DM + I) was given SC insulin, and its serum IGF-I levels remained decreased. Liver GH receptor (GHR) and GH binding protein (GHBP) mRNA levels, as well as liver membrane GH binding assays were deeply decreased in the 30d DM group in comparison to controls. GHR message and binding capacity remained decreased in the 30d DM + I group. Renal GHR mRNA was decreased at 21d DM but not at 14d DM, whereas GHBP mRNA remained unchanged throughout the experiment. In conclusion, increased serum GH levels are documented in NOD diabetic mice, similarly to the changes described in humans. The decrease in GHR levels and decreased serum IGF-I in spite of increased circulating GH suggest a state of GH resistance. PMID:11469393

  8. Rotavirus acceleration of type 1 diabetes in non-obese diabetic mice depends on type I interferon signalling.

    PubMed

    Pane, Jessica A; Fleming, Fiona E; Graham, Kate L; Thomas, Helen E; Kay, Thomas W H; Coulson, Barbara S

    2016-07-13

    Rotavirus infection is associated with childhood progression to type 1 diabetes. Infection by monkey rotavirus RRV accelerates diabetes onset in non-obese diabetic (NOD) mice, which relates to regional lymph node infection and a T helper 1-specific immune response. When stimulated ex vivo with RRV, plasmacytoid dendritic cells (pDCs) from naïve NOD mice secrete type I interferon, which induces the activation of bystander lymphocytes, including islet-autoreactive T cells. This is our proposed mechanism for diabetes acceleration by rotaviruses. Here we demonstrate bystander lymphocyte activation in RRV-infected NOD mice, which showed pDC activation and strong upregulation of interferon-dependent gene expression, particularly within lymph nodes. The requirement for type I interferon signalling was analysed using NOD mice lacking a functional type I interferon receptor (NOD.IFNAR1(-/-) mice). Compared with NOD mice, NOD.IFNAR1(-/-) mice showed 8-fold higher RRV titers in lymph nodes and 3-fold higher titers of total RRV antibody in serum. However, RRV-infected NOD.IFNAR1(-/-) mice exhibited delayed pDC and lymphocyte activation, no T helper 1 bias in RRV-specific antibodies and unaltered diabetes onset when compared with uninfected controls. Thus, the type I interferon signalling induced by RRV infection is required for bystander lymphocyte activation and accelerated type 1 diabetes onset in genetically susceptible mice.

  9. Rotavirus acceleration of type 1 diabetes in non-obese diabetic mice depends on type I interferon signalling

    PubMed Central

    Pane, Jessica A.; Fleming, Fiona E.; Graham, Kate L.; Thomas, Helen E.; Kay, Thomas W. H.; Coulson, Barbara S.

    2016-01-01

    Rotavirus infection is associated with childhood progression to type 1 diabetes. Infection by monkey rotavirus RRV accelerates diabetes onset in non-obese diabetic (NOD) mice, which relates to regional lymph node infection and a T helper 1-specific immune response. When stimulated ex vivo with RRV, plasmacytoid dendritic cells (pDCs) from naïve NOD mice secrete type I interferon, which induces the activation of bystander lymphocytes, including islet-autoreactive T cells. This is our proposed mechanism for diabetes acceleration by rotaviruses. Here we demonstrate bystander lymphocyte activation in RRV-infected NOD mice, which showed pDC activation and strong upregulation of interferon-dependent gene expression, particularly within lymph nodes. The requirement for type I interferon signalling was analysed using NOD mice lacking a functional type I interferon receptor (NOD.IFNAR1−/− mice). Compared with NOD mice, NOD.IFNAR1−/− mice showed 8-fold higher RRV titers in lymph nodes and 3-fold higher titers of total RRV antibody in serum. However, RRV-infected NOD.IFNAR1−/− mice exhibited delayed pDC and lymphocyte activation, no T helper 1 bias in RRV-specific antibodies and unaltered diabetes onset when compared with uninfected controls. Thus, the type I interferon signalling induced by RRV infection is required for bystander lymphocyte activation and accelerated type 1 diabetes onset in genetically susceptible mice. PMID:27405244

  10. Rotavirus acceleration of type 1 diabetes in non-obese diabetic mice depends on type I interferon signalling.

    PubMed

    Pane, Jessica A; Fleming, Fiona E; Graham, Kate L; Thomas, Helen E; Kay, Thomas W H; Coulson, Barbara S

    2016-01-01

    Rotavirus infection is associated with childhood progression to type 1 diabetes. Infection by monkey rotavirus RRV accelerates diabetes onset in non-obese diabetic (NOD) mice, which relates to regional lymph node infection and a T helper 1-specific immune response. When stimulated ex vivo with RRV, plasmacytoid dendritic cells (pDCs) from naïve NOD mice secrete type I interferon, which induces the activation of bystander lymphocytes, including islet-autoreactive T cells. This is our proposed mechanism for diabetes acceleration by rotaviruses. Here we demonstrate bystander lymphocyte activation in RRV-infected NOD mice, which showed pDC activation and strong upregulation of interferon-dependent gene expression, particularly within lymph nodes. The requirement for type I interferon signalling was analysed using NOD mice lacking a functional type I interferon receptor (NOD.IFNAR1(-/-) mice). Compared with NOD mice, NOD.IFNAR1(-/-) mice showed 8-fold higher RRV titers in lymph nodes and 3-fold higher titers of total RRV antibody in serum. However, RRV-infected NOD.IFNAR1(-/-) mice exhibited delayed pDC and lymphocyte activation, no T helper 1 bias in RRV-specific antibodies and unaltered diabetes onset when compared with uninfected controls. Thus, the type I interferon signalling induced by RRV infection is required for bystander lymphocyte activation and accelerated type 1 diabetes onset in genetically susceptible mice. PMID:27405244

  11. The natural killer T lymphocyte: a player in the complex regulation of autoimmune diabetes in non-obese diabetic mice

    PubMed Central

    Cardell, S L

    2006-01-01

    Manipulation of the immune response to specifically prevent autoaggression requires an understanding of the complex interactions that occur during the pathogenesis of autoimmunity. Much attention has been paid to conventional T lymphocytes recognizing peptide antigens presented by classical major histocompatibility complex (MHC) class I and II molecules, as key players in the destructive autoreactive process. A pivotal role for different types of regulatory T lymphocytes in modulating the development of disease is also well established. Lately, CD1d-restricted natural killer T (NKT) lymphocytes have been the subject of intense investigation because of their ability to regulate a diversity of immune responses. The non-classical antigen presenting molecule CD1d presents lipids and glycolipids to this highly specialized subset of T lymphocytes found in both humans and mice. From experimental models of autoimmunity, evidence is accumulating that NKT cells can protect from disease. One of the best studied is the murine type 1 diabetes model, the non-obese diabetic (NOD) mouse. While the NKT cell population was first recognized to be deficient in NOD mice, augmenting NKT cell activity has been shown to suppress the development of autoimmune disease in this strain. The mechanism by which CD1d-restricted T cells exert this function is still described incompletely, but investigations in NOD mice are starting to unravel specific effects of NKT cell regulation. This review focuses on the role of CD1d-restricted NKT cells in the control of autoimmune diabetes. PMID:16412042

  12. Biphasic Decline of β-Cell Function with Age in Euglycemic Non-Obese Diabetic (NOD) Mice Parallels Diabetes Onset

    PubMed Central

    Cechin, Sirlene R.; Lopez-Ocejo, Omar; Karpinsky-Semper, Darla; Buchwald, Peter

    2015-01-01

    A gradual decline in insulin response is known to precede the onset of type 1 diabetes (T1D). To track age-related changes in the β-cell function of non-obese diabetic (NOD) mice, the most commonly used animal model for T1D, and to establish differences between those who do and do not become hyperglycemic, we performed a long-term longitudinal oral glucose tolerance test (OGTT) study (10–42 weeks) in combination with immunofluorescence imaging of islet morphology and cell proliferation. We observed a clear biphasic decline in insulin secretion (AUC0–30min) even in euglycemic animals. A first phase (10–28 weeks) consisted of a relatively rapid decline and paralleled diabetes development in the same cohort of animals. This was followed by a second phase (29–42 weeks) during which insulin secretion declined much slower while no additional animals became diabetic. Blood glucose profiles showed a corresponding, but less pronounced change: the area under the concentration curve (AUC0–150min) increased with age, and fit with a bilinear model indicated a rate-change in the trendline around 28 weeks. In control NOD scids, no such changes were observed. Islet morphology also changed with age as islets become surrounded by mononuclear infiltrates, and, in all mice, islets with immune cell infiltration around them showed increased β-cell proliferation. In conclusion, insulin secretion declines in a biphasic manner in all NOD mice. This trend, as well as increased β-cell proliferation, is present even in the NODs that never become diabetic, whereas, it is absent in control NOD scid mice. PMID:26099053

  13. Vaccination of non-obese diabetic mice with a fragment of peptide P277 attenuates insulin-dependent diabetes mellitus.

    PubMed

    Ma, Yan-Jun; Lu, Yong; Hou, Jing; Dong, Yuan-Kai; Du, Ming-Zhu; Xing, Yun; Ge, Chi-Yu; Xu, Mao-Lei; Jin, Liang; Cao, Rong-Yue; Li, Tai-Ming; Wu, Jie; Liu, Jing-Jing

    2011-09-01

    P277 is a peptide derived from the HSP60 regions, have potent immunological effect on insulin-dependent diabetes mellitus (IDDM) and its phase III clinical trials are currently under investigation. However, we recently discovered a positive correlation between anti-P277 autoantibodies and the presence of endothelial cells damage in inducing vascular leak syndrome. Therefore, the aim of our study was to demonstrate the critical peptide epitope of P277 to IDDM and to highlight the effects of this peptide therapy on inflammation of the islets. Groups of 4-week old female non-obese diabetic (NOD) mice were immunized one time every three weeks for three times with a residue of P277, showing a significant effect of down-regulating immunity to P277 protein and preventing the development of IDDM. Immunologic results including the suppression of T-cell proliferation, the increase of interleukin-10 (IL-10) production and reduction of interferon-γ (IFN-γ) production caused immune tolerance to P277. Hence, a functional role of the key epitope in P277 peptide capable of preventing IDDM is suggested, which could be modified to develop a novel safe and effective peptide vaccine against IDDM by reconstructing P277 in the further studies.

  14. Genetic Analysis of Substrain Divergence in Non-Obese Diabetic (NOD) Mice.

    PubMed

    Simecek, Petr; Churchill, Gary A; Yang, Hyuna; Rowe, Lucy B; Herberg, Lieselotte; Serreze, David V; Leiter, Edward H

    2015-03-03

    The non-obese diabetic (NOD) mouse is a polygenic model for type 1 diabetes that is characterized by insulitis, a leukocytic infiltration of the pancreatic islets. During ~35 years since the original inbred strain was developed in Japan, NOD substrains have been established at different laboratories around the world. Although environmental differences among NOD colonies capable of impacting diabetes incidence have been recognized, differences arising from genetic divergence have not been analyzed previously. We use both mouse diversity array and whole-exome capture sequencing platforms to identify genetic differences distinguishing five NOD substrains. We describe 64 single-nucleotide polymorphisms, and two short indels that differ in coding regions of the five NOD substrains. A 100-kb deletion on Chromosome 3 distinguishes NOD/ShiLtJ and NOD/ShiLtDvs from three other substrains, whereas a 111-kb deletion in the Icam2 gene on Chromosome 11 is unique to the NOD/ShiLtDvs genome. The extent of genetic divergence for NOD substrains is compared with similar studies for C57BL6 and BALB/c substrains. As mutations are fixed to homozygosity by continued inbreeding, significant differences in substrain phenotypes are to be expected. These results emphasize the importance of using embryo freezing methods to minimize genetic drift within substrains and of applying appropriate genetic nomenclature to permit substrain recognition when one is used.

  15. IDO-Expressing Fibroblasts Protect Islet Beta Cells From Immunological Attack and Reverse Hyperglycemia in Non-Obese Diabetic Mice.

    PubMed

    Zhang, Yun; Jalili, Reza B; Kilani, Ruhangiz T; Elizei, Sanam Salimi; Farrokhi, Ali; Khosravi-Maharlooei, Mohsen; Warnock, Garth L; Ao, Ziliang; Marzban, Lucy; Ghahary, Aziz

    2016-09-01

    Indoleamine 2,3-dioxygenase (IDO) induces immunological tolerance in physiological and pathological conditions. Therefore, we used dermal fibroblasts with stable IDO expression as a cell therapy to: (i) Investigate the factors determining the efficacy of this cell therapy for autoimmune diabetes in non-obese diabetic (NOD) mice; (ii) Scrutinize the potential immunological mechanisms. Newly diabetic NOD mice were randomly injected with either 10 × 10(6) (10M) or 15 × 10(6) (15M) IDO-expressing dermal fibroblasts. Blood glucose levels (BGLs), body weight, plasma kynurenine levels, insulitis severity, islet beta cell function, autoreactive CD8(+) T cells, Th17 cells and regulatory T cells (Tregs) were then investigated in these mice. IL-1β and cleaved caspase-3 levels were assessed in islets co-cultured with IDO-expressing fibroblasts. BGLs in 83% mice treated with 15M IDO-expressing fibroblasts recovered to normal up to 120 days. However, only 17% mice treated with 10M IDO-expressing cells were reversed to normoglycemia. A 15M IDO-expressing fibroblasts significantly reduced infiltrated immune cells in islets and recovered the functionality of remaining islet beta cells in NOD mice. Additionally, they successfully inhibited autoreactive CD8(+) T cells and Th17 cells as well as increased Tregs in different organs of NOD mice. Islet beta cells co-cultured with IDO-expressing fibroblasts had reduced IL-1β levels and cell apoptosis. Both cell number and IDO enzymatic activity contributes to the efficiency of IDO cell therapy. Optimized IDO-expressing fibroblasts successfully reverse the progression of diabetes in NOD mice through induction of Tregs as well as inhibition of beta cell specific autoreactive CD8(+) T cells and Th17 cells. J. Cell. Physiol. 231: 1964-1973, 2016. © 2016 Wiley Periodicals, Inc.

  16. Induction of autoimmune cholangitis in non-obese diabetic (NOD).1101 mice following a chemical xenobiotic immunization

    PubMed Central

    Wakabayashi, K; Yoshida, K; Leung, P S C; Moritoki, Y; Yang, G-X; Tsuneyama, K; Lian, Z-X; Hibi, T; Ansari, A A; Wicker, L S; Ridgway, W M; Coppel, R L; Mackay, I R; Gershwin, M E

    2009-01-01

    Our laboratory has suggested that loss of tolerance to pyruvate dehydrogenase (PDC-E2) leads to an anti-mitochondrial antibody response and autoimmune cholangitis, similar to human primary biliary cirrhosis (PBC). We have suggested that this loss of tolerance can be induced either via chemical xenobiotic immunization or exposure to select bacteria. Our work has also highlighted the importance of genetic susceptibility. Using the non-obese diabetic (NOD) congenic strain 1101 (hereafter referred to as NOD.1101 mice), which has chromosome 3 regions from B6 introgressed onto a NOD background, we exposed animals to 2-octynoic acid (2OA) coupled to bovine serum albumin (BSA). 2OA has been demonstrated previously by a quantitative structural activity relationship to react as well as or better than lipoic acid to anti-mitochondrial antibodies. We demonstrate herein that NOD.1101 mice immunized with 2OA-BSA, but not with BSA alone, develop high titre anti-mitochondrial antibodies and histological features, including portal infiltrates enriched in CD8+ cells and liver granulomas, similar to human PBC. We believe this model will allow the rigorous dissection of early immunogenetic cause of biliary damage. PMID:19094117

  17. Treated of type 1 diabetes mellitus in non-obese diabetic mice by transplantation of allogeneic bone marrow and pancreatic tissue

    SciTech Connect

    Yasumizu, R.; Sugiura, K.; Iwai, H.; Inaba, M.; Makino, S.; Ida, T.; Imura, H.; Hamashima, Y.; Good, R.A.; Ikehara, S.

    1987-09-01

    Non-obese diabetic (NOD) mice provide a model for type 1 diabetes mellitus. We previously showed that allogeneic bone marrow transplantation (ABMT) can prevent and treat insulitis and overt diabetes in NOD mice. However, ABMT alone could not be used to treat overt diabetes in NOD mice whose islets had been completely destroyed. To provide insulin-producing cells, pancreatic tissue from newborn mice was grafted under the renal capsules in combination with ABMT. The aims of concomitant ABMT are as follows. (i) It induces immunological tolerance to the donor-type major histocompatibility complex determinants and permits the host to accept subsequent pancreatic allografts from the bone marrow donor. (ii) ABMT replaces abnormal stem cells with normal stem cells. After transplantation of bone marrow plus newborn pancreas, NOD mice showed reduction of the glycosuria and a normal response in the glucose-tolerance test. Immunohistological study revealed the presence of clustered insulin-containing beta cells in the grafted pancreatic transplants. ABMT may become a viable treatment of established type 1 diabetes mellitus in humans.

  18. Maternal dietary n-6/n-3 fatty acid ratio affects type 1 diabetes development in the offspring of non-obese diabetic mice.

    PubMed

    Kagohashi, Yukiko; Abiru, Norio; Kobayashi, Masakazu; Hashimoto, Michio; Shido, Osamu; Otani, Hiroki

    2010-12-01

    Environment factors, including maternal or infant dietary nutrition have been reported to have an influence on the pathogenesis of type 1 diabetes. In the present study, to investigate the effect of maternal or post-weaning offspring's nutrition, in particular the essential fatty acid ratio (n-6/n-3) on the development of type 1 diabetes, we prepared two kinds of chows with n-6/n-3 ratios of 3.0 (L) and 14.5 (H), and provided them to mothers of non-obese diabetic (NOD) mice during gestation and lactation and to the offspring after weaning. The n-6/n-3 ratios in breast milk and erythrocyte membrane of NOD offspring became nearly the same with that of the maternal diet at 2 weeks after birth. In the L chow-fed offspring from L chow-fed mother (LLL), levels of insulitis were higher than those in the H chow-fed offspring from H chow-fed mother (HHH) at 4 weeks of age, while the levels in the LLL offspring became lower than those in the HHH after 6 weeks. Early insulin autoantibody expressions were found from 2 to 6 weeks in the HHH offspring, but not in the LLL. The LLL offspring exhibited strong suppression of overt diabetes development in regard to the onset and accumulated incidence of diabetes compared to the HHH. The study with combined L and H chows during gestation, lactation in mother and in post-weaning offspring revealed that only the LLH chow significantly suppressed the development of diabetes with similar kinetics to LLL chow, although the other combinations may delay the onset of diabetes. The present findings suggest that n-6/n-3 ratio of the maternal diet during gestation and lactation rather than that of offspring after weaning strongly affects the development of overt diabetes in NOD mice. PMID:20846138

  19. A combination hydrogel microparticle-based vaccine prevents type 1 diabetes in non-obese diabetic mice

    PubMed Central

    Yoon, Young Mee; Lewis, Jamal S.; Carstens, Matthew R.; Campbell-Thompson, Martha; Wasserfall, Clive H.; Atkinson, Mark A.; Keselowsky, Benjamin G.

    2015-01-01

    Targeted delivery of self-antigens to the immune system in a mode that stimulates a tolerance-inducing pathway has proven difficult. To address this hurdle, we developed a vaccine based-approach comprised of two synthetic controlled-release biomaterials, poly(lactide-co-glycolide; PLGA) microparticles (MPs) encapsulating denatured insulin (key self-antigen in type 1 diabetes; T1D), and PuraMatrixTM peptide hydrogel containing granulocyte macrophage colony-stimulating factor (GM-CSF) and CpG ODN1826 (CpG), which were included as vaccine adjuvants to recruit and activate immune cells. Although CpG is normally considered pro-inflammatory, it also has anti-inflammatory effects, including enhancing IL-10 production. Three subcutaneous administrations of this hydrogel (GM-CSF/CpG)/insulin-MP vaccine protected 40% of NOD mice from T1D. In contrast, all control mice became diabetic. In vitro studies indicate CpG stimulation increased IL-10 production, as a potential mechanism. Multiple subcutaneous injections of the insulin containing formulation resulted in formation of granulomas, which resolved by 28 weeks. Histological analysis of these granulomas indicated infiltration of a diverse cadre of immune cells, with characteristics reminiscent of a tertiary lymphoid organ, suggesting the creation of a microenvironment to recruit and educate immune cells. These results demonstrate the feasibility of this injectable hydrogel/MP based vaccine system to prevent T1D. PMID:26279095

  20. Aqueous leaf extract of Passiflora alata Curtis promotes antioxidant and anti-inflammatory effects and consequently preservation of NOD mice beta cells (non-obese diabetic).

    PubMed

    Figueiredo, D; Colomeu, Talita Cristina; Schumacher, Nayara Simon Gonzalez; Stivanin-Silva, L G; Cazarin, Cinthia Baú Betim; Meletti, Laura Maria Molina; Fernandes, Luís Gustavo Romani; Prado, Marcelo Alexandre; Zollner, R L

    2016-06-01

    Passiflora alata Curtis (P. alata) leaves have anti-inflammatory properties; the present study aimed to investigate the anti-diabetogenic properties of P. alata aqueous leaf extract. HPLC analysis identified the phenolic compounds catechin, epicatechin and rutin. The aqueous extract was administered for 30weeks to non-obese diabetic (NOD) mice presenting a decrease of 28.6% in diabetes incidence and the number of inflammatory cells in pancreatic islets, when compared with the control group (water). The P. alata group presented an antioxidant effect and decreased lipid peroxidation in the serum of NOD mice. Increased numbers of insulin-positive cells were also observed in the pancreatic islets of the treated group. The diabetic group exhibited higher levels in the glucose tolerance test and glycemic index, in comparison to the P. alata-treated group and non-diabetic control BALB/c mice. In addition, the P. alata extract reduced the percentage and the proliferation index of NOD mice lymphocytes submitted to in vitro dose/response mitogenic stimulation assays. These results suggest that the aqueous extract of P. alata has anti-inflammatory properties, contributing to the protection of beta cells in pancreatic islets in NOD mice, and presents potential for use a supporting approach to treat type 1 diabetes.

  1. Aqueous leaf extract of Passiflora alata Curtis promotes antioxidant and anti-inflammatory effects and consequently preservation of NOD mice beta cells (non-obese diabetic).

    PubMed

    Figueiredo, D; Colomeu, Talita Cristina; Schumacher, Nayara Simon Gonzalez; Stivanin-Silva, L G; Cazarin, Cinthia Baú Betim; Meletti, Laura Maria Molina; Fernandes, Luís Gustavo Romani; Prado, Marcelo Alexandre; Zollner, R L

    2016-06-01

    Passiflora alata Curtis (P. alata) leaves have anti-inflammatory properties; the present study aimed to investigate the anti-diabetogenic properties of P. alata aqueous leaf extract. HPLC analysis identified the phenolic compounds catechin, epicatechin and rutin. The aqueous extract was administered for 30weeks to non-obese diabetic (NOD) mice presenting a decrease of 28.6% in diabetes incidence and the number of inflammatory cells in pancreatic islets, when compared with the control group (water). The P. alata group presented an antioxidant effect and decreased lipid peroxidation in the serum of NOD mice. Increased numbers of insulin-positive cells were also observed in the pancreatic islets of the treated group. The diabetic group exhibited higher levels in the glucose tolerance test and glycemic index, in comparison to the P. alata-treated group and non-diabetic control BALB/c mice. In addition, the P. alata extract reduced the percentage and the proliferation index of NOD mice lymphocytes submitted to in vitro dose/response mitogenic stimulation assays. These results suggest that the aqueous extract of P. alata has anti-inflammatory properties, contributing to the protection of beta cells in pancreatic islets in NOD mice, and presents potential for use a supporting approach to treat type 1 diabetes. PMID:27039211

  2. p21 is associated with the proliferation and apoptosis of bone marrow-derived mesenchymal stem cells from non-obese diabetic mice.

    PubMed

    Gu, Z; Jiang, J; Xia, Y; Yue, X; Yan, M; Tao, T; Cao, X; Da, Z; Liu, H; Liu, H; Miao, Y; Li, L; Wang, Z

    2013-11-01

    Recent studies have shown that autologous and allogeneic transplantation of the BM-MSCs had therapeutic effects on T1DM, whereas the BM-MSCs from the NOD mice itself did not have this therapeutic effect. We previously demonstrated that Bone Marrow (BM) -MSCs from the non-obese diabetic (NOD) mice had the abnormal migration and adhesion. So we hypothesized that the proliferation and apoptosis of the BM-MSCs from the NOD mice were dysregulated. Our team compared the proliferation and apoptosis between NOD mice and imprinting control region (ICR) mice. Then we assessed whether the NF-κB-p53/p21 pathway was involved in the process. The cell proliferation ability of the BM-MSCs from the NOD mice were significantly decreased, while the percent of apoptotic cells was increased compared to those from the ICR mice. The p21 expression was significantly increased in the NOD-MSCs. The p65 level was enhanced in the BM-MSCs from the NOD mice when compared to the ICR mice, coincided with the expression of p21. Expressions of p65 and p21 were significantly decreased in the -BM-MSCs treated with p65 inhibitor. The knockdown p21 expression reversed the abnormal proliferation, colony formation and apoptosis of the BM-MSCs from the NOD mice. These data provide important preclinical references supporting the basis for further development of autologous MSC-based therapies for type1 diabetes mellitus (T1DM).

  3. Low incidence of spontaneous type 1 diabetes in non-obese diabetic mice raised on gluten-free diets is associated with changes in the intestinal microbiome.

    PubMed

    Marietta, Eric V; Gomez, Andres M; Yeoman, Carl; Tilahun, Ashenafi Y; Clark, Chad R; Luckey, David H; Murray, Joseph A; White, Bryan A; Kudva, Yogish C; Rajagopalan, Govindarajan

    2013-01-01

    Human and animal studies strongly suggest that dietary gluten could play a causal role in the etiopathogenesis of type 1 diabetes (T1D). However, the mechanisms have not been elucidated. Recent reports indicate that the intestinal microbiome has a major influence on the incidence of T1D. Since diet is known to shape the composition of the intestinal microbiome, we investigated using non-obese diabetic (NOD) mice whether changes in the intestinal microbiome could be attributed to the pro- and anti-diabetogenic effects of gluten-containing and gluten-free diets, respectively. NOD mice were raised on gluten-containing chows (GCC) or gluten-free chows (GFC). The incidence of diabetes was determined by monitoring blood glucose levels biweekly using a glucometer. Intestinal microbiome composition was analyzed by sequencing 16S rRNA amplicons derived from fecal samples. First of all, GCC-fed NOD mice had the expected high incidence of hyperglycemia whereas NOD mice fed with a GFC had significantly reduced incidence of hyperglycemia. Secondly, when the fecal microbiomes were compared, Bifidobacterium, Tannerella, and Barnesiella species were increased (p = 0.03, 0.02, and 0.02, respectively) in the microbiome of GCC mice, where as Akkermansia species was increased (p = 0.02) in the intestinal microbiomes of NOD mice fed GFC. Thirdly, both of the gluten-free chows that were evaluated, either egg white based (EW-GFC) or casein based (C-GFC), significantly reduced the incidence of hyperglycemia. Interestingly, the gut microbiome from EW-GFC mice was similar to C-GFC mice. Finally, adding back gluten to the gluten-free diet reversed its anti-diabetogenic effect, reduced Akkermansia species and increased Bifidobacterium, Tannerella, and Barnesiella suggesting that the presence of gluten is directly responsible for the pro-diabetogenic effects of diets and it determines the gut microflora. Our novel study thus suggests that dietary gluten could modulate the incidence of

  4. Low incidence of spontaneous type 1 diabetes in non-obese diabetic mice raised on gluten-free diets is associated with changes in the intestinal microbiome.

    PubMed

    Marietta, Eric V; Gomez, Andres M; Yeoman, Carl; Tilahun, Ashenafi Y; Clark, Chad R; Luckey, David H; Murray, Joseph A; White, Bryan A; Kudva, Yogish C; Rajagopalan, Govindarajan

    2013-01-01

    Human and animal studies strongly suggest that dietary gluten could play a causal role in the etiopathogenesis of type 1 diabetes (T1D). However, the mechanisms have not been elucidated. Recent reports indicate that the intestinal microbiome has a major influence on the incidence of T1D. Since diet is known to shape the composition of the intestinal microbiome, we investigated using non-obese diabetic (NOD) mice whether changes in the intestinal microbiome could be attributed to the pro- and anti-diabetogenic effects of gluten-containing and gluten-free diets, respectively. NOD mice were raised on gluten-containing chows (GCC) or gluten-free chows (GFC). The incidence of diabetes was determined by monitoring blood glucose levels biweekly using a glucometer. Intestinal microbiome composition was analyzed by sequencing 16S rRNA amplicons derived from fecal samples. First of all, GCC-fed NOD mice had the expected high incidence of hyperglycemia whereas NOD mice fed with a GFC had significantly reduced incidence of hyperglycemia. Secondly, when the fecal microbiomes were compared, Bifidobacterium, Tannerella, and Barnesiella species were increased (p = 0.03, 0.02, and 0.02, respectively) in the microbiome of GCC mice, where as Akkermansia species was increased (p = 0.02) in the intestinal microbiomes of NOD mice fed GFC. Thirdly, both of the gluten-free chows that were evaluated, either egg white based (EW-GFC) or casein based (C-GFC), significantly reduced the incidence of hyperglycemia. Interestingly, the gut microbiome from EW-GFC mice was similar to C-GFC mice. Finally, adding back gluten to the gluten-free diet reversed its anti-diabetogenic effect, reduced Akkermansia species and increased Bifidobacterium, Tannerella, and Barnesiella suggesting that the presence of gluten is directly responsible for the pro-diabetogenic effects of diets and it determines the gut microflora. Our novel study thus suggests that dietary gluten could modulate the incidence of

  5. Low Incidence of Spontaneous Type 1 Diabetes in Non-Obese Diabetic Mice Raised on Gluten-Free Diets Is Associated with Changes in the Intestinal Microbiome

    PubMed Central

    Marietta, Eric V.; Gomez, Andres M.; Yeoman, Carl; Tilahun, Ashenafi Y.; Clark, Chad R.; Luckey, David H.; Murray, Joseph A.; White, Bryan A.; Kudva, Yogish C.; Rajagopalan, Govindarajan

    2013-01-01

    Human and animal studies strongly suggest that dietary gluten could play a causal role in the etiopathogenesis of type 1 diabetes (T1D). However, the mechanisms have not been elucidated. Recent reports indicate that the intestinal microbiome has a major influence on the incidence of T1D. Since diet is known to shape the composition of the intestinal microbiome, we investigated using non-obese diabetic (NOD) mice whether changes in the intestinal microbiome could be attributed to the pro- and anti-diabetogenic effects of gluten-containing and gluten-free diets, respectively. NOD mice were raised on gluten-containing chows (GCC) or gluten-free chows (GFC). The incidence of diabetes was determined by monitoring blood glucose levels biweekly using a glucometer. Intestinal microbiome composition was analyzed by sequencing 16S rRNA amplicons derived from fecal samples. First of all, GCC-fed NOD mice had the expected high incidence of hyperglycemia whereas NOD mice fed with a GFC had significantly reduced incidence of hyperglycemia. Secondly, when the fecal microbiomes were compared, Bifidobacterium, Tannerella, and Barnesiella species were increased (p = 0.03, 0.02, and 0.02, respectively) in the microbiome of GCC mice, where as Akkermansia species was increased (p = 0.02) in the intestinal microbiomes of NOD mice fed GFC. Thirdly, both of the gluten-free chows that were evaluated, either egg white based (EW-GFC) or casein based (C-GFC), significantly reduced the incidence of hyperglycemia. Interestingly, the gut microbiome from EW-GFC mice was similar to C-GFC mice. Finally, adding back gluten to the gluten-free diet reversed its anti-diabetogenic effect, reduced Akkermansia species and increased Bifidobacterium, Tannerella, and Barnesiella suggesting that the presence of gluten is directly responsible for the pro-diabetogenic effects of diets and it determines the gut microflora. Our novel study thus suggests that dietary gluten could modulate the incidence of

  6. Oral Administration of Recombinant Lactococcus lactis Expressing HSP65 and Tandemly Repeated P277 Reduces the Incidence of Type I Diabetes in Non-Obese Diabetic Mice

    PubMed Central

    Ma, Yanjun; Liu, Jingjing; Hou, Jing; Dong, Yuankai; Lu, Yong; Jin, Liang; Cao, Rongyue; Li, Taiming; Wu, Jie

    2014-01-01

    Diabetes mellitus type 1 (DM1) is an autoimmune disease that gradually destroys insulin-producing beta-cells. We have previously reported that mucosal administration of fusion protein of HSP65 with tandem repeats of P277 (HSP65-6P277) can reduce the onset of DM1 in non-obese diabetic (NOD) mice. To deliver large amounts of the fusion protein and to enhance long-term immune tolerance effects, in the present study, we investigated the efficacy of using orally administrated L. lactis expressing HSP65-6P277 to reduce the incidence of DM1 in NOD mice. L. lactis strain NZ9000 was engineered to express HSP65-6P277 either constitutively or by nisin induction. After immunization via gavage with the recombinant L. lactis strains to groups of 4-week old female NOD mice for 36 weeks, we observed that oral administration of recombinant L. Lactis resulted in the prevention of hyperglycemia, improved glucose tolerance and reduced insulitis. Immunologic analysis showed that treatment with recombinant L. lactis induced HSP65- and P277- specific T cell immuno-tolerance, as well as antigen-specific proliferation of splenocytes. The results revealed that the DM1-preventing function was in part caused by a reduction in the pro-inflammatory cytokine IFN-γ and an increase in the anti-inflammatory cytokine IL-10. Orally administered recombinant L. lactis delivering HSP65-6P277 may be an effective therapeutic approach in preventing DM1. PMID:25157497

  7. Transcriptomic Insights into the Response of Placenta and Decidua Basalis to the CpG Oligodeoxynucleotide Stimulation in Non-Obese Diabetic Mice and Wild-Type Controls

    PubMed Central

    Liu, Xiao-Rui; Guo, Yu-Na; Qin, Chuan-Mei; Qin, Xiao-Li; Tao, Fei; Su, Fei; Tian, Fu-Ju; Zhang, Yan; Lin, Yi

    2016-01-01

    Intrauterine infection is one of the most frequent causes of miscarriage. CpG oligodeoxynucleotide (CpG ODN) can mimic intrauterine infection. CpG ODN-induced embryo-resorption was observed consistently in the NK-cell deficient non-obese diabetic (NOD) mice but not in the wild-type (WT) mice. To elucidate the molecular mechanisms of differential pregnancy outcomes, differentially expressed genes (DEGs) in the placenta and decidua basalis was revealed by RNA-Seq with CpG ODN or control ODN treatment. Common DEGs in the WT and NOD mice were enriched in antimicrobial/antibacterial humoral responses that may be activated as a primary response to bacterial infection. The susceptibility to CpG ODN-induced embryo-resorption in the NOD mice might mainly be attributed to M1 macrophage polarization and the immunodeficient status, such as the down-regulation in antigen processing and presentation, allograft rejection, and natural killer cell mediated cytotoxicity. In contrast, the WT mice with normal immune systems could activate multiple immune responses and be resistant to CpG ODN-induced embryo-resorption, such as M2 macrophage differentiation and activation regulated by complement component C1q and peroxisome proliferation-activated receptor (PPAR) signaling pathways. Collectively, this study suggests that the immunodeficient status of NOD mice and the macrophage polarization regulated by C1q and PPAR signaling might be the basis for differential pregnancy outcomes between the NOD and WT mice. PMID:27527166

  8. Protein kinase C expression in salivary gland acinar epithelial cells in non-obese diabetic mice, an experimental model for Sjögren's syndrome.

    PubMed

    Tensing, E-K; Ma, J; Hukkanen, M; Fox, H S; Li, T-F; Törnwall, J; Konttinen, Y T

    2005-01-01

    We planned to investigate the expression of protein kinase C (PKC) isoforms in acinar epithelial cells of salivary glands in the non-obese diabetic (NOD) mouse to find out if they develop changes of the PKC system like those seen in the human counterpart, i.e. in Sjögren's syndrome. Parotid, submandibular, and sublingual glands from NOD and control BALB/c mice were stained with a panel of monoclonal antibodies directed against conventional (alpha, beta, and gamma), novel (delta, epsilon, and theta), and atypical (lambda and iota) PKC isoforms using the streptavidin/HRP method. Similarly to human labial salivary glands, acinar epithelial cells of the healthy control BALB/c mice contained two of the conventional PKC isoforms, alpha and beta. Acinar and ductal epithelial cells also contained the atypical PKC isoforms lambda and iota. PKC isoforms gamma, delta, epsilon, and theta were not found. NOD mice which displayed focal sialadenitis contained the same conventional and atypical PKC isoforms. The acinar cells in NOD mice, in contrast to the Sjögren's syndrome patients, did not lack PKC alpha or beta. On the contrary, PKC alpha and beta staining was stronger than in the control BALB/c mice. The present results demonstrate that both conventional and atypical PKC isoforms participate in the salivary epithelial cell biology and that there are mouse strain-associated and/or disease state-associated changes in their expression. The lack of PKC alpha and beta isoforms found in Sjögren's syndrome was not reproduced in NOD mice, which discloses one more difference between the human disease and its NOD mouse model.

  9. Expression of cholera toxin B–proinsulin fusion protein in lettuce and tobacco chloroplasts – oral administration protects against development of insulitis in non-obese diabetic mice

    PubMed Central

    Ruhlman, Tracey; Ahangari, Raheleh; Devine, Andrew; Samsam, Mohtahsem; Daniell, Henry

    2008-01-01

    Summary Lettuce and tobacco chloroplast transgenic lines expressing the cholera toxin B subunit–human proinsulin (CTB-Pins) fusion protein were generated. CTB-Pins accumulated up to ~16% of total soluble protein (TSP) in tobacco and up to ~2.5% of TSP in lettuce. Eight milligrams of powdered tobacco leaf material expressing CTB-Pins or, as negative controls, CTB–green fluorescent protein (CTB-GFP) or interferon–GFP (IFN-GFP), or untransformed leaf, were administered orally, each week for 7 weeks, to 5-week-old female non-obese diabetic (NOD) mice. The pancreas of CTB-Pins-treated mice showed decreased infiltration of cells characteristic of lymphocytes (insulitis); insulin-producing β-cells in the pancreatic islets of CTB-Pins-treated mice were significantly preserved, with lower blood or urine glucose levels, by contrast with the few β-cells remaining in the pancreatic islets of the negative controls. Increased expression of immunosuppressive cytokines, such as interleukin-4 and interleukin-10 (IL-4 and IL-10), was observed in the pancreas of CTB-Pins-treated NOD mice. Serum levels of immunoglobulin G1 (IgG1), but not IgG2a, were elevated in CTB-Pins-treated mice. Taken together, T-helper 2 (Th2) lymphocyte-mediated oral tolerance is a likely mechanism for the prevention of pancreatic insulitis and the preservation of insulin-producing β-cells. This is the first report of expression of a therapeutic protein in transgenic chloroplasts of an edible crop. Transplastomic lettuce plants expressing CTB-Pins grew normally and transgenes were maternally inherited in T1 progeny. This opens up the possibility for the low-cost production and delivery of human therapeutic proteins, and a strategy for the treatment of various other autoimmune diseases. PMID:17490448

  10. Dimethyl sulfoxide inhibits spontaneous diabetes and autoimmune recurrence in non-obese diabetic mice by inducing differentiation of regulatory T cells

    SciTech Connect

    Lin, Gu-Jiun; Sytwu, Huey-Kang; Yu, Jyh-Cherng; Chen, Yuan-Wu; Kuo, Yu-Liang; Yu, Chiao-Chi; Chang, Hao-Ming; Chan, De-Chuan; Huang, Shing-Hwa

    2015-01-15

    Type 1 diabetes mellitus (T1D) is caused by the destruction of insulin-producing β cells in pancreatic islets by autoimmune T cells. Islet transplantation has been established as an effective therapeutic strategy for T1D. However, the survival of islet grafts can be disrupted by recurrent autoimmunity. Dimethyl sulfoxide (DMSO) is a solvent for organic and inorganic substances and an organ-conserving agent used in solid organ transplantations. DMSO also exerts anti-inflammatory, reactive oxygen species scavenger and immunomodulatory effects and therefore exhibits therapeutic potential for the treatment of several human inflammatory diseases. In this study, we investigated the therapeutic potential of DMSO in the inhibition of autoimmunity. We treated an animal model of islet transplantation (NOD mice) with DMSO. The survival of the syngeneic islet grafts was significantly prolonged. The population numbers of CD8, DC and Th1 cells were decreased, and regulatory T (Treg) cell numbers were increased in recipients. The expression levels of IFN-γ and proliferation of T cells were also reduced following DMSO treatment. Furthermore, the differentiation of Treg cells from naive CD4 T cells was significantly increased in the in vitro study. Our results demonstrate for the first time that in vivo DMSO treatment suppresses spontaneous diabetes and autoimmune recurrence in NOD mice by inhibiting the Th1 immune response and inducing the differentiation of Treg cells. - Highlights: • We report a therapeutic potential of DMSO in autoimmune diabetes. • DMSO exhibits an immune modulatory effect. • DMSO treatment increases regulatory T cell differentiation. • The increase in STAT5 signaling pathway explains the effect of DMSO in Tregs.

  11. Bone marrow cells are a source of undifferentiated cells to prevent Sjögren’s syndrome and to preserve salivary glands function in the non-obese diabetic mice

    PubMed Central

    Khalili, Saeed; Liu, Younan; Sumita, Yoshinori; Maria, Ola M.; Blank, David; Key, Sharon; Mezey, Eva; Tran, Simon D.

    2013-01-01

    Non-obese diabetic (NOD) mice develop Sjögren’s-like syndrome (Ss) and a gradual loss of saliva secretory function. Our previous study showed that injections of matched normal spleen cells with Complete Freund’s Adjuvant (CFA) reversed salivary gland dysfunction in 14-week-old NOD mice, which had established Ss. The spleen and bone marrow are closely related organs, and both are among the first sites of hematopoiesis during gestation. Noticing a rapidly increasing number of clinical trials using bone marrow (BM) cells treatments for autoimmune diseases, we tested if BM cells can prevent Ss and restore salivary glands’ function. We injected CFA and MHC class I-matched normal BM cells in 7-week-old NOD mice, which had not yet developed Ss. We found at week 52 post-treatment that all NOD mice receiving BM cells and CFA had a recovery of salivary flow and were protected from Ss and diabetes. BM cells-treated mice had their salivary function restored quantitatively and qualitatively. Saliva flow was higher (p < 0.05) in BM cells-transplanted mice when compared to control mice, which continued to deteriorate over time. Total proteins, epidermal growth factor, amylase, and electrolytes concentrations in saliva of BM cells-treated mice were not significantly changed at week 44 and 52 post-therapy when compared to pre-therapy (when the mice did not have Ss). Restoration of salivary flow could have resulted from a combination of rescue and paracrine effects from BM cells. This study suggests that a combined immuno- and cell-based therapy can permanently prevent Ss and restored salivary function in NOD mice. PMID:20732442

  12. Partial and transient modulation of the CD3-T-cell receptor complex, elicited by low-dose regimens of monoclonal anti-CD3, is sufficient to induce disease remission in non-obese diabetic mice.

    PubMed

    Mehta, Devangi S; Christmas, Rudy A; Waldmann, Herman; Rosenzweig, Michael

    2010-05-01

    It has been established that a total of 250 microg of monoclonal anti-mouse CD3 F(ab')(2) fragments, administered daily (50 microg per dose), induces remission of diabetes in the non-obese diabetic (NOD) mouse model of autoimmune diabetes by preventing beta cells from undergoing further autoimmune attack. We evaluated lower-dose regimens of monoclonal anti-CD3 F(ab')(2) in diabetic NOD mice for their efficacy and associated pharmacodynamic (PD) effects, including CD3-T-cell receptor (TCR) complex modulation, complete blood counts and proportions of circulating CD4(+), CD8(+) and CD4(+) FoxP3(+) T cells. Four doses of 2 microg (total dose 8 microg) induced 53% remission of diabetes, similarly to the 250 microg dose regimen, whereas four doses of 1 microg induced only 16% remission. While the 250 microg dose regimen produced nearly complete and sustained modulation of the CD3 -TCR complex, lower doses, spaced 3 days apart, which induced similar remission rates, elicited patterns of transient and partial modulation. In treated mice, the proportions of circulating CD4(+) and CD8(+) T cells decreased, whereas the proportions of CD4(+) FoxP3(+) T cells increased; these effects were transient. Mice with greater residual beta-cell function, estimated using blood glucose and C-peptide levels at the initiation of treatment, were more likely to enter remission than mice with more advanced disease. Thus, lower doses of monoclonal anti-CD3 that produced only partial and transient modulation of the CD3-TCR complex induced remission rates comparable to higher doses of monoclonal anti-CD3. Accordingly, in a clinical setting, lower-dose regimens may be efficacious and may also improve the safety profile of therapy with monoclonal anti-CD3, potentially including reductions in cytokine release-related syndromes and maintenance of pathogen-specific immunosurveillance during treatment.

  13. The H1-receptor antagonist cetirizine ameliorates high-fat diet-induced glucose intolerance in male C57BL/6 mice, but not diabetes outcome in female non-obese diabetic (NOD) mice

    PubMed Central

    Anvari, Ebrahim; Wang, Xuan; Sandler, Stellan

    2015-01-01

    Background It has been proposed that the histamine 1-receptor (H1-receptor) not only promotes allergic reactions, but also modulates innate immunity and autoimmune reactions. In line with this, we have recently reported that the H1-receptor antagonist cetirizine partially counteracts cytokine-induced beta-cell signaling and destruction. Therefore, the aim of this study was to determine whether cetirizine affects diabetes in NOD mice, a model for human type 1 diabetes, and glucose intolerance in high-fat diet C57BL/6 mice, a model for human glucose intolerance. Methods Female NOD mice were treated with cetirizine in the drinking water (25 mg/kg body weight) from 9 until 30 weeks of age during which precipitation of diabetes was followed. Male C57BL/6 mice were given a high-fat diet from 5 weeks of age. When the mice were 12 weeks of age cetirizine was given for 2 weeks in the drinking water. The effects of cetirizine were analyzed by blood glucose determinations, glucose tolerance tests, and insulin sensitivity tests. Results Cetirizine did not affect diabetes development in NOD mice. On the other hand, cetirizine treatment for 1 week protected against high-fat diet-induced hyperglycemia. The glucose tolerance after 2 weeks of cetirizine treatment was improved in high-fat diet mice. We observed no effect of cetirizine on the insulin sensitivity of high-fat diet mice. Conclusion Our results suggest a protective effect of cetirizine against high-fat diet-induced beta-cell dysfunction, but not against autoimmune beta-cell destruction. PMID:25291144

  14. Comprehensive Survey of miRNA-mRNA Interactions Reveals That Ccr7 and Cd247 (CD3 zeta) are Posttranscriptionally Controlled in Pancreas Infiltrating T Lymphocytes of Non-Obese Diabetic (NOD) Mice

    PubMed Central

    Macedo, Claudia; Sakamoto-Hojo, Elza T.; Donadi, Eduardo A.; Passos, Geraldo A.

    2015-01-01

    In autoimmune type 1 diabetes mellitus (T1D), auto-reactive clones of CD4+ and CD8+ T lymphocytes in the periphery evolve into pancreas-infiltrating T lymphocytes (PILs), which destroy insulin-producing beta-cells through inflammatory insulitis. Previously, we demonstrated that, during the development of T1D in non-obese diabetic (NOD) mice, a set of immune/inflammatory reactivity genes were differentially expressed in T lymphocytes. However, the posttranscriptional control involving miRNA interactions that occur during the evolution of thymocytes into PILs remains unknown. In this study, we postulated that miRNAs are differentially expressed during this period and that these miRNAs can interact with mRNAs involved in auto-reactivity during the progression of insulitis. To test this hypothesis, we used NOD mice to perform, for the first time, a comprehensive survey of miRNA and mRNA expression as thymocytes mature into peripheral CD3+ T lymphocytes and, subsequently, into PILs. Reconstruction of miRNA-mRNA interaction networks for target prediction revealed the participation of a large set of miRNAs that regulate mRNA targets related to apoptosis, cell adhesion, cellular regulation, cellular component organization, cellular processes, development and the immune system, among others. The interactions between miR-202-3p and the Ccr7 chemokine receptor mRNA or Cd247 (Cd3 zeta chain) mRNA found in PILs are highlighted because these interactions can contribute to a better understanding of how the lack of immune homeostasis and the emergence of autoimmunity (e.g., T1D) can be associated with the decreased activity of Ccr7 or Cd247, as previously observed in NOD mice. We demonstrate that these mRNAs are controlled at the posttranscriptional level in PILs. PMID:26606254

  15. Non-Obese Diabetes and Its Associated Factors in an Underdeveloped Area of South China, Guangxi

    PubMed Central

    Tang, Zhenzhu; Fang, Zhifeng; Huang, Wei; Liu, Zhanhua; Chen, Yuzhu; Li, Zhongyou; Zhu, Ting; Wang, Qichun; Simpson, Steve; Taylor, Bruce V.; Lin, Rui

    2016-01-01

    Background: Little research has been conducted on the prevalence of diabetes mellitus in underdeveloped areas in China, especially stratified into obesity and non-obese diabetes. The aim of the present study was to investigate the prevalence and associated factors of non-obese diabetes in an underdeveloped area in South China, Guangxi. Methods: Data derived from the Chinese Health and Nutrition Survey 2010–2012 involved a sample of 3874 adults from Guangxi. Questionnaires and oral glucose-tolerance tests were conducted, and fasting and 2-h glucose levels and serum lipids were measured. Logistic regression analysis was performed to assess associated factors for non-obese diabetes. Results: 68.2% and 62.2% of instances of newly detected diabetes were those of non-obese diabetes based on BMI (NODB) and based on WC (NODW), respectively. The male sex, an age older than 50 years, lower education, hypertension, and hypertriglyceridemia were significantly associated with a higher risk of both NODB and NODW, while some associated factors for NODB were found different from those associated with NODW, and an interaction effect was found to increase the risk of NODW. Conclusions: Our study indicated that non-obese diabetes was highly prevalent in an underdeveloped area of South China. Non-obese diabetes should be considered for increased public attention in these areas. PMID:27706056

  16. Over-expression of Stat5b confers protection against diabetes in the non-obese diabetic (NOD) mice via up-regulation of CD4{sup +}CD25{sup +} regulatory T cells

    SciTech Connect

    Jin, Yulan; Purohit, Sharad; Chen, Xueqin; Yi, Bing; She, Jin-Xiong

    2012-08-10

    Highlights: Black-Right-Pointing-Pointer This is the first study to provide direct evidence of the role of Stat5b in NOD mice. Black-Right-Pointing-Pointer Over-expression of wild type Stat5b transgene protects NOD mice against diabetes. Black-Right-Pointing-Pointer This protection may be mediated by the up-regulation of CD4{sup +}CD25{sup +} Tregs. -- Abstract: The signal transducers and activators of transcription (STAT) family of proteins play a critical role in cytokine signaling required for fine tuning of immune regulation. Previous reports showed that a mutation (L327M) in the Stat5b protein leads to aberrant cytokine signaling in the NOD mice. To further elaborate the role of Stat5b in diabetes, we established a NOD transgenic mouse that over-expresses the wild type Stat5b gene. The incidences of spontaneous diabetes as well as cyclophosphamide-induced diabetes were significantly reduced and delayed in the Stat5b transgenic NOD mice compared to their littermate controls. The total cell numbers of CD4{sup +} T cells and especially CD8{sup +} T cells in the spleen and pancreatic lymph node were increased in the Stat5b transgenic NOD mice. Consistent with these findings, CD4{sup +} and CD8{sup +} T cells from the Stat5b transgenic NOD mice showed a higher proliferation capacity and up-regulation of multiple cytokines including IL-2, IFN-{gamma}, TNF-{alpha} and IL-10 as well as anti-apoptotic gene Bcl-xl. Furthermore, the number and proportion of CD4{sup +}CD25{sup +} regulatory T cells were significantly increased in transgenic mice although in vitro suppression ability of the regulatory T-cells was not affected by the transgene. Our results suggest that Stat5b confers protection against diabetes in the NOD mice by regulating the numbers and function of multiple immune cell types, especially by up-regulating CD4{sup +}CD25{sup +} regulatory T cells.

  17. Mechanism underlying defective interferon gamma-induced IDO expression in non-obese diabetic mouse fibroblasts.

    PubMed

    Hosseini-Tabatabaei, Azadeh; Jalili, Reza Baradar; Li, Yunyuan; Kilani, Ruhangiz T; Moeen Rezakhanlou, Alireza; Ghahary, Aziz

    2012-01-01

    Indoleamine 2,3-dioxygenase (IDO) can locally suppress T cell-mediated immune responses. It has been shown that defective self-tolerance in early prediabetic female non-obese diabetic (NOD) mice can be attributed to the impaired interferon-gamma (IFN-γ)- induced IDO expression in dendritic cells of these animals. As IFN-γ can induce IDO in both dendritic cells and fibroblasts, we asked the question of whether there exists a similar defect in IFN-γ-induced IDO expression in NOD mice dermal fibroblasts. To this end, we examined the effect of IFN-γ on expression of IDO and its enzymatic activity in NOD dermal fibroblasts. The results showed that fibroblasts from either prediabetic (8 wks of age) female or male, and diabetic female or male (12 and 24 wks of age respectively) NOD mice failed to express IDO in response to IFN-γ treatment. To find underlying mechanisms, we scrutinized the IFN- γ signaling pathway and investigated expression of other IFN-γ-modulated factors including major histocompatibility complex class I (MHC-I) and type I collagen (COL-I). The findings revealed a defect of signal transducer and activator of transcription 1 (STAT1) phosphorylation in NOD cells relative to that of controls. Furthermore, we found an increase in MHC-I and suppression of COL-I expression in fibroblasts from both NOD and control mice following IFN-γ treatment; indicating that the impaired response to IFN-γ in NOD fibroblasts is specific to IDO gene. Finally, we showed that an IFN-γ-independent IDO expression pathway i.e. lipopolysaccharide (LPS)-mediated-c-Jun kinase is operative in NOD mice fibroblast. In conclusion, the findings of this study for the first time indicate that IFN-γ fails to induce IDO expression in NOD dermal fibroblasts; this may partially be due to defective STAT1 phosphorylation in IFN-γ-induced-IDO signaling pathway.

  18. Age-related deregulation of Aire and peripheral tissue antigen genes in the thymic stroma of non-obese diabetic (NOD) mice is associated with autoimmune type 1 diabetes mellitus (DM-1).

    PubMed

    Fornari, Thaís A; Donate, Paula B; Macedo, Claudia; Marques, Márcia M C; Magalhães, Danielle A; Passos, Geraldo A S

    2010-09-01

    Gene expression of peripheral tissue antigens (PTAs) in stromal medullary thymic epithelial cells (mTECs) is a key process to the negative selection of autoreactive thymocytes. This phenomenon was termed "promiscuous gene expression" (PGE), which is partially controlled by the Aire gene. Nevertheless, reasons for the correlation of Aire and PTAs with the emergence of autoimmune diseases are largely unknown, though it may be a result of a chronological effect. Although the effect of Aire mutations in pathogenic autoimmunity is well know, it could not be a unique cause for autoimmunity. Independently of mutations, temporal deregulation of Aire expression may imbalance Aire-dependent PTAs and/or wide PGE. This deregulation may be an early warning sign for autoimmune diseases as it guarantees autoantigen representation in the thymus. To assess this hypothesis, we studied the expression levels of Aire, Aire-dependent (Ins2) and Aire-independent (Gad67 and Col2a1) PTAs using real-time-PCR of the thymic stromal cells of NOD mice during the development of autoimmune type 1 diabetes mellitus (DM-1). Wide PGE was studied by microarrays in which the PTA genes were identified through parallel CD80(+) mTEC 3.10 cell line expression profiling. The results show that Aire gene was down-regulated in young pre-autoimmune (pre-diabetic) NOD mice. PGE and specific PTA genes were down-regulated in adult autoimmune diabetic animals. These findings represent evidence indicating that chronological deregulation of genes important to negative selection may be associated with the development of an autoimmune disease (DM-1) in mice.

  19. Resveratrol improves salivary dysfunction in a non-obese diabetic (NOD) mouse model of Sjögren’s syndrome

    PubMed Central

    Inoue, Hiroko; Kishimoto, Atsuhiro; Ushikoshi-Nakayama, Ryoko; Hasaka, Ayaka; Takahashi, Ayako; Ryo, Koufuchi; Muramatsu, Takashi; Ide, Fumio; Mishima, Kenji; Saito, Ichiro

    2016-01-01

    Resveratrol is a natural polyphenol produced by plants in response to environmental stress. This compound has been shown to have pharmacological effects against a wide range of diseases including neurological, hepatic, cardiovascular and autoimmune conditions. The non-obese diabetic (NOD) mouse, in which loss of lacrimal and salivary gland function occurs, has been studied as an animal model for Sjögren’s syndrome. In this study, we confirmed that administration of resveratrol results in increased secretion of saliva in NOD mice. Although resveratrol enhanced Sirt1 activity, inflammatory cell infiltration was not affected. Moreover, expression of the anti-inflammatory cytokine IL-10 in salivary glands was enhanced in the resveratrol-administered group. Thus, we confirmed a novel therapeutic effect for resveratrol on salivary dysfunction in Sjögren’s syndrome. PMID:27698537

  20. Resveratrol improves salivary dysfunction in a non-obese diabetic (NOD) mouse model of Sjögren’s syndrome

    PubMed Central

    Inoue, Hiroko; Kishimoto, Atsuhiro; Ushikoshi-Nakayama, Ryoko; Hasaka, Ayaka; Takahashi, Ayako; Ryo, Koufuchi; Muramatsu, Takashi; Ide, Fumio; Mishima, Kenji; Saito, Ichiro

    2016-01-01

    Resveratrol is a natural polyphenol produced by plants in response to environmental stress. This compound has been shown to have pharmacological effects against a wide range of diseases including neurological, hepatic, cardiovascular and autoimmune conditions. The non-obese diabetic (NOD) mouse, in which loss of lacrimal and salivary gland function occurs, has been studied as an animal model for Sjögren’s syndrome. In this study, we confirmed that administration of resveratrol results in increased secretion of saliva in NOD mice. Although resveratrol enhanced Sirt1 activity, inflammatory cell infiltration was not affected. Moreover, expression of the anti-inflammatory cytokine IL-10 in salivary glands was enhanced in the resveratrol-administered group. Thus, we confirmed a novel therapeutic effect for resveratrol on salivary dysfunction in Sjögren’s syndrome.

  1. Exercise Improves Host Response to Influenza Viral Infection in Obese and Non-Obese Mice through Different Mechanisms

    PubMed Central

    Warren, Kristi J.; Olson, Molly M.; Thompson, Nicholas J.; Cahill, Mackenzie L.; Wyatt, Todd A.; Yoon, Kyoungjin J.; Loiacono, Christina M.; Kohut, Marian L.

    2015-01-01

    Obesity has been associated with greater severity of influenza virus infection and impaired host defense. Exercise may confer health benefits even when weight loss is not achieved, but it has not been determined if regular exercise improves immune defense against influenza A virus (IAV) in the obese condition. In this study, diet-induced obese mice and lean control mice exercised for eight weeks followed by influenza viral infection. Exercise reduced disease severity in both obese and non-obese mice, but the mechanisms differed. Exercise reversed the obesity-associated delay in bronchoalveolar-lavage (BAL) cell infiltration, restored BAL cytokine and chemokine production, and increased ciliary beat frequency and IFNα-related gene expression. In non-obese mice, exercise treatment reduced lung viral load, increased Type-I-IFN-related gene expression early during infection, but reduced BAL inflammatory cytokines and chemokines. In both obese and non-obese mice, exercise increased serum anti-influenza virus specific IgG2c antibody, increased CD8+ T cell percentage in BAL, and reduced TNFα by influenza viral NP-peptide-responding CD8+ T cells. Overall, the results suggest that exercise “restores” the immune response of obese mice to a phenotype similar to non-obese mice by improving the delay in immune activation. In contrast, in non-obese mice exercise treatment results in an early reduction in lung viral load and limited inflammatory response. PMID:26110868

  2. Comparison of metformin and chlorpropamide in non-obese, maturity-onset diabetics uncontrolled by diet.

    PubMed Central

    Clarke, B F; Campbell, I W

    1977-01-01

    The clinical effectiveness of metformin was compared with that of chlorpropamide in closely similar groups of 216 non-obese patients recently diagnosed as cases of maturity-onset diabetes that could not be controlled by diet. The incidences of primary and secondary drug failures in each group and the numbers of patients satisfactorily maintained on each of the hypoglycaemic agents throughout the first year proved remarkably similar. In 61 of the successfully treated patients who were studied by crossover to the other drug and observed for a further year the mean blood glucose concentrations at the end of the year were roughly comparable, but the mean weight response was a small loss of 1.5 +/- 3.8 kg with metformin but a gain of 4.6 +/- 3.9 kg with chlorpropamide. Thus for non-obese, maturity-onset diabetics whose disease cannot be controlled by diet and who require oral treatment sulphonylureas and biguanides are equally effective, the choice depending on whether the patient is underweight and the severity of symptoms. PMID:589351

  3. Optimization of protocols for derivation of mouse embryonic stem cell lines from refractory strains, including the non obese diabetic mouse.

    PubMed

    Davies, Timothy J; Fairchild, Paul J

    2012-07-01

    The derivation of pluripotent embryonic stem cells (ESCs) from a variety of genetic backgrounds remains a desirable objective in the generation of mice functionally deficient in genes of interest and the modeling of human disease. Nevertheless, disparity in the ease with which different strains of mice yield ESC lines has long been acknowledged. Indeed, the generation of bona fide ESCs from the non obese diabetic (NOD) mouse, a well-characterized model of human type I diabetes, has historically proved especially difficult to achieve. Here, we report the development of protocols for the derivation of novel ESC lines from C57Bl/6 mice based on the combined use of high concentrations of leukemia inhibitory factor and serum-replacement, which is equally applicable to fresh and cryo-preserved embryos. Further, we demonstrate the success of this approach using Balb/K and CBA/Ca mice, widely considered to be refractory strains. CBA/Ca ESCs contributed to the somatic germ layers of chimeras and displayed a very high competence at germline transmission. Importantly, we were able to use the same protocol for the derivation of ESC lines from nonpermissive NOD mice. These ESCs displayed a normal karyotype that was robustly stable during long-term culture, were capable of forming teratomas in vivo and germline competent chimeras after injection into recipient blastocysts. Further, these novel ESC lines efficiently formed embryoid bodies in vitro and could be directed in their differentiation along the dendritic cell lineage, thus illustrating their potential application to the generation of cell types of relevance to the pathogenesis of type I diabetes. PMID:21933027

  4. Differences in emotional distress among inpatients with type 1, obese type 2, and non-obese type 2 diabetes mellitus.

    PubMed

    Miyawaki, Yoshiko; Iwahashi, Hiromi; Okauchi, Yukiyoshi; Sudo, Yoshiko; Fujiwara, Yuko; Omote, Yayoko; Imagawa, Akihisa; Shimomura, Iichiro

    2015-01-01

    Objective The purpose of this study was to determine the differences in emotional distress among three groups of inpatients with type 1, obese type 2, and non-obese type 2 diabetes during hospitalization. Methods The 42 participating inpatients were divided into three groups: type 1 diabetes (n=11), obese type 2 diabetes [body mass index (BMI) ≥25 kg/m(2); n=24], and non-obese type 2 diabetes (BMI <25 kg/m(2); n=7). The Problem Areas in Diabetes (PAID) scale, which is a self-administered questionnaire to assess emotional distress in the patients with diabetes, was performed at admission and discharge. Results The total PAID score was similar and tended to improve during hospitalization in all three groups, although there were differences among the groups in the scores of particular questions. At admission, the score of the question "worrying about low blood sugar reactions?" was significantly different among the three groups and highest in the patients with type 1 diabetes. At discharge, the score of "not accepting diabetes?" was significantly different among the three groups and highest in the patients with non-obese type 2 diabetes, while that of "feeling unsatisfied with your diabetes physician?" was significantly different among the three groups and highest in the patients with obese type 2 diabetes. The score of "feelings of deprivation regarding food and meals?" significantly worsened in the patients with obese type 2 diabetes during hospitalization compared with the patients in with non-obese type 2 diabetes. Conclusion The characteristics of emotional distress during hospitalization varied among the patients with the three types of diabetes, thus emphasizing the importance of tailoring support according to the type of diabetes.

  5. Differences in emotional distress among inpatients with type 1, obese type 2, and non-obese type 2 diabetes mellitus.

    PubMed

    Miyawaki, Yoshiko; Iwahashi, Hiromi; Okauchi, Yukiyoshi; Sudo, Yoshiko; Fujiwara, Yuko; Omote, Yayoko; Imagawa, Akihisa; Shimomura, Iichiro

    2015-01-01

    Objective The purpose of this study was to determine the differences in emotional distress among three groups of inpatients with type 1, obese type 2, and non-obese type 2 diabetes during hospitalization. Methods The 42 participating inpatients were divided into three groups: type 1 diabetes (n=11), obese type 2 diabetes [body mass index (BMI) ≥25 kg/m(2); n=24], and non-obese type 2 diabetes (BMI <25 kg/m(2); n=7). The Problem Areas in Diabetes (PAID) scale, which is a self-administered questionnaire to assess emotional distress in the patients with diabetes, was performed at admission and discharge. Results The total PAID score was similar and tended to improve during hospitalization in all three groups, although there were differences among the groups in the scores of particular questions. At admission, the score of the question "worrying about low blood sugar reactions?" was significantly different among the three groups and highest in the patients with type 1 diabetes. At discharge, the score of "not accepting diabetes?" was significantly different among the three groups and highest in the patients with non-obese type 2 diabetes, while that of "feeling unsatisfied with your diabetes physician?" was significantly different among the three groups and highest in the patients with obese type 2 diabetes. The score of "feelings of deprivation regarding food and meals?" significantly worsened in the patients with obese type 2 diabetes during hospitalization compared with the patients in with non-obese type 2 diabetes. Conclusion The characteristics of emotional distress during hospitalization varied among the patients with the three types of diabetes, thus emphasizing the importance of tailoring support according to the type of diabetes. PMID:26466689

  6. Defective signalling in salivary glands precedes the autoimmune response in the non-obese diabetic mouse model of sialadenitis

    PubMed Central

    Rosignoli, F; Roca, V; Meiss, R; Leceta, J; Gomariz, R P; Pérez Leirós, C

    2005-01-01

    The spontaneous non-obese diabetic (NOD) mouse model of Sjögren's syndrome provides a valuable tool to study the onset and progression of both the autoimmune response and secretory dysfunction. Our purpose was to analyse the temporal decline of salivary secretion in NOD mice in relation to the autoimmune response and alterations in various signalling pathways involved in saliva secretion within each salivary gland. A progressive loss of nitric oxide synthase activity in submandibular and parotid glands started at 12 weeks of age and paralleled the decline in salivary secretion. This defect was associated with a lower response to vasoactive intestinal peptide in salivary flow rate, cAMP and nitric oxide/cGMP production. No signs of mononuclear infiltrates or local cytokine production were detectable in salivary glands in the time period studied (10–16 weeks of age). Our data support a disease model for sialadenitis in NOD mice in which the early stages are characterized by defective neurotransmitter-mediated signalling in major salivary glands that precedes the autoimmune response. PMID:16297151

  7. Improvement of Type 2 Diabetes Mellitus in Obese and Non-Obese Patients after the Duodenal Switch Operation

    PubMed Central

    Frenken, M.; Cho, E. Y.; Karcz, W. K.; Grueneberger, J.; Kuesters, S.

    2011-01-01

    Introduction. Type 2 diabetes mellitus (T2DM) is one of the most important obesity-related comorbidities. This study was undertaken to characterise the effect of the biliopancreatic diversion with duodenal switch (BPD-DS) in morbidly obese and nonmorbidly obese diabetic patients. Methods. Outcome of 74 obese diabetic patients after BPD-DS and 16 non-obese diabetic patients after BPD or gastric bypass surgery was evaluated. Insulin usage, HbA1c-levels, and index of HOMA-IR (homeostasis model assessment of insulin resistence) were measured. Results. A substantial fraction of patients is free of insulin and shows an improved insulin sensitivity early after the operation, another fraction gets free of insulin in a 12-month period after the operation and a small fraction of long-term insulin users will not get free of insulin but nevertheless shows an improved metabolic status (less insulin needed, normal HbA1c-levels). Conclusion. BPD-DS leads to an improvement of T2DM in obese and non-obese patients. Nevertheless, more data is needed to clarify indications and mechanisms of action and to adjust our operation techniques to the needs of non-obese diabetic patients. PMID:21461399

  8. Tissue-Specific Stem Cells Obtained by Reprogramming of Non-Obese Diabetic (NOD) Mouse-Derived Pancreatic Cells Confer Insulin Production in Response to Glucose

    PubMed Central

    Saitoh, Issei; Sato, Masahiro; Soda, Miki; Inada, Emi; Iwase, Yoko; Murakami, Tomoya; Ohshima, Hayato; Hayasaki, Haruaki; Noguchi, Hirofumi

    2016-01-01

    Type 1 diabetes occurs due to the autoimmune destruction of pancreatic β-cells in islets. Transplantation of islets is a promising option for the treatment of patients with type 1 diabetes that experience hypoglycemic unawareness despite maximal care, but the present shortage of donor islets hampers such transplantation. Transplantation of insulin-producing cells derived from the patients themselves would be one of the most promising approaches to cure type 1 diabetes. Previously, we demonstrated that insulin-producing cells could be produced by transfecting murine pancreatic cells with Yamanaka’s reprogramming factors. Non-obese diabetic (NOD) mice are naturally occurring mutant mice defective in insulin production due to autoimmune ablation of pancreatic β-cells. In this study, we showed that glucose-sensitive insulin-producing cells are successfully generated by transfecting primary pancreatic cells from NOD mice (aged 6 months old) with a plasmid harboring the cDNAs for Oct-3/4, Sox2, Klf4, and c-Myc. Transfection was repeated 4 times in a 2 day-interval. Sixty-five days after final transfection, cobblestone-like colonies appeared. They proliferated in vitro and expressed pluripotency-related genes as well as Pdx1, a transcription factor specific to tissue-specific stem cells for the β-cell lineage. Transplantation of these cells into nude mice failed to produce teratoma unlike induced pluripotent stem cells (iPSCs). Induction of these cells to the pancreatic β-cell lineage demonstrated their capability to produce insulin in response to glucose. These findings suggest that functional pancreatic β-cells can be produced from patients with type 1 diabetes. We call these resultant cells as “induced tissue-specific stem cells from the pancreas” (iTS-P) that could be valuable sources of safe and effective materials for cell-based therapy in type 1 diabetes. PMID:27662374

  9. The non-obese diabetic mouse sequence, annotation and variation resource: an aid for investigating type 1 diabetes

    PubMed Central

    Steward, Charles A.; Gonzalez, Jose M.; Trevanion, Steve; Sheppard, Dan; Kerry, Giselle; Gilbert, James G. R.; Wicker, Linda S.; Rogers, Jane; Harrow, Jennifer L.

    2013-01-01

    Model organisms are becoming increasingly important for the study of complex diseases such as type 1 diabetes (T1D). The non-obese diabetic (NOD) mouse is an experimental model for T1D having been bred to develop the disease spontaneously in a process that is similar to humans. Genetic analysis of the NOD mouse has identified around 50 disease loci, which have the nomenclature Idd for insulin-dependent diabetes, distributed across at least 11 different chromosomes. In total, 21 Idd regions across 6 chromosomes, that are major contributors to T1D susceptibility or resistance, were selected for finished sequencing and annotation at the Wellcome Trust Sanger Institute. Here we describe the generation of 40.4 mega base-pairs of finished sequence from 289 bacterial artificial chromosomes for the NOD mouse. Manual annotation has identified 738 genes in the diabetes sensitive NOD mouse and 765 genes in homologous regions of the diabetes resistant C57BL/6J reference mouse across 19 candidate Idd regions. This has allowed us to call variation consequences between homologous exonic sequences for all annotated regions in the two mouse strains. We demonstrate the importance of this resource further by illustrating the technical difficulties that regions of inter-strain structural variation between the NOD mouse and the C57BL/6J reference mouse can cause for current next generation sequencing and assembly techniques. Furthermore, we have established that the variation rate in the Idd regions is 2.3 times higher than the mean found for the whole genome assembly for the NOD/ShiLtJ genome, which we suggest reflects the fact that positive selection for functional variation in immune genes is beneficial in regard to host defence. In summary, we provide an important resource, which aids the analysis of potential causative genes involved in T1D susceptibility. Database URLs: http://www.sanger.ac.uk/resources/mouse/nod/; http://vega

  10. Association between Serum Vitamin D Level and Glycemic and Inflammatory Markers in Non-obese Patients with Type 2 Diabetes

    PubMed Central

    Haidari, Fatemeh; Zakerkish, Mehrnoosh; Karandish, Majid; Saki, Azadeh; Pooraziz, Sakineh

    2016-01-01

    Background: Low serum 25-hydroxy vitamin D (25(OH)D) has been shown to correlate with an increased risk of type 2 diabetes mellitus (T2DM). The objective of this study was to investigate the association between serum 25(OH)D and glycemic and inflammatory markers in non-obese patients with T2DM. Methods: Eighty-four non-obese patients with T2DM were recruited in this cross-sectional study. Demographic, anthropometric, and dietary information was obtained from all the participants. The serum concentrations of glucose, HbA1C, insulin, 25(OH)D, and inflammatory markers including tumor necrosis factor-alpha (TNF-α) and high sensitive C-reactive protein (hs-CRP) were measured. A homeostatic model of insulin resistance (HOMA-IR) was also evaluated. Results: The mean serum concentration of 25(OH)D was 11.01±5.55 ng/mL. Severe deficiency, deficiency, and insufficiency of vitamin D were detected in 60.71%, 35.72%, and 3.57% of the participants, respectively. The results showed that those in the lowest group of serum 25(OH)D had significantly higher TNF-α than did those in the highest group (P=0.026). Although the association between serum 25(OH)D and fasting blood sugar and TNF-α was statistically significant (P=0.049 and P=0.044, respectively), the other glycemic markers and hs-CRP did not have any significant relationships with 25(OH)D. Conclusion: According to the high prevalence of vitamin D deficiency in the diabetic patients and the inverse relationship between serum 25(OH)D and fasting blood sugar and TNF-α in this study, vitamin D status may be a determining factor of systemic inflammation in patients with T2DM. Further studies with larger sample sizes are suggested in this regard. PMID:27582585

  11. Inflammation and impaired endothelium-dependant vasodilatation in non obese women with gestational diabetes mellitus: preliminary results

    PubMed Central

    2013-01-01

    Background To evaluate whether abnormal endothelial function, a common finding in gestational diabetes mellitus (GDM) pregnancies, can be explained by inflammatory cytokines. Methods Forearm skin blood flow (FSBF), into response to acetylcholine (Ach) (endothelium-dependent vasodilatation), were measured in 24 pregnant control subjects and 28 gestational diabetes mellitus (GDM) women, in the third trimester of gestation. A fasting glycemic and lipidic panel was obtained, and inflammatory cytokines (TNF-α and IL-6) and adiponectin were also determined. Results FSBF is significantly reduced in GDM group compared with control subjects (344.59 ± 57.791 vs.176.38 ± 108.52, P < 0.05). Among all subjects, FSBF showed a strong negative correlation with TNF-α and IL-6 (r = −0.426, P < 0.0001 and r = −0.564, P < 0.0001, respectively) and positive correlation with adiponectin (r = 0.468, P < 0.0001). Conclusions Endothelial function, an early marker of macrovascular disease, is present in non-obese pregnancies complicated by GDM. This alteration seems to be directly related to inflammatory status, which may represent a patho-physiological link between GDM and type 2 diabetes and, later on, metabolic syndrome. PMID:23805905

  12. Novel Mode of Defective Neural Tube Closure in the Non-Obese Diabetic (NOD) Mouse Strain.

    PubMed

    Salbaum, J Michael; Kruger, Claudia; MacGowan, Jacalyn; Herion, Nils J; Burk, David; Kappen, Claudia

    2015-01-01

    Failure to close the neural tube results in birth defects, with severity ranging from spina bifida to lethal anencephaly. Few genetic risk factors for neural tube defects are known in humans, highlighting the critical role of environmental risk factors, such as maternal diabetes. Yet, it is not well understood how altered maternal metabolism interferes with embryonic development, and with neurulation in particular. We present evidence from two independent mouse models of diabetic pregnancy that identifies impaired migration of nascent mesodermal cells in the primitive streak as the morphogenetic basis underlying the pathogenesis of neural tube defects. We conclude that perturbed gastrulation not only explains the neurulation defects, but also provides a unifying etiology for the broad spectrum of congenital malformations in diabetic pregnancies. PMID:26593875

  13. Novel Mode of Defective Neural Tube Closure in the Non-Obese Diabetic (NOD) Mouse Strain

    PubMed Central

    Salbaum, J. Michael; Kruger, Claudia; MacGowan, Jacalyn; Herion, Nils J.; Burk, David; Kappen, Claudia

    2015-01-01

    Failure to close the neural tube results in birth defects, with severity ranging from spina bifida to lethal anencephaly. Few genetic risk factors for neural tube defects are known in humans, highlighting the critical role of environmental risk factors, such as maternal diabetes. Yet, it is not well understood how altered maternal metabolism interferes with embryonic development, and with neurulation in particular. We present evidence from two independent mouse models of diabetic pregnancy that identifies impaired migration of nascent mesodermal cells in the primitive streak as the morphogenetic basis underlying the pathogenesis of neural tube defects. We conclude that perturbed gastrulation not only explains the neurulation defects, but also provides a unifying etiology for the broad spectrum of congenital malformations in diabetic pregnancies. PMID:26593875

  14. Mitochondrial function assessed by 31P MRS and BOLD MRI in non-obese type 2 diabetic rats.

    PubMed

    Liu, Yuchi; Mei, Xunbai; Li, Jielei; Lai, Nicola; Yu, Xin

    2016-08-01

    The study aims to characterize age-associated changes in skeletal muscle bioenergetics by evaluating the response to ischemia-reperfusion in the skeletal muscle of the Goto-Kakizaki (GK) rats, a rat model of non-obese type 2 diabetes (T2D). (31)P magnetic resonance spectroscopy (MRS) and blood oxygen level-dependent (BOLD) MRI was performed on the hindlimb of young (12 weeks) and adult (20 weeks) GK and Wistar (control) rats. (31)P-MRS and BOLD-MRI data were acquired continuously during an ischemia and reperfusion protocol to quantify changes in phosphate metabolites and muscle oxygenation. The time constant of phosphocreatine recovery, an index of mitochondrial oxidative capacity, was not statistically different between GK rats (60.8 ± 13.9 sec in young group, 83.7 ± 13.0 sec in adult group) and their age-matched controls (62.4 ± 11.6 sec in young group, 77.5 ± 7.1 sec in adult group). During ischemia, baseline-normalized BOLD-MRI signal was significantly lower in GK rats than in their age-matched controls. These results suggest that insulin resistance leads to alterations in tissue metabolism without impaired mitochondrial oxidative capacity in GK rats. PMID:27511984

  15. Bioluminescence imaging reveals dynamics of beta cell loss in the non-obese diabetic (NOD) mouse model.

    PubMed

    Virostko, John; Radhika, Armandla; Poffenberger, Greg; Dula, Adrienne N; Moore, Daniel J; Powers, Alvin C

    2013-01-01

    We generated a mouse model (MIP-Luc-VU-NOD) that enables non-invasive bioluminescence imaging (BLI) of beta cell loss during the progression of autoimmune diabetes and determined the relationship between BLI and disease progression. MIP-Luc-VU-NOD mice displayed insulitis and a decline in bioluminescence with age which correlated with beta cell mass, plasma insulin, and pancreatic insulin content. Bioluminescence declined gradually in female MIP-Luc-VU-NOD mice, reaching less than 50% of the initial BLI at 10 weeks of age, whereas hyperglycemia did not ensue until mice were at least 16 weeks old. Mice that did not become diabetic maintained insulin secretion and had less of a decline in bioluminescence than mice that became diabetic. Bioluminescence measurements predicted a decline in beta cell mass prior to the onset of hyperglycemia and tracked beta cell loss. This model should be useful for investigating the fundamental processes underlying autoimmune diabetes and developing new therapies targeting beta cell protection and regeneration.

  16. Analysis of Maternal and Fetal Cardiovascular Systems During Hyperglycemic Pregnancy in the Non-Obese Diabetic Mouse

    PubMed Central

    Aasa, Kristiina L.; Kwong, Kenneth K.; Adams, Michael A.; Croy, B. Anne

    2013-01-01

    Pre-conception or gestationally-induced diabetes increases morbidities and elevates long-term cardiovascular disease risks in women and their children. Spontaneously hyperglycemic (d)-NOD/ShiLtJ females, a type 1 diabetes model, develop bradycardia and hypotension after midpregnancy compared with normoglycemic, age and gestation day (gd)-matched controls (c-NOD). We hypothesized that onset of the placental circulation at gd9–10 and rapid fetal growth from gd14 correlate with aberrant hemodynamic outcomes in d-NOD females. To develop further gestational time course correlations between maternal cardiac and renal parameters, high-frequency ultrasonography was applied to virgin and gd8–16 d- and c-NODs. Cardiac output and left ventricular (LV) mass increased in c- but not d-NODs. Ultrasound and postmortem histopathology showed overall greater LV dilation in d- than c-NOD mice in mid-late gestation. These changes suggest blunted remodeling and altered functional adaptation of d-NOD hearts. Umbilical cord ultrasounds revealed lower fetal heart rates from gd12 and lower umbilical flow velocities at gd14 and 16 in d- versus c-NOD pregnancies. From gd14–16, d-NOD fetal losses exceeded those of c-NOD. Similar aberrant responses in human diabetic pregnancies may elevate postpartum maternal and child cardiovascular risk, particularly if mothers lack adequate prenatal care or have poor glycemic control over gestation. PMID:23636813

  17. Effect of an isocaloric diet containing fiber-enriched flour on anthropometric and biochemical parameters in healthy non-obese non-diabetic subjects

    PubMed Central

    Briganti, Silvia; Ermetici, Federica; Malavazos, Alexis E.; Dozio, Elena; Giubbilini, Paola; Rigolini, Roberta; Goggi, Silvia; Morricone, Lelio; Romanelli, Massimiliano Marco Corsi

    2015-01-01

    We studied the effect of soluble fiber-enriched products on anthropometric and biochemical variables in 30 healthy non-obese, non-diabetic subjects. This was a randomized, controlled crossover, single-blind, dietary intervention study performed for 8 weeks. Subjects received an isocaloric diet with fiber-enriched products for the first 4 weeks and with regular flour products for the following 4 weeks, or vice versa. Weight, height, measures of fat distribution (waist, hip circumference), glucose, insulin and triglycerides were measured at baseline, after 4 and 8 weeks of intervention. BMI and insulin sensitivity indices were calculated. Weight and BMI decreased in the first period of isocaloric diet in both groups, regardless of the type of flour consumed (weight p<0.01, p<0.001 respectively; BMI p = 0.01, p<0.001 respectively). At the end of the 8 weeks, weight and BMI further decreased in the group consuming the fiber-enriched diet (p<0.01). Insulin resistance, estimated with the Homeostasis Model Assessment index and the Lipid Accumulation Product index, improved in all subjects after the fiber-enriched flour diet (p = 0.03, p = 0.02, respectively). In conclusion, an isocaloric diet supplemented with fiber-enriched products may improve measures of fatness and insulin sensitivity in healthy non-obese non-diabetic subjects. We might hypothesize a similar effect also in subjects with metabolic abnormalities. PMID:26566307

  18. Elimination of infused branched-chain amino-acids from plasma of patients with non-obese type 2 diabetes mellitus.

    PubMed

    Marchesini, G; Bianchi, G P; Vilstrup, H; Capelli, M; Zoli, M; Pisi, E

    1991-04-01

    Increased plasma levels of branched-chain amino-acids (BCAA) have been demonstrated in poorly controlled diabetes mellitus, and related to absolute or relative insulin deficiency. To study the pathogenesis of this alteration, the elimination of BCAA from plasma was measured in 8 patients with non-obese type 2 diabetes mellitus and in 8 age-matched control subjects during steady-state BCAA concentrations induced by a primed-continuous infusion. Fasting BCAA levels were increased by 40-50% in patients with diabetes. The plasma clearances of valine, isoleucine, and leucine, calculated as infusion rate divided by steady-state concentration, were reduced by 20% in diabetics, despite 50% hyperinsulinemia (P < 0.01). Basal BCAA levels and BCAA clearance were negatively correlated (r(2) = 0.46 - 0.56). The endogenous basal appearance rates of BCAA, estimated by the basal concentrations multiplied by the plasma clearances, were normal in diabetics, and there was no difference in the apparent volumes of distribution of BCAA. The increased basal concentration of BCAA in poorly controlled type 2 diabetics (693 [SD 114; n = 8] mumol/l vs 479 [88; n = 8] in controls (P < 0.005) is attributable to changes in plasma clearances, without any change in the efflux of BCAA into plasma. This may be due to insulin resistance.

  19. Human peripheral blood leucocyte non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain gene mouse model of xenogeneic graft-versus-host-like disease and the role of host major histocompatibility complex

    PubMed Central

    King, M A; Covassin, L; Brehm, M A; Racki, W; Pearson, T; Leif, J; Laning, J; Fodor, W; Foreman, O; Burzenski, L; Chase, T H; Gott, B; Rossini, A A; Bortell, R; Shultz, L D; Greiner, D L

    2009-01-01

    Immunodeficient non-obese diabetic (NOD)-severe combined immune-deficient (scid) mice bearing a targeted mutation in the gene encoding the interleukin (IL)-2 receptor gamma chain gene (IL2rγnull) engraft readily with human peripheral blood mononuclear cells (PBMC). Here, we report a robust model of xenogeneic graft-versus-host-like disease (GVHD) based on intravenous injection of human PBMC into 2 Gy conditioned NOD-scid IL2rγnull mice. These mice develop xenogeneic GVHD consistently (100%) following injection of as few as 5 × 106 PBMC, regardless of the PBMC donor used. As in human disease, the development of xenogeneic GVHD is highly dependent on expression of host major histocompatibility complex class I and class II molecules and is associated with severely depressed haematopoiesis. Interrupting the tumour necrosis factor-α signalling cascade with etanercept, a therapeutic drug in clinical trials for the treatment of human GVHD, delays the onset and progression of disease. This model now provides the opportunity to investigate in vivo mechanisms of xenogeneic GVHD as well as to assess the efficacy of therapeutic agents rapidly. PMID:19659776

  20. Altered Plasma Lysophosphatidylcholines and Amides in Non-Obese and Non-Diabetic Subjects with Borderline-To-Moderate Hypertriglyceridemia: A Case-Control Study

    PubMed Central

    Jung, Saem; Lee, Sang-Hyun; Lee, Jong Ho

    2015-01-01

    Hypertriglyceridemia (HTG) is a risk factor for atherosclerotic cardiovascular disease (CVD). We investigated alterations in plasma metabolites associated with borderline-to-moderate HTG (triglycerides (TG) 150-500 mg/dL). Using UPLC-LTQ-Orbitrap mass spectrometry analysis, the metabolomics profiles of 111 non-diabetic and non-obese individuals with borderline-to-moderate HTG were compared with those of 111 age- and sex-matched controls with normotriglyceridemia (NTG, TG <150 mg/dL). When compared to the NTG control group, the HTG group exhibited higher plasma levels of lysophosphatidylcholines (lysoPCs), including C14:0 (q = 0.001) and C16:0 (q = 1.8E-05), and several amides, including N-ethyldodecanamide (q = 2.9E-05), N-propyldodecanamide (q = 3.5E-05), palmitoleamide (q = 2.9E-06), and palmitic amide (q = 0.019). The metabolomic profiles of the HTG group also exhibited lower plasma levels of cis-4-octenedioic acid (q<1.0E-9) and docosanamide (q = 0.002) compared with those of the NTG controls. LysoPC 16:0 and palmitoleamide emerged as the primary metabolites able to discriminate the HTG group from the NTG group in a partial least-squares discriminant analysis and were positively associated with the fasting triglyceride levels. We identified alterations in lysoPCs, amides, and cis-4-octenedioic acid among non-diabetic and non-obese individuals with borderline-to-moderate HTG. These results provide novel insights into the metabolic alterations that occur in the early metabolic stages of HTG. This information may facilitate the design of early interventions to prevent disease progression. PMID:25856314

  1. [Impaired insulin secretion in isolated islets of Goto-Kakizaki rats, an animal model of non obese type 2 diabetes, is a primary event].

    PubMed

    Seiça, Raquel M; Suzuki, K I; Santos, Rosa M; Do Rosário, Luis M

    2004-01-01

    The development of type 2 diabetes is associated with the impairment of insulin secretion. To evaluate the evolution of the secretory response, a chronological study comparing normal Wistar (W) vs Goto-Kakizaki (GK) rats, an animal model of non obese type 2 diabetes, was done. Glucose and arginine were tested in collagenase isolated islets of Langerhans with perfusion and ELISA immunoassay techniques. Fasting glycaemia and insulinemia and glucose tolerance were also evaluated. We have seen, in W rats, a mild glucose intolerance in the first two weeks of age. GK rats were always glucose intolerant with hyperglycaemia and hyperinsulinemia at fasten after one month old. Wistar islets had a characteristic biphasic response to glucose after the first two weeks of age. GK islets were always glucose irresponsive. Arginine induced an increase in insulin secretion in both animal models, independent of age, although GK rats had always a smaller response when compared to W rats. We concluded that 1) in W rats, a biphasic insulin secretion in response to glucose is observed after the first two weeks of age, simultaneously with glycaemia stabilization 2) in GK rats, both first and second phases of glucose-induced insulin release are significantly reduced and a smaller reduction in response to arginine is observed. This beta-cell disfunction is a primary event in this model of type 2 diabetes, preceding fasting hyperglycaemia and hyperinsulinemia.

  2. Reversible lacrimal gland-protective regulatory T-cell dysfunction underlies male-specific autoimmune dacryoadenitis in the non-obese diabetic mouse model of Sjögren syndrome.

    PubMed

    Lieberman, Scott M; Kreiger, Portia A; Koretzky, Gary A

    2015-06-01

    CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells are required to maintain immunological tolerance; however, defects in specific organ-protective Treg cell functions have not been demonstrated in organ-specific autoimmunity. Non-obese diabetic (NOD) mice spontaneously develop lacrimal and salivary gland autoimmunity and are a well-characterized model of Sjögren syndrome. Lacrimal gland disease in NOD mice is male-specific, but the role of Treg cells in this sex-specificity is not known. This study aimed to determine if male-specific autoimmune dacryoadenitis in the NOD mouse model of Sjögren syndrome is the result of lacrimal gland-protective Treg cell dysfunction. An adoptive transfer model of Sjögren syndrome was developed by transferring cells from the lacrimal gland-draining cervical lymph nodes of NOD mice to lymphocyte-deficient NOD-SCID mice. Transfer of bulk cervical lymph node cells modelled the male-specific dacryoadenitis that spontaneously develops in NOD mice. Female to female transfers resulted in dacryoadenitis if the CD4(+) CD25(+) Treg-enriched population was depleted before transfer; however, male to male transfers resulted in comparable dacryoadenitis regardless of the presence or absence of Treg cells within the donor cell population. Hormone manipulation studies suggested that this Treg cell dysfunction was mediated at least in part by androgens. Surprisingly, male Treg cells were capable of preventing the transfer of dacryoadenitis to female recipients. These data suggest that male-specific factors promote reversible dysfunction of lacrimal gland-protective Treg cells and, to our knowledge, form the first evidence for reversible organ-protective Treg cell dysfunction in organ-specific autoimmunity.

  3. A novel ALMS1 splice mutation in a non-obese juvenile-onset insulin-dependent syndromic diabetic patient.

    PubMed

    Sanyoura, May; Woudstra, Cédric; Halaby, George; Baz, Patrick; Senée, Valérie; Guillausseau, Pierre-Jean; Zalloua, Pierre; Julier, Cécile

    2014-01-01

    Insulin-dependent juvenile-onset diabetes may occur in the context of rare syndromic presentations suggesting monogenic inheritance rather than common multifactorial autoimmune type 1 diabetes. Here, we report the case of a Lebanese patient diagnosed with juvenile-onset insulin-dependent diabetes presenting ketoacidosis, early-onset retinopathy with optic atrophy, hearing loss, diabetes insipidus, epilepsy, and normal weight and stature, who later developed insulin resistance. Despite similarities with Wolfram syndrome, we excluded the WFS1 gene as responsible for this disease. Using combined linkage and candidate gene study, we selected ALMS1, responsible for Alström syndrome, as a candidate gene. We identified a novel splice mutation in intron 18 located 3 bp before the intron-exon junction (IVS18-3T>G), resulting in exon 19 skipping and consequent frameshift generating a truncated protein (V3958fs3964X). The clinical presentation of the patient significantly differed from typical Alström syndrome by the absence of truncal obesity and short stature, and by the presence of ketoacidotic insulin-dependent diabetes, optic atrophy and diabetes insipidus. Our observation broadens the clinical spectrum of Alström syndrome and suggests that ALMS1 mutations may be considered in patients who initially present with an acute onset of insulin-dependent diabetes.

  4. Abnormalities in the Metabolism of Fatty Acids and Triacylglycerols in the Liver of the Goto-Kakizaki Rat: A Model for Non-Obese Type 2 Diabetes.

    PubMed

    Karahashi, Minako; Hirata-Hanta, Yuko; Kawabata, Kohei; Tsutsumi, Daisuke; Kametani, Misaki; Takamatsu, Nanako; Sakamoto, Takeshi; Yamazaki, Tohru; Asano, Satoshi; Mitsumoto, Atsushi; Kawashima, Yoichi; Kudo, Naomi

    2016-08-01

    The Goto-Kakizaki (GK) rat is widely used as an animal model for spontaneous-onset type 2 diabetes without obesity; nevertheless, little information is available on the metabolism of fatty acids and triacylglycerols (TAG) in their livers. We investigated the mechanisms underlying the alterations in the metabolism of fatty acids and TAG in their livers, in comparison with Zucker (fa/fa) rats, which are obese and insulin resistant. Lipid profiles, the expression of genes for enzymes and proteins related to the metabolism of fatty acid and TAG, de novo synthesis of fatty acids and TAG in vivo, fatty acid synthase activity in vitro, fatty acid oxidation in liver slices, and very-low-density-lipoprotein (VLDL)-TAG secretion in vivo were estimated. Our results revealed that (1) the TAG accumulation was moderate, (2) the de novo fatty acid synthesis was increased by upregulation of fatty acid synthase in a post-transcriptional manner, (3) fatty acid oxidation was also augmented through the induction of carnitine palmitoyltransferase 1a, and (4) the secretion rate of VLDL-TAG remained unchanged in the livers of GK rats. These results suggest that, despite the fact that GK rats exhibit non-obese type 2 diabetes, the upregulation of de novo lipogenesis is largely compensated by the upregulation of fatty acid oxidation, resulting in only moderate increase in TAG accumulation in the liver. PMID:27372943

  5. Comparative study of peripheral neuropathy and nerve regeneration in NOD and ICR diabetic mice.

    PubMed

    Homs, Judit; Ariza, Lorena; Pagès, Gemma; Verdú, Enrique; Casals, Laura; Udina, Esther; Chillón, Miguel; Bosch, Assumpció; Navarro, Xavier

    2011-09-01

    The non-obese diabetic (NOD) mouse was suggested as an adequate model for diabetic autonomic neuropathy. We evaluated sensory-motor neuropathy and nerve regeneration following sciatic nerve crush in NOD males rendered diabetic by multiple low doses of streptozotocin, in comparison with similarly treated Institute for Cancer Research (ICR) mice, a widely used model for type I diabetes. Neurophysiological values for both strains showed a decline in motor and sensory nerve conduction velocity at 7 and 8 weeks after induction of diabetes in the intact hindlimb. However, amplitudes of compound muscle and sensory action potentials (CMAPs and CNAPs) were significantly reduced in NOD but not in ICR diabetic mice. Morphometrical analysis showed myelinated fiber loss in highly hyperglycemic NOD mice, but no significant changes in fiber size. There was a reduction of intraepidermal nerve fibers, more pronounced in NOD than in ICR diabetic mice. Interestingly, aldose reductase and poly(ADP-ribose) polymerase (PARP) activities were increased already at 1 week of hyperglycemia, persisting until the end of the experiment in both strains. Muscle and nerve reinnervation was delayed in diabetic mice following sciatic nerve crush, being more marked in NOD mice. Thus, diabetes of mid-duration induces more severe peripheral neuropathy and slower nerve regeneration in NOD than in ICR mice.

  6. Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice.

    PubMed

    Brown, Kirsty; Godovannyi, Artem; Ma, Caixia; Zhang, YiQun; Ahmadi-Vand, Zahra; Dai, Chaunbin; Gorzelak, Monika A; Chan, YeeKwan; Chan, Justin M; Lochner, Arion; Dutz, Jan P; Vallance, Bruce A; Gibson, Deanna L

    2016-02-01

    Accumulating evidence supports that the intestinal microbiome is involved in Type 1 diabetes (T1D) pathogenesis through the gut-pancreas nexus. Our aim was to determine whether the intestinal microbiota in the non-obese diabetic (NOD) mouse model played a role in T1D through the gut. To examine the effect of the intestinal microbiota on T1D onset, we manipulated gut microbes by: (1) the fecal transplantation between non-obese diabetic (NOD) and resistant (NOR) mice and (2) the oral antibiotic and probiotic treatment of NOD mice. We monitored diabetes onset, quantified CD4+T cells in the Peyer's patches, profiled the microbiome and measured fecal short-chain fatty acids (SCFA). The gut microbiota from NOD mice harbored more pathobionts and fewer beneficial microbes in comparison with NOR mice. Fecal transplantation of NOD microbes induced insulitis in NOR hosts suggesting that the NOD microbiome is diabetogenic. Moreover, antibiotic exposure accelerated diabetes onset in NOD mice accompanied by increased T-helper type 1 (Th1) and reduced Th17 cells in the intestinal lymphoid tissues. The diabetogenic microbiome was characterized by a metagenome altered in several metabolic gene clusters. Furthermore, diabetes susceptibility correlated with reduced fecal SCFAs. In an attempt to correct the diabetogenic microbiome, we administered VLS#3 probiotics to NOD mice but found that VSL#3 colonized the intestine poorly and did not delay diabetes. We conclude that NOD mice harbor gut microbes that induce diabetes and that their diabetogenic microbiome can be amplified early in life through antibiotic exposure. Protective microbes like VSL#3 are insufficient to overcome the effects of a diabetogenic microbiome.

  7. Anti-Diabetic Activities of Gastrodia elata Blume Water Extracts Are Mediated Mainly by Potentiating Glucose-Stimulated Insulin Secretion and Increasing β-Cell Mass in Non-Obese Type 2 Diabetic Animals

    PubMed Central

    Yang, Hye Jeong; Kim, Min Jung; Kwon, Dae Young; Kim, Da Sol; Lee, Young Hyun; Kim, Ji Eun; Park, Sunmin

    2016-01-01

    The brain is an important modulator of glucose metabolism, and is known to respond Gastrodia elata Blume water extract (GEB). Therefore, we examined whether long-term administration of GEB has hypoglycemic activity, and its action mechanism was explored in partially-pancreatectomized rats that exhibit similar characteristics as Asian type 2 diabetes, non-obese insulin-insufficient diabetes. The rats were provided high-fat diets supplemented with either of (1) 0.5% GEB (GEB-L), (2) 2% GEB (GEB-H), (3) 2% dextrin (control), or (4) 2% dextrin with rosiglitazone (20 mg/kg body weight; positive-control) for eight weeks. GEB dose-dependently improved hypothalamic insulin signaling, enhanced whole-body insulin sensitivity during hyperinsulinemic euglycemic clamp, and reduced hepatic glucose output in a hyperinsulinemic state. GEB dose-dependently increased the area under the curve of the serum insulin levels at the first and second phases during hyperglycemic clamp compared to the control, whereas the positive control had no effect. Insulin sensitivity during the hyperglycemic state also improved, dose-dependently, in response to GEB compared with that of the control, but was less than the positive control. GEB-H increased the mass of β-cells by potentiating proliferation and decreasing apoptosis. In conclusion, GEB could be a therapeutic agent for treating Asian type 2 diabetes. PMID:26978400

  8. Daintain/AIF-1 (Allograft Inflammatory Factor-1) accelerates type 1 diabetes in NOD mice

    SciTech Connect

    Zhao, Yan-Ying; Huang, Xin-Yuan; Chen, Zheng-Wang

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer Daintain/AIF-1 is over-expressed in the blood of NOD mice suffering from insulitis. Black-Right-Pointing-Pointer Daintain/AIF-1 stimulates white blood cell proliferation in NOD mice. Black-Right-Pointing-Pointer Daintain/AIF-1 increases blood glucose levels and triggers type 1 diabetes. Black-Right-Pointing-Pointer Daintain/AIF-1 accelerates insulitis, while its antibody prevents insulitis. Black-Right-Pointing-Pointer Daintain/AIF-1 enhances the levels of nitric oxide in the pancreases of NOD mice. -- Abstract: A large body of experimental evidence suggests that cytokines trigger pancreatic {beta}-cell death in type 1 diabetes mellitus. Daintain/AIF-1 (Allograft Inflammatory Factor-1), a specific marker for activated macrophages, is accumulated in the pancreatic islets of pre-diabetic BB rats. In the present study, we demonstrate that daintain/AIF-1 is released into blood and the levels of daintain/AIF-1 in the blood of type 1 diabetes-prone non-obese diabetic (NOD) mice suffering from insulitis are significantly higher than that in healthy NOD mice. When injected intravenously into NOD mice, daintain/AIF-1 stimulates white blood cell proliferation, increases the concentrations of blood glucose, impairs insulin expression, up-regulates nitric oxide (NO) production in pancreases and accelerates diabetes in NOD mice, while the antibody against daintain/AIF-1 delays or prevents insulitis in NOD mice. These results imply daintain/AIF-1 triggers type 1 diabetes probably via arousing immune cells activation and induction of NO production in pancreas of NOD mice.

  9. [Lipid peroxidation and the response of the antioxidant defense system in the obese type 2 diabetic compared with the non-obese type 2 diabetic].

    PubMed

    Gaxiola-Robles, Ramón; Bitzer-Quintero, Oscar Kurt; Méndez-Rodríguez, Lía Celina; Labrada-Martagón, Vanessa; García-González, Adolfo; Ramírez-Jirano, Luis Javier; Veléz-Alavez, Marcela; Zenteno-Savín, Tania

    2013-11-01

    Introducción: La diabetes se asocia a un incremento en la peroxidación de lípidos, cuantificada a partir del nivel de sustancias reactivas al ácido tiobarbitúrico (TBARS). En paralelo, se activa el sistema de defensa antioxidante (SDA) para delimitar el daño. Objetivo: Determinar el grado de peroxidación de lípidos en individuos obesos diabéticos tipo 2 (DM2) y la respuesta del SDA en comparación con individuos con DM2 sin obesidad. Método: Se evaluó el daño a lípidos a través de la medición de las TBARS en dos grupos de 30 individuos. Se evaluó la respuesta del SDA por medio de la medición de la actividad de las enzimas catalasa (CAT), superóxido dismutasa (SOD) y glutatión peroxidasa (GPx). Resultados: El grupo de DM2 obesos presentó un índice de masa corporal (IMC) promedio de 38.6 ± 3.5 kg m-2 en comparación con el grupo control 24.7 ± 3.6 kg m-2 (p.

  10. Gene therapy with neurogenin3, betacellulin and SOCS1 reverses diabetes in NOD mice.

    PubMed

    Li, R; Buras, E; Lee, J; Liu, R; Liu, V; Espiritu, C; Ozer, K; Thompson, B; Nally, L; Yuan, G; Oka, K; Chang, B; Samson, S; Yechoor, V; Chan, L

    2015-11-01

    Islet transplantation for type 1 diabetes is limited by a shortage of donor islets and requirement for immunosuppression. We approached this problem by inducing in vivo islet neogenesis in non-obese diabetic (NOD) diabetic mice, a model of autoimmune diabetes. We demonstrate that gene therapy with helper-dependent adenovirus carrying neurogenin3 (Ngn3), an islet lineage-defining transcription factor, and betacellulin (Btc), an islet growth factor, leads to the induction of periportal insulin-positive cell clusters in the liver, which are rapidly destroyed. To specifically accord protection to these 'neo-islets' from cytokine-mediated destruction, we overexpressed suppressor of cytokine signaling 1 (SOCS1) gene, using a rat insulin promoter in combination with Ngn3 and Btc. With this approach, about half of diabetic mice attained euglycemia sustained for over 4 months, regain glucose tolerance and appropriate glucose-stimulated insulin secretion. Histological analysis revealed periportal islet hormone-expressing 'neo-islets' in treated mouse livers. Despite evidence of persistent 'insulitis' with activated T cells, these 'neo-islets' persist to maintain euglycemia. This therapy does not affect diabetogenicity of splenocytes, as they retain the ability to transfer diabetes. This study thus provides a proof-of-concept for engineering in vivo islet neogenesis with targeted resistance to cytokine-mediated destruction to provide a long-term reversal of diabetes in NOD mice. PMID:26172077

  11. Immune responses to an encapsulated allogeneic islet {beta}-cell line in diabetic NOD mice

    SciTech Connect

    Black, Sasha P. . E-mail: Sasha.Black@ca.crl.com; Constantinidis, Ioannis; Cui, Hong; Tucker-Burden, Carol; Weber, Collin J.; Safley, Susan A.

    2006-02-03

    Our goal is to develop effective islet grafts for treating type 1 diabetes. Since human islets are scarce, we evaluated the efficacy of a microencapsulated insulin-secreting conditionally transformed allogeneic {beta}-cell line ({beta}TC-tet) in non-obese diabetic mice treated with tetracycline to inhibit cell growth. Relatively low serum levels of tetracycline controlled proliferation of {beta}TC-tet cells without inhibiting effective control of hyperglycemia in recipients. There was no significant host cellular reaction to the allografts or host cell adherence to microcapsules, and host cytokine levels were similar to those of sham-operated controls. We conclude that encapsulated allogeneic {beta}-cell lines may be clinically relevant, because they effectively restore euglycemia and do not elicit a strong cellular immune response following transplantation. To our knowledge, this is First extensive characterization of the kinetics of host cellular and cytokine responses to an encapsulated islet cell line in an animal model of type 1 diabetes.

  12. Stable activity of diabetogenic cells with age in NOD mice: dynamics of reconstitution and adoptive diabetes transfer in immunocompromised mice

    PubMed Central

    Kaminitz, Ayelet; Mizrahi, Keren; Ash, Shifra; Ben-Nun, Avi; Askenasy, Nadir

    2014-01-01

    The non-obese diabetic (NOD) mouse is a prevalent disease model of type 1 diabetes. Immune aberrations that cause and propagate autoimmune insulitis in these mice are being continually debated, with evidence supporting both dominance of effector cells and insufficiency of suppressor mechanisms. In this study we assessed the behaviour of NOD lymphocytes under extreme expansion conditions using adoptive transfer into immunocompromised NOD.SCID (severe combined immunodeficiency) mice. CD4+ CD25+ T cells do not cause islet inflammation, whereas splenocytes and CD4+ CD25− T cells induce pancreatic inflammation and hyperglycaemia in 80–100% of the NOD.SCID recipients. Adoptively transferred effector T cells migrate to the lymphoid organs and pancreas, proliferate, are activated in the target organ in situ and initiate inflammatory insulitis. Reconstitution of all components of the CD4+ subset emphasizes the plastic capacity of different cell types to adopt effector and suppressor phenotypes. Furthermore, similar immune profiles of diabetic and euglycaemic NOD.SCID recipients demonstrate dissociation between fractional expression of CD25 and FoxP3 and the severity of insulitis. There were no evident and consistent differences in diabetogenic activity and immune reconstituting activity of T cells from pre-diabetic (11 weeks) and new onset diabetic NOD females. Similarities in immune phenotypes and variable distribution of effector and suppressor subsets in various stages of inflammation commend caution in interpretation of quantitative and qualitative aberrations as markers of disease severity in adoptive transfer experiments. PMID:24601987

  13. Stable activity of diabetogenic cells with age in NOD mice: dynamics of reconstitution and adoptive diabetes transfer in immunocompromised mice.

    PubMed

    Kaminitz, Ayelet; Mizrahi, Keren; Ash, Shifra; Ben-Nun, Avi; Askenasy, Nadir

    2014-07-01

    The non-obese diabetic (NOD) mouse is a prevalent disease model of type 1 diabetes. Immune aberrations that cause and propagate autoimmune insulitis in these mice are being continually debated, with evidence supporting both dominance of effector cells and insufficiency of suppressor mechanisms. In this study we assessed the behaviour of NOD lymphocytes under extreme expansion conditions using adoptive transfer into immunocompromised NOD.SCID (severe combined immunodeficiency) mice. CD4(+)  CD25(+) T cells do not cause islet inflammation, whereas splenocytes and CD4(+)  CD25(-) T cells induce pancreatic inflammation and hyperglycaemia in 80-100% of the NOD.SCID recipients. Adoptively transferred effector T cells migrate to the lymphoid organs and pancreas, proliferate, are activated in the target organ in situ and initiate inflammatory insulitis. Reconstitution of all components of the CD4(+) subset emphasizes the plastic capacity of different cell types to adopt effector and suppressor phenotypes. Furthermore, similar immune profiles of diabetic and euglycaemic NOD.SCID recipients demonstrate dissociation between fractional expression of CD25 and FoxP3 and the severity of insulitis. There were no evident and consistent differences in diabetogenic activity and immune reconstituting activity of T cells from pre-diabetic (11 weeks) and new onset diabetic NOD females. Similarities in immune phenotypes and variable distribution of effector and suppressor subsets in various stages of inflammation commend caution in interpretation of quantitative and qualitative aberrations as markers of disease severity in adoptive transfer experiments.

  14. Retinylamine Benefits Early Diabetic Retinopathy in Mice*

    PubMed Central

    Liu, Haitao; Tang, Jie; Du, Yunpeng; Lee, Chieh Allen; Golczak, Marcin; Muthusamy, Arivalagan; Antonetti, David A.; Veenstra, Alexander A.; Amengual, Jaume; von Lintig, Johannes; Palczewski, Krzysztof; Kern, Timothy S.

    2015-01-01

    Recent evidence suggests an important role for outer retinal cells in the pathogenesis of diabetic retinopathy (DR). Here we investigated the effect of the visual cycle inhibitor retinylamine (Ret-NH2) on the development of early DR lesions. Wild-type (WT) C57BL/6J mice (male, 2 months old when diabetes was induced) were made diabetic with streptozotocin, and some were given Ret-NH2 once per week. Lecithin-retinol acyltransferase (LRAT)-deficient mice and P23H mutant mice were similarly studied. Mice were euthanized after 2 (WT and Lrat−/−) and 8 months (WT) of study to assess vascular histopathology, accumulation of albumin, visual function, and biochemical and physiological abnormalities in the retina. Non-retinal effects of Ret-NH2 were examined in leukocytes treated in vivo. Superoxide generation and expression of inflammatory proteins were significantly increased in retinas of mice diabetic for 2 or 8 months, and the number of degenerate retinal capillaries and accumulation of albumin in neural retina were significantly increased in mice diabetic for 8 months compared with nondiabetic controls. Administration of Ret-NH2 once per week inhibited capillary degeneration and accumulation of albumin in the neural retina, significantly reducing diabetes-induced retinal superoxide and expression of inflammatory proteins. Superoxide generation also was suppressed in Lrat−/− diabetic mice. Leukocytes isolated from diabetic mice treated with Ret-NH2 caused significantly less cytotoxicity to retinal endothelial cells ex vivo than did leukocytes from control diabetics. Administration of Ret-NH2 once per week significantly inhibited the pathogenesis of lesions characteristic of early DR in diabetic mice. The visual cycle constitutes a novel target for inhibition of DR. PMID:26139608

  15. Effects of plasmid DNA injection on cyclophosphamide-accelerated diabetes in NOD mice.

    PubMed

    Filippova, M; Liu, J; Escher, A

    2001-03-01

    Type 1 diabetes results in most cases from the destruction of insulin-secreting beta cells by the immune system. Several immunization methods based on administration of autoantigenic polypeptides such as insulin and glutamic acid decarboxylase (GAD) have been used to prevent autoimmune diabetes in the non-obese diabetic (NOD) mouse. In the work presented here, a gene-based approach was taken for a similar purpose. A plasmid carrying different cDNAs was used to investigate the effects of injecting naked DNA on cyclophosphamide-accelerated diabetes in female NOD mice. Four-week-old animals received intramuscular injections of plasmid DNA encoding either intracellular GAD, a secreted form of GAD, or a secreted form of a soft coral luciferase. Monitoring of glycosuria and hyperglycemia indicated that injection of plasmid DNA encoding secreted GAD and secreted luciferase could prevent and delay diabetes, respectively. In contrast, injection of DNA encoding intracellular GAD did not suppress the disease significantly. Analysis of anti-GAD IgG(1) antibody titers in animal sera indicated that diabetes prevention after injection of GAD-encoding DNA was possibly associated with increased Th2-type activity. These results suggest that cellular localization of GAD is a factor to consider in the design of GAD-based genetic vaccines for the prevention of autoimmune diabetes.

  16. Erectile Dysfunction in Young Non-Obese Type II Diabetic Goto-Kakizaki Rats is Associated with Decreased eNOS Phosphorylation at Ser1177

    PubMed Central

    Carneiro, Fernando S.; Giachini, Fernanda R.C.; Carneiro, Zidonia N.; Lima, Victor V.; Ergul, Adviye; Webb, R. Clinton; Tostes, Rita C.

    2011-01-01

    Introduction Diabetes mellitus (DM) is a risk factor for erectile dysfunction (ED). Although type 2 DM is responsible for 90–95% diabetes cases, type 1 DM experimental models are commonly used to study diabetes-associated ED. Aim Goto-Kakizaki (GK) rat model is relevant to ED studies since the great majority of patients with type 2 diabetes display mild deficits in glucose-stimulated insulin secretion, insulin resistance, and hyperglycemia. We hypothesized that GK rats display ED which is associated with decreased nitric oxide (NO) bioavailability. Methods Wistar and GK rats were used at 10 and 18 weeks of age. Changes in the ratio of intracavernosal pressure/mean arterial pressure (ICP/MAP) after electrical stimulation of cavernosal nerve were determined in vivo. Cavernosal contractility was induced by electrical field stimulation (EFS) and phenylephrine (PE). In addition, nonadrenergic-noncholinergic (NANC)- and sodium nitroprusside (SNP)-induced relaxation were determined. Cavernosal neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) mRNA and protein expression were also measured. Main Outcome Measure GK diabetic rats display ED associated with decreased cavernosal expression of eNOS protein. Results GK rats at 10 and 18 weeks demonstrated impaired erectile function represented by decreased ICP/MAP responses. Ten-week-old GK animals displayed increased PE responses and no changes in EFS-induced contraction. Conversely, contractile responses to EFS and PE were decreased in cavernosal tissue from GK rats at 18 weeks of age. Moreover, GK rats at 18 weeks of age displayed increased NANC-mediated relaxation, but not to SNP. In addition, ED was associated with decreased eNOS protein expression at both ages. Conclusion Although GK rats display ED, they exhibit changes in cavernosal reactivity that would facilitate erectile responses. These results are in contrast to those described in other experimental diabetes models. This may be due

  17. Ghrelin reverses experimental diabetic neuropathy in mice

    SciTech Connect

    Kyoraku, Itaru; Shiomi, Kazutaka; Kangawa, Kenji; Nakazato, Masamitsu

    2009-11-20

    Ghrelin, an acylated peptide produced in the stomach, increases food intake and growth hormone secretion, suppresses inflammation and oxidative stress, and promotes cell survival and proliferation. We investigated the pharmacological potential of ghrelin in the treatment of polyneuropathy in uncontrolled streptozotocin (STZ)-induced diabetes in mice. Ghrelin or desacyl-ghrelin was administered daily for 4 weeks after STZ-induced diabetic polyneuropathy had developed. Ghrelin administration did not alter food intake, body weight gain, blood glucose levels, or plasma insulin levels when compared with mice given saline or desacyl-ghrelin administration. Ghrelin administration ameliorated reductions in motor and sensory nerve conduction velocities in diabetic mice and normalized their temperature sensation and plasma concentrations of 8-isoprostaglandin {alpha}, an oxidative stress marker. Desacyl-ghrelin failed to have any effect. Ghrelin administration in a mouse model of diabetes ameliorated polyneuropathy. Thus, ghrelin's effects represent a novel therapeutic paradigm for the treatment of this otherwise intractable disorder.

  18. Sodium meta-arsenite prevents the development of autoimmune diabetes in NOD mice

    SciTech Connect

    Lee, Y.S.; Kim, D.; Lee, E.K.; Kim, S.; Choi, C.S.; Jun, H.S.

    2015-04-15

    Sodium meta-arsenite (SA) is an orally available arsenic compound. We investigated the effects of SA on the development of autoimmune type 1 diabetes. Female non-obese diabetic (NOD) mice were orally intubated with SA (5 mg/kg/day) from 8 weeks of age for 8 weeks. The cumulative incidence of diabetes was monitored until 30 weeks of age, islet histology was examined, and lymphocytes including T cells, B cells, CD4+ IFN-γ+ cells, CD8+ IFN-γ+ cells, CD4+ IL-4+ cells, and regulatory T cells were analyzed. We also investigated the diabetogenic ability of splenocytes using an adoptive transfer model and the effect of SA on the proliferation, activation, and expression of glucose transporter 1 (Glut1) in splenocytes treated with SA in vitro and splenocytes isolated from SA-treated mice. SA treatment decreased the incidence of diabetes and delayed disease onset. SA treatment reduced the infiltration of immunocytes in islets, and splenocytes from SA-treated mice showed a reduced ability to transfer diabetes. The number of total splenocytes and T cells and both the number and the proportion of CD4+ IFN-γ+ and CD8+ IFN-γ+ T cells in the spleen were significantly reduced in SA-treated NOD mice compared with controls. The number, but not the proportion, of regulatory T cells was decreased in SA-treated NOD mice. Treatment with SA either in vitro or in vivo inhibited proliferation of splenocytes. In addition, the expression of Glut1 and phosphorylated ERK1/2 was decreased by SA treatment. These results suggest that SA reduces proliferation and activation of T cells, thus preventing autoimmune diabetes in NOD mice. - Highlights: • SA prevents the development of diabetes and delays the age of onset in NOD mice. • SA decreases the number but not the proportion of T lymphocytes in NOD mice. • SA reduces IFN-γ-producing T lymphocytes in NOD mice. • SA reduces proliferation and activation of T lymphocytes in vitro and in vivo. • SA reduces the expression of glucose

  19. Skin fragility in obese diabetic mice: possible involvement of elevated oxidative stress and upregulation of matrix metalloproteinases.

    PubMed

    Ibuki, Ai; Akase, Tomoko; Nagase, Takashi; Minematsu, Takeo; Nakagami, Gojiro; Horii, Motoko; Sagara, Hiroshi; Komeda, Takashi; Kobayashi, Masayuki; Shimada, Tsutomu; Aburada, Masaki; Yoshimura, Kotaro; Sugama, Junko; Sanada, Hiromi

    2012-03-01

    The purpose of this study was to test the hypothesis that obese diabetic mice exhibit marked skin fragility, which is caused by increased oxidative stress and increased matrix metalloproteinase (MMP) gene expression in the subcutaneous adipose tissue. Scanning electron microscopy of skin samples from Tsumura-Suzuki obese diabetic (TSOD) mice revealed thinner collagen bundles, and decreased density and convolution of the collagen fibres. Furthermore, skin tensile strength measurements confirmed that the dorsal skin of TSOD mice was more fragile to tensile force than that of non-obese mice. The mRNA expressions of heme oxygenase 1 (Hmox1), a marker of oxidative stress, Mmp2 and Mmp14 were increased in the adipose tissue of TSOD mice. Antioxidant experiments were subsequently performed to determine whether the changes in collagen fibres and skin fragility were caused by oxidative stress. Strikingly, oral administration of the antioxidant dl-α-tocopherol acetate (vitamin E) decreased Hmox1, Mmp2 and Mmp14 mRNA expressions, and improved the skin tensile strength and structure of collagen fibres in TSOD mice. These findings suggest that the skin fragility in TSOD mice is associated with dermal collagen damage and weakened tensile strength, and that oxidative stress and MMP overexpression in the subcutaneous adipose tissue may, at least in part, affect dermal fragility via a paracrine pathway. These observations may contribute to novel clinical interventions, such as dietary supplementation with antioxidants or application of skin cream containing antioxidants, which may overcome skin fragility in obese patients with diabetes.

  20. Linkage on chromosome 3 of autoimmune diabetes and defective Fc receptor for lgG in NOD mice

    SciTech Connect

    Prins, J.B.; Todd, J.A.; Rodrigues, N.R.; Ghosh, S. ); Hogarth, P.M. ); Wicker, L.S.; Podolin, P.L.; Gaffney, E.; Peterson, L.B.; Fischer, P.A.; Sirotina, A. )

    1993-04-30

    A congenic, non-obese diabetic (NOD) mouse strain that contains a segment of chromosome 3 from the diabetes-resistant mouse strain B6.PL-Thy-1[sup a] was less susceptible to diabetes than NOD mice. A fully penetrant immunological defect also mapped to this segment, which encodes the high-affinity Fc receptor for immunoglobulin G (lgG), Fc[gamma]Rl. The NOD Fcgr1 allele, which results in a deletion of the cytoplasmic tail, caused a 73 percent reduction in the turnover of cell surface receptor-antibody complexes. The development of congenic strains and the characterization of Mendelian traits that are specific to the disease phenotype demonstrate the feasibility of dissecting the pathophysiology of complex, non-Mendelian diseases.

  1. Polymeric Gene Delivery for Diabetic Treatment

    PubMed Central

    2011-01-01

    Several polymers were used to delivery genes to diabetic animals. Polyaminobutyl glycolic acid was utilized to deliver IL-10 plasmid DNA to prevent autoimmune insulitis of non-obese diabetic (NOD) mouse. Polyethylene glycol grafted polylysine was combined with antisense glutamic acid decarboxylase (GAD) MRNA to represent GAD autoantigene expression. GLP1 and TSTA (SP-EX4) were delivered by bioreducible polymer to stop diabetic progression. Fas siRNA delivery was carried out to treat diabetic NOD mice animal. PMID:21977450

  2. Consumption of acidic water alters the gut microbiome and decreases the risk of diabetes in NOD mice.

    PubMed

    Wolf, Kyle J; Daft, Joseph G; Tanner, Scott M; Hartmann, Riley; Khafipour, Ehsan; Lorenz, Robin G

    2014-04-01

    Infant formula and breastfeeding are environmental factors that influence the incidence of Type 1 Diabetes (T1D) as well as the acidity of newborn diets. To determine if altering the intestinal microbiome is one mechanism through which an acidic liquid plays a role in T1D, we placed non-obese diabetic (NOD)/ShiLtJt mice on neutral (N) or acidified H2O and monitored the impact on microbial composition and diabetes incidence. NOD-N mice showed an increased development of diabetes, while exhibiting a decrease in Firmicutes and an increase in Bacteroidetes, Actinobacteria, and Proteobacteria from as early as 2 weeks of age. NOD-N mice had a decrease in the levels of Foxp3 expression in CD4(+)Foxp3(+) cells, as well as decreased CD4(+)IL17(+) cells, and a lower ratio of IL17/IFNγ CD4+ T-cells. Our data clearly indicates that a change in the acidity of liquids consumed dramatically alters the intestinal microbiome, the presence of protective Th17 and Treg cells, and the incidence of diabetes. This data suggests that early dietary manipulation of intestinal microbiota may be a novel mechanism to delay T1D onset in genetically pre-disposed individuals.

  3. Inhibition of Autoimmune Diabetes in NOD Mice by miRNA Therapy.

    PubMed

    Wang, Duncheng; Shanina, Iryna; Toyofuku, Wendy M; Horwitz, Marc S; Scott, Mark D

    2015-01-01

    Autoimmune destruction of the pancreatic islets in Type 1 diabetes is mediated by both increased proinflammatory (Teff) and decreased regulatory (Treg) T lymphocytes resulting in a significant decrease in the Treg:Teff ratio. The non-obese diabetic (NOD) mouse is an excellent in vivo model for testing potential therapeutics for attenuating the decrease in the Treg:Teff ratio and inhibiting disease pathogenesis. Here we show for the first time that a bioreactor manufactured therapeutic consisting of a complex of miRNA species (denoted as TA1) can effectively reset the NOD immune system from a proinflammatory to a tolerogenic state thus preventing or delaying autoimmune diabetes. Treatment of NOD mice with TA1 resulted in a systemic broad-spectrum upregulation of tolerogenic T cell subsets with a parallel downregulation of Teff subsets yielding a dramatic increase in the Treg:Teff ratio. Moreover, the murine-derived TA1 was highly effective in the inhibition of allorecognition of HLA-disparate human PBMC. TA1 demonstrated dose-responsiveness and exhibited equivalent or better inhibition of allorecognition driven proliferation than etanercept (a soluble TNF receptor). These findings demonstrate that miRNA-based therapeutics can effectively attenuate or arrest autoimmune disease processes and may be of significant utility in a broad range of autoimmune diseases including Type 1 diabetes. PMID:26674203

  4. Exercise training modifies gut microbiota in normal and diabetic mice.

    PubMed

    Lambert, Jennifer E; Myslicki, Jason P; Bomhof, Marc R; Belke, Darrell D; Shearer, Jane; Reimer, Raylene A

    2015-07-01

    Cecal microbiota from type 2 diabetic (db/db) and control (db/(+)) mice was obtained following 6 weeks of sedentary or exercise activity. qPCR analysis revealed a main effect of exercise, with greater abundance of select Firmicutes species and lower Bacteroides/Prevotella spp. in both normal and diabetic exercised mice compared with sedentary counterparts. Conversely, Bifidobacterium spp. was greater in exercised normal but not diabetic mice (exercise × diabetes interaction). How exercise influences gut microbiota requires further investigation.

  5. Anti-diabetic effects of rice hull smoke extract in alloxan-induced diabetic mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We investigated the protective effect of a liquid rice hull smoke extract (RHSE) against diabetes in alloxan-induced diabetic mice. Anti-diabetic effects of RHSE were evaluated in both the rat insulinoma-1 cell line (INS-1) and diabetic ICR mice induced by inraperitoneal (ip) injection of alloxan. ...

  6. Rapamycin selectively alters serum chemistry in diabetic mice

    PubMed Central

    Tabatabai-Mir, Hooman; Sataranatarajan, Kavithalakshmi; Lee, Hak Joo; Bokov, Alex F.; Fernandez, Elizabeth; Diaz, Vivian; Choudhury, Goutam Ghosh; Richardson, Arlan; Kasinath, Balakuntalam S.

    2012-01-01

    The study was undertaken to explore the effect of rapamycin, an anti-inflammatory agent, on the metabolic profile of type 2 diabetic mice. Seven-month-old diabetic db/db mice and their lean littermate non-diabetic controls (db/m) were randomized to receive control chow or chow mixed with rapamycin (2.24 mg/kg/day) (each group n =20, males and females) for 4 months and sacrificed. Serum samples were analyzed for the measurement of glucose, creatinine, blood urea nitrogen (BUN), alkaline phosphatase (ALP), alanine aminotransferase (ALT), total cholesterol, total triglyceride, and total protein, using the automated dry chemistry analysis. Rapamycin elevated serum glucose in female diabetic mice. Serum creatinine tended to be higher in diabetic mice but was not affected by rapamycin; there was no difference in BUN levels among the groups. Serum ALP was elevated in diabetic mice and rapamycin lowered it only in female diabetic mice; serum ALT levels were increased in female diabetic mice, unaffected by rapamycin. Serum total protein was elevated in diabetic mice of both genders but was not affected by rapamycin. Diabetic mice from both genders had elevated serum cholesterol and triglycerides; rapamycin did not affect serum cholesterol but decreased serum total triglycerides in male diabetic mice. We conclude that rapamycin elicits complex metabolic responses in aging diabetic mice, worsening hyperglycemia in females but improving ALP in female diabetic and total triglycerides in male diabetic mice, respectively. The metabolic effects of rapamycin should be considered while performing studies with rapamycin in mice. PMID:22953036

  7. Rapamycin selectively alters serum chemistry in diabetic mice.

    PubMed

    Tabatabai-Mir, Hooman; Sataranatarajan, Kavithalakshmi; Lee, Hak Joo; Bokov, Alex F; Fernandez, Elizabeth; Diaz, Vivian; Choudhury, Goutam Ghosh; Richardson, Arlan; Kasinath, Balakuntalam S

    2012-01-01

    The study was undertaken to explore the effect of rapamycin, an anti-inflammatory agent, on the metabolic profile of type 2 diabetic mice. Seven-month-old diabetic db/db mice and their lean littermate non-diabetic controls (db/m) were randomized to receive control chow or chow mixed with rapamycin (2.24 mg/kg/day) (each group n =20, males and females) for 4 months and sacrificed. Serum samples were analyzed for the measurement of glucose, creatinine, blood urea nitrogen (BUN), alkaline phosphatase (ALP), alanine aminotransferase (ALT), total cholesterol, total triglyceride, and total protein, using the automated dry chemistry analysis. Rapamycin elevated serum glucose in female diabetic mice. Serum creatinine tended to be higher in diabetic mice but was not affected by rapamycin; there was no difference in BUN levels among the groups. Serum ALP was elevated in diabetic mice and rapamycin lowered it only in female diabetic mice; serum ALT levels were increased in female diabetic mice, unaffected by rapamycin. Serum total protein was elevated in diabetic mice of both genders but was not affected by rapamycin. Diabetic mice from both genders had elevated serum cholesterol and triglycerides; rapamycin did not affect serum cholesterol but decreased serum total triglycerides in male diabetic mice. We conclude that rapamycin elicits complex metabolic responses in aging diabetic mice, worsening hyperglycemia in females but improving ALP in female diabetic and total triglycerides in male diabetic mice, respectively. The metabolic effects of rapamycin should be considered while performing studies with rapamycin in mice. PMID:22953036

  8. Bromocriptine-Induced Hyperglycemia in Nonobese Diabetic Mice: Kinetics and Mechanisms of Action

    PubMed Central

    Durant, Sylvie; Coulaud, Josiane; Homo-Delarche, Francoise

    2007-01-01

    The effects of bromocriptine (10 mg/kg), known to inhibit prolactin secretion and lower autoimmune processes, were studied on glucose homeostasis in non-fasted non-obese diabetic mice, a spontaneous model of type 1 diabetes. Hyperglycemia was observed 120 and 240 min after i.p. but not s.c. injection. Bromocriptine administration i.p. led to rapid and marked hyperglycemia characterized by sexual dimorphism with males having higher glycemia than females. Bromocriptine induced a rapid but transient decrease in insulinemia in males only and biphasic increases in glucagon levels and a sustained stimulatory effect on circulating corticosterone in both sexes. Bromocriptine-induced hyperglycemia involved D2-dopaminergic receptors, as demonstrated by the inhibitory effect of the D2-dopamine antagonist, metoclopramide (10 mg/kg). Simultaneous injection of bromocriptine and metoclopramide also blocked the rise in blood corticosterone. In conclusion, by inducing hyperglycemia, i.p. bromocriptine administration to prediabetic autoimmune mice may counteract its beneficial anti-immunostimulatory effects. PMID:18084676

  9. Blood-stage malaria infection in diabetic mice.

    PubMed Central

    Elased, K; De Souza, J B; Playfair, J H

    1995-01-01

    Infection of mice with blood-stage Plasmodium yoelii and P. chabaudi malaria induced hypoglycaemia in normal mice and normalized the hyperglycaemia of mice made moderately diabetic with streptozotocin (STZ). Injection of parasite supernatants induced hypoglycaemia accompanied by hyperinsulinaemia in normal mice, and in STZ-diabetic mice induced a profound drop in blood glucose and restored insulin secretion; however, severely diabetic mice (two injections of STZ) remained hyperglycaemic with no change in insulin levels. We conclude that malaria infection and parasite-derived molecules lower blood glucose concentration, but only in the presence of some residual pancreatic function. Diabetic mice were less anaemic, exerted a significant control of parasitaemia, and showed enhanced phagocytic activity compared with normal mice. PMID:7882567

  10. HCELL Expression on Murine MSC Licenses Pancreatotropism and Confers Durable Reversal of Autoimmune Diabetes in NOD Mice

    PubMed Central

    Abdi, Reza; Moore, Robert; Sakai, Shinobu; Donnelly, Conor B.; Mounayar, Marwan; Sackstein, Robert

    2015-01-01

    Type 1 diabetes (T1D) is an immune-mediated disease resulting in destruction of insulin-producing pancreatic beta cells. Mesenchymal stem cells (MSCs) possess potent immunomodulatory properties, garnering increasing attention as cellular therapy for T1D and other immunologic diseases. However, MSCs generally lack homing molecules, hindering their colonization at inflammatory sites following intravenous (IV) administration. Here we analyzed whether enforced E-selectin ligand expression on murine MSCs could impact their effect in reversing hyperglycemia in non-obese diabetic (NOD) mice. Though murine MSCs natively do not express the E-selectin binding determinant sialyl Lewisx (sLex), we found that fucosyltransferase-mediated α(1,3)-exofucosylation of murine MSCs resulted in sLex display uniquely on cell surface CD44 thereby creating HCELL, the E-selectin-binding glycoform of CD44. Following IV infusion into diabetic NOD mice, allogeneic HCELL+ MSCs showed 3-fold greater peri-islet infiltrates compared to buffer-treated (i.e., HCELL−) MSCs, with distribution in proximity to E-selectin-expressing microvessels. Exofucosylation had no effect on MSC immunosuppressive capacity in in vitro assays, however, though engraftment was temporary for both HCELL+ and HCELL− MSCs, administration of HCELL+ MSCs resulted in durable reversal of hyperglycemia, whereas only transient reversal was observed following administration of HCELL− MSCs. Notably, exofucosylation of MSCs generated from CD44−/− mice induced prominent membrane expression of sLex, but IV administration of these MSCs into hyperglycemic NOD mice showed no enhanced pancreatotropism or reversal of hyperglycemia. These findings provide evidence that glycan engineering to enforce HCELL expression boosts trafficking of infused MSCs to pancreatic islets of NOD mice and substantially improves their efficacy in reversing autoimmune diabetes. PMID:25641589

  11. Inactivation of TNF-α ameliorates diabetic neuropathy in mice

    PubMed Central

    Yamakawa, Isamu; Terashima, Tomoya; Katagi, Miwako; Oi, Jiro; Urabe, Hiroshi; Sanada, Mitsuru; Kawai, Hiromichi; Chan, Lawrence; Yasuda, Hitoshi; Maegawa, Hiroshi; Kimura, Hiroshi

    2011-01-01

    Tumor necrosis factor (TNF)-α is a potent proinflammatory cytokine involved in the pathogenesis of diabetic neuropathy. We inactivated TNF-α to determine if it is a valid therapeutic target for the treatment of diabetic neuropathy. We effected the inactivation in diabetic neuropathy using two approaches: by genetic inactivation of TNF-α (TNF-α−/− mice) or by neutralization of TNF-α protein using the monoclonal antibody infliximab. We induced diabetes using streptozotocin in wild-type and TNF-α−/− mice. We measured serum TNF-α concentration and the level of TNF-α mRNA in the dorsal root ganglion (DRG) and evaluated nerve function by a combination of motor (MNCV) and sensory (SNCV) nerve conduction velocities and tail flick test, as well as cytological analysis of intraepidermal nerve fiber density (IENFD) and immunostaining of DRG for NF-κB p65 serine-276 phosphorylated and cleaved caspase-3. Compared with nondiabetic mice, TNF-α+/+ diabetic mice displayed significant impairments of MNCV, SNCV, tail flick test, and IENFD as well as increased expression of NF-κB p65 and cleaved caspase-3 in their DRG. In contrast, although nondiabetic TNF-α−/− mice showed mild abnormalities of IENFD under basal conditions, diabetic TNF-α−/− mice showed no evidence of abnormal nerve function tests compared with nondiabetic mice. A single injection of infliximab in diabetic TNF-α+/+ mice led to suppression of the increased serum TNF-α and amelioration of the electrophysiological and biochemical deficits for at least 4 wk. Moreover, the increased TNF-α mRNA expression in diabetic DRG was also attenuated by infliximab, suggesting infliximab's effects may involve the local suppression of TNF-α. Infliximab, an agent currently in clinical use, is effective in targeting TNF-α action and expression and amelioration of diabetic neuropathy in mice. PMID:21810933

  12. Mycophenolate Mofetil Ameliorates Diabetic Nephropathy in db/db Mice

    PubMed Central

    Seo, Jung-Woo; Kim, Yang Gyun; Lee, Sang Ho; Lee, Arah; Kim, Dong-Jin; Jeong, Kyung-Hwan; Lee, Kyung Hye; Hwang, Seung Joon; Woo, Jong Shin; Lim, Sung Jig; Kim, Weon; Moon, Ju-Young

    2015-01-01

    Chronic low-grade inflammation is an important factor in the pathogenesis of diabetic complication. Mycophenolate mofetil (MMF) has an anti-inflammatory effect, inhibiting lymphocyte proliferation. Previous studies showed attenuation of diabetic nephropathy with MMF, but the underlying mechanisms were unclear. This study aimed to identify the effect of MMF on diabetic nephropathy and investigate its action mechanisms in type 2 diabetic mice model. Eight-week-old db/db and control mice (db/m mice) received vehicle or MMF at a dose of 30 mg/kg/day for 12 weeks. MMF-treated diabetic mice showed decreased albuminuria, attenuated mesangial expansion, and profibrotic mRNA expressions despite the high glucose level. The number of infiltrated CD4+ and CD8+ T cells in the kidney was significantly decreased in MMF-treated db/db mice and it resulted in attenuating elevated intrarenal TNF-α and IL-17. The renal chemokines expression and macrophages infiltration were also attenuated by MMF treatment. The decreased expression of glomerular nephrin and WT1 was recovered with MMF treatment. MMF prevented the progression of diabetic nephropathy in db/db mice independent of glycemic control. These results suggest that the effects of MMF in diabetic nephropathy are mediated by CD4+ T cell regulation and related cytokines. PMID:26345532

  13. Type 1 Diabetes Prone NOD Mice Have Diminished Cxcr1 mRNA Expression in Polymorphonuclear Neutrophils and CD4+ T Lymphocytes

    PubMed Central

    Haurogné, Karine; Pavlovic, Marija; Rogniaux, Hélène; Bach, Jean-Marie; Lieubeau, Blandine

    2015-01-01

    In humans, CXCR1 and CXCR2 are two homologous proteins that bind ELR+ chemokines. Both receptors play fundamental roles in neutrophil functions such as migration and reactive oxygen species production. Mouse Cxcr1 and Cxcr2 genes are located in an insulin-dependent diabetes genetic susceptibility locus. The non obese diabetic (NOD) mouse is a spontaneous well-described animal model for insulin-dependent type 1 diabetes. In this disease, insulin deficiency results from the destruction of insulin-producing beta cells by autoreactive T lymphocytes. This slow-progressing disease is dependent on both environmental and genetic factors. Here, we report descriptive data about the Cxcr1 gene in NOD mice. We demonstrate decreased expression of mRNA for Cxcr1 in neutrophils and CD4+ lymphocytes isolated from NOD mice compared to other strains, related to reduced NOD Cxcr1 gene promoter activity. Looking for Cxcr1 protein, we next analyze the membrane proteome of murine neutrophils by mass spectrometry. Although Cxcr2 protein is clearly found in murine neutrophils, we did not find evidence of Cxcr1 peptides using this method. Nevertheless, in view of recently-published experimental data obtained in NOD mice, we argue for possible Cxcr1 involvement in type 1 diabetes pathogenesis. PMID:26230114

  14. Identification and Antioxidant Activity of the Extracts of Eugenia uniflora Leaves. Characterization of the Anti-Inflammatory Properties of Aqueous Extract on Diabetes Expression in an Experimental Model of Spontaneous Type 1 Diabetes (NOD Mice).

    PubMed

    Schumacher, Nayara Simon Gonzalez; Colomeu, Talita Cristina; de Figueiredo, Daniella; Carvalho, Virginia de Campos; Cazarin, Cinthia Baú Betim; Prado, Marcelo Alexandre; Meletti, Laura Maria Molina; Zollner, Ricardo de Lima

    2015-01-01

    Medical and folklore reports suggest that Eugenia uniflora (E. uniflora) is a functional food that contains numerous compounds in its composition, with anti-inflammatory, antioxidant and anti-diabetic effects. In the present study, we investigated the best solvents (water, ethanol and methanol/acetone) for extracting bioactive compounds of E. uniflora leaves, assessing total phenols and the antioxidant activity of the extracts by 2,2-Diphenyl-1-picrylhydrazyl (DPPH), Ferric Reducing Antioxidant Power (FRAP), 2,2'-Azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and Oxygen Radical Absorbance Capacity (ORAC) assays, identifying hydrolysable tannins and three phenolic compounds (ellagic acid, gallic acid and rutin) present in the leaves. In addition, we evaluated the incidence of diabetes, degree of insulitis, serum insulin, hepatic glutathione and tolerance test glucose in non-obese diabetic (NOD) mice. Our results suggest that the aqueous extract presents antioxidant activity and high total phenols, which were used as a type 1 diabetes mellitus (DM-1) treatment in NOD mice. We verified that the chronic consumption of aqueous extract reduces the inflammatory infiltrate index in pancreatic islets, maintaining serum insulin levels and hepatic glutathione, and reducing serum lipid peroxidation as well as the risk for diabetes. PMID:26783951

  15. Identification and Antioxidant Activity of the Extracts of Eugenia uniflora Leaves. Characterization of the Anti-Inflammatory Properties of Aqueous Extract on Diabetes Expression in an Experimental Model of Spontaneous Type 1 Diabetes (NOD Mice)

    PubMed Central

    Simon Gonzalez Schumacher, Nayara; Colomeu, Talita Cristina; de Figueiredo, Daniella; Carvalho, Virginia de Campos; Baú Betim Cazarin, Cinthia; Prado, Marcelo Alexandre; Molina Meletti, Laura Maria; de Lima Zollner, Ricardo

    2015-01-01

    Medical and folklore reports suggest that Eugenia uniflora (E. uniflora) is a functional food that contains numerous compounds in its composition, with anti-inflammatory, antioxidant and anti-diabetic effects. In the present study, we investigated the best solvents (water, ethanol and methanol/acetone) for extracting bioactive compounds of E. uniflora leaves, assessing total phenols and the antioxidant activity of the extracts by 2,2-Diphenyl-1-picrylhydrazyl (DPPH), Ferric Reducing Antioxidant Power (FRAP), 2,2′-Azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and Oxygen Radical Absorbance Capacity (ORAC) assays, identifying hydrolysable tannins and three phenolic compounds (ellagic acid, gallic acid and rutin) present in the leaves. In addition, we evaluated the incidence of diabetes, degree of insulitis, serum insulin, hepatic glutathione and tolerance test glucose in non-obese diabetic (NOD) mice. Our results suggest that the aqueous extract presents antioxidant activity and high total phenols, which were used as a type 1 diabetes mellitus (DM-1) treatment in NOD mice. We verified that the chronic consumption of aqueous extract reduces the inflammatory infiltrate index in pancreatic islets, maintaining serum insulin levels and hepatic glutathione, and reducing serum lipid peroxidation as well as the risk for diabetes. PMID:26783951

  16. Involvement of splenic iron accumulation in the development of nonalcoholic steatohepatitis in Tsumura Suzuki Obese Diabetes mice

    PubMed Central

    Murotomi, Kazutoshi; Arai, Shigeyuki; Uchida, Satoko; Endo, Shin; Mitsuzumi, Hitoshi; Tabei, Yosuke; Yoshida, Yasukazu; Nakajima, Yoshihiro

    2016-01-01

    Nonalcoholic steatohepatitis (NASH) is a common hepatic manifestation of metabolic syndrome and can lead to hepatic cirrhosis and cancer. It is considered that NASH is caused by multiple parallel events, including abnormal lipid metabolism, gut-derived-endotoxin-induced inflammation, and adipocytokines derived from adipose tissue, suggesting that other tissues are involved in NASH development. Previous studies demonstrated that spleen enlargement is observed during the course of NASH pathogenesis. However, the involvement of splenic status in the progression of NASH remains unclear. In this study, we examined hepatic and splenic histopathological findings in the early stage of NASH using the Tsumura Suzuki Obese Diabetes (TSOD) mouse model established for assessing NASH. We found that 12-week-old TSOD mice clearly exhibited the histopathological features of NASH in the early stage. At this age, the spleen of TSOD mice showed markedly higher iron level than that of control Tsumura Suzuki Non Obesity (TSNO) mice. The level of accumulated iron was significantly decreased by feeding a diet with glucosyl hesperidin, a bioactive flavonoid, accompanied with alleviation of hepatic lesions. Furthermore, we found that splenic iron level was positively correlated with the severity of NASH manifestations, suggesting that abnormalities in the spleen are involved in the development of NASH. PMID:26932748

  17. IFN-{gamma} gene expression in pancreatic islet-infiltrating mononuclear cells correlates with autoimmune diabetes in nonobese diabetic mice

    SciTech Connect

    Rabinovitch, A.; Suarez-Pinzon, W.L.; Sorensen, O.

    1995-05-01

    Insulin-dependent diabetes mellitus in nonobese diabetic (NOD) mice results from selective destruction of pancreatic islet {beta}-cells following islet filtration by mononuclear leukocytes. Cytokines produced by islet-infiltrating mononuclear cells may be involved in {beta}-cell destruction. Therefore, we analyzed cytokine mRNA expression, by reverse-transcriptase PCR (RT-PCR) assay, in mononuclear leukocytes isolated from pancreatic islets of four groups of mice: diabetes-prone female NOD mice; female NOD mice protected from diabetes by injection of CFA at an early age; male NOD mice with a low diabetes incidence; and female BALB/c mice that do not develop diabetes. We found that mRNA levels of IL-1{beta}, IL-2, IL-4, IL-10, and IFN-{gamma} in mononuclear cells from islets of diabetes-prone female NOD mice increased progressively as these cells infiltrated the islets from age 5 wk to diabetes onset (>13 wk). However, only IFN-{gamma} mRNA levels were significantly higher in islet mononuclear cells from 12-wk-old diabetes-prone female NOD mice than from less diabetes-prone NOD mice (CFA-treated females, and males) and normal mice (BALB/c). In contrast, IL-4 mRNA levels were lower in islet mononuclear cells from diabetes-prone female NOD mice than from NOD mice with low diabetes incidence (CFA-treated females and males). Splenic cell mRNA levels of IFN-{gamma} and IL-4 were not different in the four groups of mice. These results suggest that islet {beta}-cell destruction and diabetes in female NOD mice are dependent upon intra-islet IFN-{gamma} production by mononuclear cells, and that CFA-treated female NOD mice and male NOD mice may be protected from diabetes development by down-regulation of IFN-{gamma} production in the islets. 56 refs., 4 figs., 3 tabs.

  18. Modulation of renal superoxide dismutase by telmisartan therapy in C57BL/6-Ins2Akita diabetic mice

    PubMed Central

    Fujita, Hiroki; Fujishima, Hiromi; Morii, Tsukasa; Sakamoto, Takuya; Komatsu, Koga; Hosoba, Mihoko; Narita, Takuma; Takahashi, Keiko; Takahashi, Takamune; Yamada, Yuichiro

    2012-01-01

    Renal superoxide excess, which is induced by an imbalance of the superoxide-producing enzyme NAD(P)H oxidase and the superoxide-scavenging enzyme superoxide dismutase (SOD) under hyperglycemia, increases oxidative stress and contributes to the development of diabetic nephropathy. In this study, we treated non-obese and hypoinsulinemic C57BL/6-Ins2Akita (C57BL/6-Akita) diabetic mice with telmisartan (5 mg kg−1 per day), an angiotensin II type 1 receptor blocker, or amlodipine (5 mg kg−1 per day), a calcium channel blocker, for 4 weeks and compared the effects of these two anti-hypertensive drugs on renal NAD(P)H oxidase, SOD and transcription factor Nrf2 (NF-E2-related factor 2), which is known to upregulate several antioxidant enzymes including SOD. Vehicle-treated C57BL/6-Akita mice exhibited higher renal NAD(P)H oxidase and lower renal SOD activity with increased levels of renal superoxide than the C57BL/6-wild-type non-diabetic mice. Interestingly, telmisartan treatment not only reduced NAD(P)H oxidase activity but also enhanced SOD activity in C57BL/6-Akita mouse kidneys, leading to a reduction of renal superoxide levels. Furthermore, telmisartan-treated C57BL/6-Akita mice increased the renal protein expression of SOD and Nrf2. In parallel with the reduction of renal superoxide levels, a reduction of urinary albumin levels and a normalization of elevated glomerular filtration rate were observed in telmisartan-treated C57BL/6-Akita mice. In contrast, treatment with amlodipine failed to modulate renal NAD(P)H oxidase, SOD and Nrf2. Finally, treatment of C57BL/6-Akita mice with apocynin, an NAD(P)H oxidase inhibitor, also increased the renal protein expression of SOD and Nrf2. Collectively, our data suggest that NAD(P)H oxidase negatively regulates renal SOD, possibly by downregulation of Nrf2, and that telmisartan could upregulate renal SOD by the suppression of NAD(P)H oxidase and subsequent upregulation of Nrf2, leading to the amelioration of

  19. Influence of whole-wheat consumption on fecal microbial community structure of obese diabetic mice

    PubMed Central

    Ivanov, Ivan; Mills, David A.

    2016-01-01

    The digestive tract of mammals and other animals is colonized by trillions of metabolically-active microorganisms. Changes in the gut microbiota have been associated with obesity in both humans and laboratory animals. Dietary modifications can often modulate the obese gut microbial ecosystem towards a more healthy state. This phenomenon should preferably be studied using dietary ingredients that are relevant to human nutrition. This study was designed to evaluate the influence of whole-wheat, a food ingredient with several beneficial properties, on gut microorganisms of obese diabetic mice. Diabetic (db/db) mice were fed standard (obese-control) or whole-wheat isocaloric diets (WW group) for eight weeks; non-obese mice were used as control (lean-control). High-throughput sequencing using the MiSeq platform coupled with freely-available computational tools and quantitative real-time PCR were used to analyze fecal bacterial 16S rRNA gene sequences. Short-chain fatty acids were measured in caecal contents using quantitative high-performance liquid chromatography photo-diode array analysis. Results showed no statistical difference in final body weights between the obese-control and the WW group. The bacterial richness (number of Operational Taxonomic Units) did not differ among the treatment groups. The abundance of Ruminococcaceae, a family containing several butyrate-producing bacteria, was found to be higher in obese (median: 6.9%) and WW-supplemented mice (5.6%) compared to lean (2.7%, p = 0.02, Kruskal-Wallis test). Caecal concentrations of butyrate were higher in obese (average: 2.91 mmol/mg of feces) but especially in WW-supplemented mice (4.27 mmol/mg) compared to lean controls (0.97 mmol/mg), while caecal succinic acid was lower in the WW group compared to obese but especially to the lean group. WW consumption was associated with ∼3 times higher abundances of Lactobacillus spp. compared to both obese and lean control mice. Analysis of weighted Uni

  20. Influence of whole-wheat consumption on fecal microbial community structure of obese diabetic mice.

    PubMed

    Garcia-Mazcorro, Jose F; Ivanov, Ivan; Mills, David A; Noratto, Giuliana

    2016-01-01

    The digestive tract of mammals and other animals is colonized by trillions of metabolically-active microorganisms. Changes in the gut microbiota have been associated with obesity in both humans and laboratory animals. Dietary modifications can often modulate the obese gut microbial ecosystem towards a more healthy state. This phenomenon should preferably be studied using dietary ingredients that are relevant to human nutrition. This study was designed to evaluate the influence of whole-wheat, a food ingredient with several beneficial properties, on gut microorganisms of obese diabetic mice. Diabetic (db/db) mice were fed standard (obese-control) or whole-wheat isocaloric diets (WW group) for eight weeks; non-obese mice were used as control (lean-control). High-throughput sequencing using the MiSeq platform coupled with freely-available computational tools and quantitative real-time PCR were used to analyze fecal bacterial 16S rRNA gene sequences. Short-chain fatty acids were measured in caecal contents using quantitative high-performance liquid chromatography photo-diode array analysis. Results showed no statistical difference in final body weights between the obese-control and the WW group. The bacterial richness (number of Operational Taxonomic Units) did not differ among the treatment groups. The abundance of Ruminococcaceae, a family containing several butyrate-producing bacteria, was found to be higher in obese (median: 6.9%) and WW-supplemented mice (5.6%) compared to lean (2.7%, p = 0.02, Kruskal-Wallis test). Caecal concentrations of butyrate were higher in obese (average: 2.91 mmol/mg of feces) but especially in WW-supplemented mice (4.27 mmol/mg) compared to lean controls (0.97 mmol/mg), while caecal succinic acid was lower in the WW group compared to obese but especially to the lean group. WW consumption was associated with ∼3 times higher abundances of Lactobacillus spp. compared to both obese and lean control mice. Analysis of weighted Uni

  1. Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice.

    PubMed

    Trammell, Samuel A J; Weidemann, Benjamin J; Chadda, Ankita; Yorek, Matthew S; Holmes, Amey; Coppey, Lawrence J; Obrosov, Alexander; Kardon, Randy H; Yorek, Mark A; Brenner, Charles

    2016-01-01

    Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD(+) metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP(+) and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies. PMID:27230286

  2. Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice

    PubMed Central

    Trammell, Samuel A.J.; Weidemann, Benjamin J.; Chadda, Ankita; Yorek, Matthew S.; Holmes, Amey; Coppey, Lawrence J.; Obrosov, Alexander; Kardon, Randy H.; Yorek, Mark A.; Brenner, Charles

    2016-01-01

    Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD+ metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP+ and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies. PMID:27230286

  3. Cardiovascular manifestations of renovascular hypertension in diabetic mice.

    PubMed

    Kashyap, Sonu; Engel, Sean; Osman, Mazen; Al-Saiegh, Yousif; Wongjarupong, Asarn; Grande, Joseph P

    2016-01-01

    Purpose. Type 2 diabetes is the leading cause of end stage renal disease in the United States. Atherosclerotic renal artery stenosis is commonly observed in diabetic patients and impacts the rate of renal and cardiovascular disease progression. We sought to test the hypothesis that renovascular hypertension, induced by unilateral renal artery stenosis, exacerbates cardiac remodeling in leptin-deficient (db/db) mice, which serves as a model of human type II diabetes. Methods. We employed a murine model of renovascular hypertension through placement of a polytetrafluoroethylene cuff on the right renal artery in db/db mice. We studied 109 wild-type (non-diabetic, WT) and 95 db/db mice subjected to renal artery stenosis (RAS) or sham surgery studied at 1, 2, 4, and 6+ weeks following surgery. Cardiac remodeling was assessed by quantitative analysis of the percent of myocardial surface area occupied by interstitial fibrosis tissue, as delineated by trichrome stained slides. Aortic pathology was assessed by histologic sampling of grossly apparent structural abnormalities or by section of ascending aorta of vessels without apparent abnormalities. Results. We noted an increased mortality in db/db mice subjected to RAS. The mortality rate of db/db RAS mice was about 23.5%, whereas the mortality rate of WT RAS mice was only 1.5%. Over 60% of mortality in the db/db mice occurred in the first two weeks following RAS surgery. Necropsy showed massive intrathoracic hemorrhage associated with aortic dissection, predominantly in the ascending aorta and proximal descending aorta. Aortas from db/db RAS mice showed more smooth muscle dropout, loss of alpha smooth muscle actin expression, medial disruption, and hemorrhage than aortas from WT mice with RAS. Cardiac tissue from db/db RAS mice had more fibrosis than did cardiac tissue from WT RAS mice. Conclusions. db/db mice subjected to RAS are prone to develop fatal aortic dissection, which is not observed in WT mice with RAS. The db

  4. Anti-Diabetic Effects of CTB-APSL Fusion Protein in Type 2 Diabetic Mice

    PubMed Central

    Liu, Yunlong; Gao, Zhangzhao; Guo, Qingtuo; Wang, Tao; Lu, Conger; Chen, Ying; Sheng, Qing; Chen, Jian; Nie, Zuoming; Zhang, Yaozhou; Wu, Wutong; Lv, Zhengbing; Shu, Jianhong

    2014-01-01

    To determine whether cholera toxin B subunit and active peptide from shark liver (CTB-APSL) fusion protein plays a role in treatment of type 2 diabetic mice, the CTB-APSL gene was cloned and expressed in silkworm (Bombyx mori) baculovirus expression vector system (BEVS), then the fusion protein was orally administrated at a dose of 100 mg/kg for five weeks in diabetic mice. The results demonstrated that the oral administration of CTB-APSL fusion protein can effectively reduce the levels of both fasting blood glucose (FBG) and glycosylated hemoglobin (GHb), promote insulin secretion and improve insulin resistance, significantly improve lipid metabolism, reduce triglycerides (TG), total cholesterol (TC) and low density lipoprotein (LDL) levels and increase high density lipoprotein (HDL) levels, as well as effectively improve the inflammatory response of type 2 diabetic mice through the reduction of the levels of inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Histopathology shows that the fusion protein can significantly repair damaged pancreatic tissue in type 2 diabetic mice, significantly improve hepatic steatosis and hepatic cell cloudy swelling, reduce the content of lipid droplets in type 2 diabetic mice, effectively inhibit renal interstitial inflammatory cells invasion and improve renal tubular epithelial cell nucleus pyknosis, thus providing an experimental basis for the development of a new type of oral therapy for type 2 diabetes. PMID:24633252

  5. Black Ginseng Extract Counteracts Streptozotocin-Induced Diabetes in Mice

    PubMed Central

    Kim, Jun Ho; Pan, Jeong Hoon; Cho, Hyung Taek; Kim, Young Jun

    2016-01-01

    Black ginseng, a new type of processed ginseng that has a unique ginsenoside profile, has been shown to display potent pharmacological activities in in vitro and in vivo models. Although red ginseng is considered beneficial for the prevention of diabetes, the relationship between black ginseng and diabetes is unknown. Therefore, this study was designed to evaluate the anti-diabetic potential of black ginseng extract (BGE) in streptozotocin (STZ)-induced insulin-deficient diabetic mice, in comparison with red ginseng extract (RGE). HPLC analyses showed that BGE has a different ginsenoside composition to RGE; BGE contains Rg5 and compound k as the major ginsenosides. BGE at 200 mg/kg reduced hyperglycemia, increased the insulin/glucose ratio and improved islet architecture and β-cell function in STZ-treated mice. The inhibition of β-cell apoptosis by BGE was associated with suppression of the cytokine—induced nuclear factor–κB—mediated signaling pathway in the pancreas. Moreover, these anti-diabetic effects of BGE were more potent than those of RGE. Collectively, our data indicate that BGE, in part by suppressing cytokine—induced apoptotic signaling, protects β-cells from oxidative injury and counteracts diabetes in mice. PMID:26751692

  6. Black Ginseng Extract Counteracts Streptozotocin-Induced Diabetes in Mice.

    PubMed

    Kim, Jun Ho; Pan, Jeong Hoon; Cho, Hyung Taek; Kim, Young Jun

    2016-01-01

    Black ginseng, a new type of processed ginseng that has a unique ginsenoside profile, has been shown to display potent pharmacological activities in in vitro and in vivo models. Although red ginseng is considered beneficial for the prevention of diabetes, the relationship between black ginseng and diabetes is unknown. Therefore, this study was designed to evaluate the anti-diabetic potential of black ginseng extract (BGE) in streptozotocin (STZ)-induced insulin-deficient diabetic mice, in comparison with red ginseng extract (RGE). HPLC analyses showed that BGE has a different ginsenoside composition to RGE; BGE contains Rg5 and compound k as the major ginsenosides. BGE at 200 mg/kg reduced hyperglycemia, increased the insulin/glucose ratio and improved islet architecture and β-cell function in STZ-treated mice. The inhibition of β-cell apoptosis by BGE was associated with suppression of the cytokine-induced nuclear factor-κB-mediated signaling pathway in the pancreas. Moreover, these anti-diabetic effects of BGE were more potent than those of RGE. Collectively, our data indicate that BGE, in part by suppressing cytokine-induced apoptotic signaling, protects β-cells from oxidative injury and counteracts diabetes in mice. PMID:26751692

  7. Histidine Decarboxylase Deficiency Prevents Autoimmune Diabetes in NOD Mice

    PubMed Central

    Alkan, Manal; Machavoine, François; Rignault, Rachel; Dam, Julie; Dy, Michel; Thieblemont, Nathalie

    2015-01-01

    Recent evidence has highlighted the role of histamine in inflammation. Since this monoamine has also been strongly implicated in the pathogenesis of type-1 diabetes, we assessed its effect in the nonobese diabetic (NOD) mouse model. To this end, we used mice (inactivated) knocked out for the gene encoding histidine decarboxylase, the unique histamine-forming enzyme, backcrossed on a NOD genetic background. We found that the lack of endogenous histamine in NOD HDC−/− mice decreased the incidence of diabetes in relation to their wild-type counterpart. Whereas the proportion of regulatory T and myeloid-derived suppressive cells was similar in both strains, histamine deficiency was associated with increased levels of immature macrophages, as compared with wild-type NOD mice. Concerning the cytokine pattern, we found a decrease in circulating IL-12 and IFN-γ in HDC−/− mice, while IL-6 or leptin remained unchanged, suggesting that histamine primarily modulates the inflammatory environment. Paradoxically, exogenous histamine given to NOD HDC−/− mice provided also protection against T1D. Our study supports the notion that histamine is involved in the pathogenesis of diabetes, thus providing additional evidence for its role in the regulation of the immune response. PMID:26090474

  8. Arginase II Deletion Increases Corpora Cavernosa Relaxation in Diabetic Mice

    PubMed Central

    Toque, Haroldo; Tostes, Rita; Yao, Lin; Xu, Zhimin; Webb, Clinton R.; Caldwell, Ruth; Caldwell, Robert

    2010-01-01

    Introduction Diabetes-induced erectile dysfunction involves elevated arginase (Arg) activity and expression. Because nitric oxide (NO) synthase and Arg share and compete for their substrate L-arginine, NO production is likely linked to regulation of Arg. Arg is highly expressed and implicated in erectile dysfunction. Aim It was hypothesized that Arg-II isoform deletion enhances relaxation function of corpora cavernosal (CC) smooth muscle in a streptozotocin (STZ) diabetic model. Methods Eight weeks after STZ-induced diabetes, vascular functional studies, Arg activity assay, and protein expression levels of Arg and constitutive NOS (using western blots) were assessed in CC tissues from non-diabetic wild type (WT), diabetic (D) WT (WT+D), Arg-II knockout (KO) and Arg-II KO+D mice (N=8–10 per group). Main Outcome Measures Inhibition or lack of arginase results in facilitation of CC relaxation in diabetic CC. Results Strips of CC from Arg-II KO mice exhibited an enhanced maximum endothelium-dependent relaxation (from 70+3% to 84+4%) and increased nitrergic relaxation (by 55%, 71%, 42%, 42%, and 24% for 1, 2, 4, 8 and 16 Hz, respectively) compared to WT mice. WT+D mice showed a significant reduction of endothelium-dependent maximum relaxation (44+8%), but this impairment of relaxation was significantly prevented in Arg-II KO+D mice (69+4%). Sympathetic-mediated and alpha-adrenergic agent-induced contractile responses also were increased in CC strips from D compared to non-D controls. Contractile responses were significantly lower in Arg-II KO control and D versus the WT groups. WT+D mice increased Arg activity (1.5-fold) and Arg-II protein expression and decreased total and phospho-eNOS at Ser-1177, and nNOS levels. These alterations were not seen in Arg-II KO mice. Additionally, the Arg inhibitor BEC (50 μM) enhanced nitrergic and endothelium-dependent relaxation in CC of WT+D mice. Conclusion These studies show for the first time that Arg-II deletion improves CC

  9. Immunization of AGE-modified albumin inhibits diabetic nephropathy progression in diabetic mice

    PubMed Central

    Mashitah, Musthika Wida; Azizah, Nurona; Samsu, Nur; Indra, Muhammad Rasjad; Bilal, Muhammad; Yunisa, Meti Verdian; Arisanti, Amildya Dwi

    2015-01-01

    Background Diabetic nephropathy (DN) is a serious vascular complication of diabetes and an important cause of end-stage renal disease. One mechanism by which hyperglycemia causes nephropathy is through the formation of advanced glycation end products (AGE). Development of vaccination would be a promising therapy for the future, while to date, anti-AGE therapy is based on medicines that are needed to be consumed lifelong. This study aimed to find out the effect of immunization of AGE-modified albumin against DN pathogenesis in streptozotocin-induced diabetic in mice. Methods We used 24 BALB/c male mice as experimental animals, which were divided into six groups, two nondiabetic groups (negative control and AGE-modified bovine serum albumin [BSA] preimmunized groups) and four streptozotocin-induced diabetic groups (diabetic control group and diabetic preimmunized groups for AGE-BSA, Keyhole limpet hemocyanin (KLH), and AGE-BSA-KLH, respectively). Results Diabetic preimmunized groups for AGE-BSA, KLH, and AGE-BSA-KLH showed amelioration in renal function and histopathology compared with the diabetic control group. Preimmunization also maintained nephrin intensity and decreased serum AGE level, kidney AGE deposition, and kidney cells apoptosis. Conclusion AGE-BSA and AGE-BSA-KLH immunizations inhibit the progression of DN. Our results strengthen the evidence that the anti-AGE antibodies have a protective role against diabetic vascular complication, especially DN. This study provides a basis for the development of DN-based immunotherapy with AGE immunization as a potential candidate. PMID:26346342

  10. Ergosterol Alleviates Kidney Injury in Streptozotocin-Induced Diabetic Mice

    PubMed Central

    Ang, Li; Yuguang, Liu; Liying, Wang; Shuying, Zhang; Liting, Xu; Shumin, Wang

    2015-01-01

    Ergosterol (ERG) has been widely used in the development of novel drugs due to its unique physiological function. However, little is known about the protective effects of ERG on diabetes. Hence, the current study was designed to evaluate the positive role of ergosterol on streptozotocin- (STZ-) induced diabetes in mice. Oral glucose tolerance test (OGTT) was carried out to assess blood glucose level. Biochemical parameters such as uric acid, creatinine, serum insulin, triglycerides (TG), and total cholesterol (TC) were also measured. Pathological condition of kidney was examined by hematoxylin-eosin (H&E) staining. The expressions of PI3K, p-PI3K, Akt, p-Akt, NF-κBp65, p-NF-κBp65, IκBα, and p-IκBα were analyzed by western blot. ERG significantly reduced the concentrations of blood glucose, uric acid, creatinine, TG, and TC. Serum insulin was elevated with ERG treatment. In addition, renal pathologic changes of diabetes mice were also alleviated by ERG. Obtained data revealed that ERG restored the levels of PI3K/Akt/NF-κB signaling-related proteins in comparison with diabetes mice. Above all, it could be assumed that ERG might play a positive role in regulating STZ-induced diabetes through suppressing PI3K/Akt/NF-κB pathway. PMID:26664454

  11. Nonobese diabetic mice and the genetics of diabetes susceptibility.

    PubMed

    Leiter, Edward H

    2005-04-01

    The nonobese diabetic mouse spontaneously develops an autoimmune, T-cell-mediated type 1 diabetes (T1D). Common and rare alleles both within a diabetogenic major histocompatibility complex (MHC) and multiple non-MHC genes combine to impair normal communication between the innate and acquired immune system, leading to loss of immune tolerance. An understanding of how variable collections of genes interact with each other and with environmental cues offers important insights as to the complexities of T1D inheritance in humans.

  12. Tree shrew (Tupaia belangeri chinensis), a novel non-obese animal model of non-alcoholic fatty liver disease

    PubMed Central

    Zhang, Linqiang; Wu, Xiaoyun; Liao, Shasha; Li, Yunhai; Zhang, Zhiguo; Chang, Qing; Xiao, Ruyue

    2016-01-01

    ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is becoming a severe public health problem that is affecting a large proportion of the world population. Generally, NAFLD in patients is usually accompanied by obesity, hyperglycemia, insulin resistance (IR) and type 2 diabetes (T2D), for which numerous animal models have been generated in order to explore the pathogenesis and therapies of NAFLD. On the contrary, quite a number of NAFLD subjects, especially in Asian regions, are non-obese and non-diabetic; however, few animal models are available for the research of non-obese NAFLD. Here, four approaches (here called approach 1 to 4) corresponding to the variable compositions of diets were used to treat tree shrews (Tupaia belangeri chinensis), which have a closer evolutionary relationship to primates than rodents. Analysis of plasma biochemical parameters, hepatic histology, and the expression of hepatic lipid metabolic genes revealed that all four approaches led to hepatic lipid accumulation, liver injury and hypercholesterolemia, but had no effect on body weight and adipose tissue generation, or glycemia. Hepatic gene expression in tree shrews treated by approach 4 might suggest a different or non-canonical pathway leading to hepatic steatosis. In conclusion, the tree shrew displays hepatic steatosis and dyslipidemia, but remains non-obese and non-diabetic under high energy diets, which suggests that the tree shrew may be useful as a novel animal model for the research of human non-obese NAFLD. PMID:27659689

  13. Cutting Edge: Nonobese Diabetic Mice Deficient in Chromogranin A Are Protected from Autoimmune Diabetes.

    PubMed

    Baker, Rocky L; Bradley, Brenda; Wiles, Timothy A; Lindsay, Robin S; Barbour, Gene; Delong, Thomas; Friedman, Rachel S; Haskins, Kathryn

    2016-01-01

    T cells reactive to β cell Ags are critical players in the development of autoimmune type 1 diabetes. Using a panel of diabetogenic CD4 T cell clones derived from the NOD mouse, we recently identified the β cell secretory granule protein, chromogranin A (ChgA), as a new autoantigen in type 1 diabetes. CD4 T cells reactive to ChgA are pathogenic and rapidly transfer diabetes into young NOD recipients. We report in this article that NOD.ChgA(-/-) mice do not develop diabetes and show little evidence of autoimmunity in the pancreatic islets. Using tetramer analysis, we demonstrate that ChgA-reactive T cells are present in these mice but remain naive. In contrast, in NOD.ChgA(+/+) mice, a majority of the ChgA-reactive T cells are Ag experienced. Our results suggest that the presence of ChgA and subsequent activation of ChgA-reactive T cells are essential for the initiation and development of autoimmune diabetes in NOD mice. PMID:26608914

  14. Severe pulmonary metastasis in obese and diabetic mice.

    PubMed

    Mori, Akinori; Sakurai, Hiroaki; Choo, Min-Kyung; Obi, Ryosuke; Koizumi, Keiichi; Yoshida, Chiho; Shimada, Yutaka; Saiki, Ikuo

    2006-12-15

    Although obesity is known as a risk factor for several human cancers, the association of obesity with cancer recurrence and metastasis remains to be characterized. Here, B16-BL6 melanoma and Lewis lung carcinoma cells were intravenously injected into diabetic (db/db) and obese (ob/ob) mice. The number of experimental lung colonies was markedly promoted in these mice when compared with C57BL/6 mice. In contrast, tumor growth at the implanted site was comparable when cells were inoculated orthotopically. The use of B16-BL6 cells stably transfected with the luciferase gene revealed that the increased metastasis reflected a difference mainly within 6 hr after the intravenous inoculation of tumor cells. Administration of recombinant leptin in ob/ob mice abolished the increase in metastasis early on as well as the decrease in the splenic NK cell number. In addition, depletion of NK cells by an anti-asialo-GM1 antibody abrogated the enhanced metastasis in db/db mice. These results demonstrate that metastasis is markedly promoted in diabetic and obese mice mainly because of decreased NK cell function during the early phase of metastasis. PMID:16998795

  15. Oral nitrite therapy improves vascular function in diabetic mice

    PubMed Central

    Sindler, Amy L; Cox-York, Kimberly; Reese, Lauren; Bryan, Nathan S; Seals, Douglas R; Gentile, Christopher L

    2016-01-01

    Aim We tested the hypothesis that short-term oral sodium nitrite supplementation would improve vascular dysfunction in obese, diabetic mice. Methods and results Vascular function was determined in control mice and in db/db mice receiving drinking water with or without sodium nitrite (50 mg/L) for 5 weeks. Nitrite supplementation increased plasma nitrite concentrations in db/db mice (0.19±0.02 μM vs 0.80±0.26μM; p < 0.05). Db/db mice had lower endothelium-dependent dilation (EDD) in response to increasing doses of acetylcholine versus heterozygous control mice (71.2% ± 14.3% vs 93% ± 7.0%; p < 0.05), and sodium nitrite supplementation restored endothelium-dependent dilation to control levels (92.9% ± 2.3% vs 93% ± 7.0%; p < 0.05). The improvement in endothelial function was accompanied by a reduction in intrinsic stiffness, but not by alterations in plasma or vascular markers of inflammation. Conclusion These data suggest that sodium nitrite may be a novel therapy for treating diabetes-related vascular dysfunction; however, the mechanisms of improvement are unknown. PMID:25696116

  16. Vitamin E and diabetic nephropathy in mice model and humans.

    PubMed

    Farid, Nakhoul; Inbal, Dahan; Nakhoul, Nakhoul; Evgeny, Farber; Miller-Lotan, Rachel; Levy, Andrew P; Rabea, Asleh

    2013-11-01

    Diabetes mellitus (DM) is associated with increased oxidative stress due to elevated glucose levels in the plasma. Glucose promotes glycosylation of both plasma and cellular proteins with increased risk for vascular events. Diabetic patients suffer from a higher incidence of cardiovascular complications such as diabetic nephropathy. Haptoglobin (Hp) is an antioxidant plasma protein which binds free hemoglobin, thus preventing heme-iron mediated oxidation. Two alleles exist at the Hp gene locus (1 and 2) encoding three possible Hp genotypes that differ in their antioxidant ability, and may respond differently to vitamin E treatment. Several clinical studies to have shown that Hp 1-1 genotype is a superior antioxidant to the Hp 2-2 genotype and Hp 2-2 genotype is associated with a higher incidence of cardiovascular disease. Vitamin E was found to have beneficial effect in patient and mice with Hp 2-2 genotype. In this review we have summarized the results of our studies in patients with diabetic nephropathy treated with vitamin E and in diabetic mice with different haptoglobin genotypes. PMID:24255894

  17. Neurobehavioral deficits in db/db diabetic mice

    PubMed Central

    Sharma, Ajaykumar N.; Elased, Khalid M.; Garrett, Teresa L.; Lucot, James B.

    2011-01-01

    Recent clinical studies indicate neurobehavioral disturbances in type-2 diabetics. However, there is paucity of preclinical research to support this concept. The validity of db/db mouse as an animal model to study type-2 diabetes and related complications is known. The present study was designed to investigate comprehensively the db/db mouse behavior as preclinical evidence of type-2 diabetes related major neurobehavioral complications. We tested juvenile (5–6 weeks) and adult (10–11 weeks) db/db mice for behavioral depression in forced swim test (FST), psychosis-like symptoms using pre-pulse inhibition (PPI) test, anxiety behavior employing elevated plus maze (EPM) test, locomotor behavior and thigmotaxis using open field test and working memory deficits in Y-maze test. Both juvenile and adult group db/db mice displayed behavioral despair with increased immobility time in FST. There was an age-dependent progression of psychosis-like symptoms with disrupted PPI in adult db/db mice. In the EPM test, db/db mice were less anxious as observed by increased percent open arms time and entries. They were also hypolocomotive as evident by a decrease in their basic and fine movements. There was no impairment of working memory in the Y-maze test in db/db mice. This is the first report of depression, psychosis-like symptoms and anxiolytic behavior of db/db mouse strain. It is tempting to speculate that this mouse strain can serve as useful preclinical model to study type-2 diabetes related neurobehavioral complications. PMID:20637218

  18. Differential central pathology and cognitive impairment in pre-diabetic and diabetic mice.

    PubMed

    Ramos-Rodriguez, Juan Jose; Ortiz, Oscar; Jimenez-Palomares, Margarita; Kay, Kevin R; Berrocoso, Esther; Murillo-Carretero, Maria Isabel; Perdomo, German; Spires-Jones, Tara; Cozar-Castellano, Irene; Lechuga-Sancho, Alfonso Maria; Garcia-Alloza, Monica

    2013-11-01

    Although age remains the main risk factor to suffer Alzheimer's disease (AD) and vascular dementia (VD), type 2 diabetes (T2D) has turned up as a relevant risk factor for dementia. However, the ultimate underlying mechanisms for this association remain unclear. In the present study we analyzed central nervous system (CNS) morphological and functional consequences of long-term insulin resistance and T2D in db/db mice (leptin receptor KO mice). We also included C57Bl6 mice fed with high fat diet (HFD) and a third group of C57Bl6 streptozotocin (STZ) treated mice. Db/db mice exhibited pathological characteristics that mimic both AD and VD, including age dependent cognitive deterioration, brain atrophy, increased spontaneous hemorrhages and tau phosphorylation, affecting the cortex preferentially. A similar profile was observed in STZ-induced diabetic mice. Moreover metabolic parameters, such as body weight, glucose and insulin levels are good predictors of many of these alterations in db/db mice. In addition, in HFD-induced hyperinsulinemia in C57Bl6 mice, we only observed mild CNS alterations, suggesting that central nervous system dysfunction is associated with well established T2D. Altogether our results suggest that T2D may promote many of the pathological and behavioral alterations observed in dementia, supporting that interventions devoted to control glucose homeostasis could improve dementia progress and prognosis.

  19. Effects of histamine H(1) receptor antagonists on depressive-like behavior in diabetic mice.

    PubMed

    Hirano, Shoko; Miyata, Shigeo; Onodera, Kenji; Kamei, Junzo

    2006-02-01

    We previously reported that streptozotocin-induced diabetic mice showed depressive-like behavior in the tail suspension test. It is well known that the central histaminergic system regulates many physiological functions including emotional behaviors. In this study, we examined the role of the central histaminergic system in the diabetes-induced depressive-like behavior in the mouse tail suspension test. The histamine contents in the hypothalamus were significantly higher in diabetic mice than in non-diabetic mice. The histamine H(1) receptor antagonist chlorpheniramine (1-10 mg/kg, s.c.) dose-dependently and significantly reduced the duration of immobility in both non-diabetic and diabetic mice. In contrast, the selective histamine H(1) receptor antagonists epinastine (0.03-0.3 microg/mouse, i.c.v.) and cetirizine (0.01-0.1 microg/mouse, i.c.v.) dose-dependently and significantly suppressed the duration of immobility in diabetic mice, but not in non-diabetic mice. Spontaneous locomotor activity was not affected by histamine H(1) receptor antagonists in either non-diabetic or diabetic mice. In addition, the number and affinity of histamine H(1) receptors in the frontal cortex were not affected by diabetes. In conclusion, we suggest that the altered neuronal system mediated by the activation of histamine H(1) receptors is involved, at least in part, in the depressive-like behavior seen in diabetic mice.

  20. The effect of B vitamin supplementation on wound healing in type 2 diabetic mice

    PubMed Central

    Mochizuki, Saeka; Takano, Mayuko; Sugano, Naoyuki; Ohtsu, Mariko; Tsunoda, Kou; Koshi, Ryosuke; Yoshinuma, Naoto

    2016-01-01

    The aim of this study was to test the effects of B-group vitamin supplements on wound healing in diabetic mice. The mice in the experimental group were treated daily with 1 g/L B6, 1.25 mg/L B12, and 62.5 mg/L folic acid in their drinking water. Full-thickness excision wounds were created with 6-mm skin biopsy punches. Each wound closure was digitally photographed. Beginning on day 3 after wounding, the wound area in the diabetic mice was statistically larger than that of normal mice (p<0.05 vs diabetic mice). The diabetic mice treated with B vitamins displayed accelerated wound closure on day 3 (wound area 42.8 ± 11.3%, p<0.05). On day 9 after wounding, the wound area in the diabetic mice was also statistically larger than that of normal mice (p<0.05 vs diabetic mice). The diabetic mice treated with B vitamins displayed accelerated wound closure on day 3 (wound area 13.2 ± 16.8%, p<0.05). In addition, the high glucose level in the diabetic animals decreased significantly in response to B vitamin treatment. In conclusion, the results of this study indicate that B vitamin supplementation may improve wound healing in diabetic mice. PMID:26798199

  1. Berberine Improves Kidney Function in Diabetic Mice via AMPK Activation

    PubMed Central

    Zhao, Long; Sun, Li-Na; Nie, Hui-Bin; Wang, Xue-Ling; Guan, Guang-Ju

    2014-01-01

    Diabetic nephropathy is a major cause of morbidity and mortality in diabetic patients. Effective therapies to prevent the development of this disease are required. Berberine (BBR) has several preventive effects on diabetes and its complications. However, the molecular mechanism of BBR on kidney function in diabetes is not well defined. Here, we reported that activation of AMP-activated protein kinase (AMPK) is required for BBR-induced improvement of kidney function in vivo. AMPK phosphorylation and activity, productions of reactive oxygen species (ROS), kidney function including serum blood urea nitrogen (BUN), creatinine clearance (Ccr), and urinary protein excretion, morphology of glomerulus were determined in vitro or in vivo. Exposure of cultured human glomerulus mesangial cells (HGMCs) to BBR time- or dose-dependently activates AMPK by increasing the thr172 phosphorylation and its activities. Inhibition of LKB1 by siRNA or mutant abolished BBR-induced AMPK activation. Incubation of cells with high glucose (HG, 30 mM) markedly induced the oxidative stress of HGMCs, which were abolished by 5-aminoimidazole-4-carboxamide ribonucleoside, AMPK gene overexpression or BBR. Importantly, the effects induced by BBR were bypassed by AMPK siRNA transfection in HG-treated HGMCs. In animal studies, streptozotocin-induced hyperglycemia dramatically promoted glomerulosclerosis and impaired kidney function by increasing serum BUN, urinary protein excretion, and decreasing Ccr, as well as increased oxidative stress. Administration of BBR remarkably improved kidney function in wildtype mice but not in AMPKα2-deficient mice. We conclude that AMPK activation is required for BBR to improve kidney function in diabetic mice. PMID:25409232

  2. Gynura procumbens Extract Alleviates Postprandial Hyperglycemia in Diabetic Mice

    PubMed Central

    Choi, Sung-In; Park, Mi Hwa; Han, Ji-Sook

    2016-01-01

    This study was designed to investigate the inhibitory effect of Gynura procumbens extract against carbohydrate digesting enzymes and its ability to ameliorate postprandial hyperglycemia in streptozotocin (STZ)-induced diabetic mice. G. procumbens extract showed prominent α-glucosidase and α-amylase inhibitory effects. The half-maximal inhibitory concentration (IC50) of G. procumbens extract against α-glucosidase and α-amylase was 0.092±0.018 and 0.084±0.027 mg/mL, respectively, suggesting that the α-amylase inhibition activity of the G. procumbens extract was more effective than that of the positive control, acarbose (IC50=0.164 mg/mL). The increase in postprandial blood glucose levels was more significantly alleviated in the G. procumbens extract group than in the control group of STZ-induced diabetic mice. Moreover, the area under the curve significantly decreased with G. procumbens extract administration in STZ-induced diabetic mice. These results suggest that G. procumbens extract may help alleviate postprandial hyperglycemia by inhibiting carbohydrate digesting enzymes. PMID:27752493

  3. A novel quantitative method for diabetic cardiac autonomic neuropathy assessment in type 1 diabetic mice.

    PubMed

    Chon, Ki H; Yang, Bufan; Posada-Quintero, Hugo F; Siu, Kin L; Rolle, Marsha; Brink, Peter; Birzgalis, Aija; Moore, Leon C

    2014-11-01

    In this work, we used a sensitive and noninvasive computational method to assess diabetic cardiovascular autonomic neuropathy (DCAN) from pulse oximeter (photoplethysmographic; PPG) recordings from mice. The method, which could be easily applied to humans, is based on principal dynamic mode (PDM) analysis of heart rate variability (HRV). Unlike the power spectral density, PDM has been shown to be able to separately identify the activities of the parasympathetic and sympathetic nervous systems without pharmacological intervention. HRV parameters were measured by processing PPG signals from conscious 1.5- to 5-month-old C57/BL6 control mice and in Akita mice, a model of insulin-dependent type 1 diabetes, and compared with the gold-standard Western blot and immunohistochemical analyses. The PDM results indicate significant cardiac autonomic impairment in the diabetic mice in comparison to the controls. When tail-cuff PPG recordings were collected and analyzed starting from 1.5 months of age in both C57/Bl6 controls and Akita mice, onset of DCAN was seen at 3 months in the Akita mice, which persisted up to the termination of the recording at 5 months. Western blot and immunohistochemical analyses also showed a reduction in nerve density in Akita mice at 3 and 4 months as compared to the control mice, thus, corroborating our PDM data analysis of HRV records. Western blot analysis of autonomic nerve proteins corroborated the PPG-based HRV analysis via the PDM approach. In contrast, traditional HRV analysis (based on either the power spectral density or time-domain measures) failed to detect the nerve rarefaction.

  4. Insulin-tumour interrelationship in EL4 lymphoma or thymoma-bearing mice. I. Alloxan-diabetic or non-diabetic mice.

    PubMed Central

    Yam, D.; Zilberstein, A.; Fink, A.; Nir, I.

    1990-01-01

    A study has been carried out in which a comparison was made between EL4 lymphoma (assumed to be an insulin-producing secreting tumour) and thymoma (an insulin-dependent tumour). Tumour development and incidence, 3H-thymidine incorporation and insulin content in tumours, the host's food intake, blood insulin, glucose and cholesterol were determined in non-diabetic and alloxan-diabetic mice. Whereas no significant differences were observed between the diabetic and non-diabetic EL4 tumour-bearing mice, the diabetic, thymoma tumour-bearing mice showed reduced tumour growth and lower tumour incidence as compared with their non-diabetic counterparts. Insulin administration to diabetic tumour bearing mice, enhanced 3H-thymidine incorporation in the thymoma tumour cells only, and the insulin content of the EL4 tumours was found to be higher than that of the thymoma tumours. Rapid diabetes remission was observed in the diabetic, EL4 tumour-bearing mice as compared with the thymoma tumour-bearing mice. PMID:2186773

  5. Protective role of adenovirus vector-mediated interleukin-10 gene therapy on endogenous islet β-cells in recent-onset type 1 diabetes in NOD mice

    PubMed Central

    LI, CHENG; ZHANG, LIJUAN; CHEN, YANYAN; LIN, XIAOJIE; LI, TANG

    2016-01-01

    The aim of the present study was to provide an animal experimental basis for the protective effect of the adenoviral vector-mediated interleukin-10 (Ad-mIL-10) gene on islet β-cells during the early stages of type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. A total of 24 female NOD mice at the onset of diabetes were allocated at random into three groups (n=8 per group): Group 1, intraperitoneally injected with 0.1 ml Ad-mIL-10; group 2, intraperitoneally injected with 0.1 ml adenovirus vector; and group 3, was a diabetic control. In addition to groups 1, 2 and 3, 8 age- and gender-matched NOD mice were intraperitoneally injected with 0.1 ml PBS and assigned to group 4 as a normal control. All mice were examined weekly for body weight, urine glucose and blood glucose values prior to onset of diabetes, and at 1, 2 and 3 weeks after that, and all mice were sacrificed 3 weeks after injection. Serum levels of interleukin (IL)-10, interferon (IFN)-γ, IL-4, insulin and C-peptide were evaluated, and in addition the degree of insulitis and the local expression of IL-10 gene in the pancreas were detected. The apoptosis rate of pancreatic β-cells was determined using a TUNEL assay. Compared with groups 2 and 3, IL-10 levels in the serum and pancreas were elevated in group 1. Serum IFN-γ levels were decreased while serum IL-4 levels and IFN-γ/IL-4 ratio were significantly increased in group 1 (P<0.01). C-peptide and insulin levels were higher in group 1 compared with groups 2 and 3, (P<0.01). Furthermore, compared with groups 2 and 3, the degree of insulitis, islet β-cell apoptosis rate and blood glucose values did not change significantly (P>0.05). The administration of the Ad-mIL-10 gene induced limited immune regulatory and protective effects on islet β-cell function in NOD mice with early T1D, while no significant reduction in insulitis, islet β-cell apoptosis rate and blood glucose was observed. PMID:27168782

  6. Piceatannol lowers the blood glucose level in diabetic mice.

    PubMed

    Uchida-Maruki, Hiroko; Inagaki, Hiroyuki; Ito, Ryouichi; Kurita, Ikuko; Sai, Masahiko; Ito, Tatsuhiko

    2015-01-01

    We previously found that passion fruit (Passiflora edulis) seeds contained a high amount of piceatannol (3,5,3',4'-trans-tetrahydroxystilbene), a natural analog of resveratrol (3,5,4'-trans-trihydroxystilbene). Resveratrol has been proposed as a potential anti-metabolic disorder compound, by its activation of sirtuin and AMP-activated protein kinase. Many reports show that resveratrol ameliorates diet-induced obesity and insulin resistance. However, it is not known whether piceatannol also affects diet-induced obesity. We explored the effect of piceatannol on high fat diet-fed mice. The results showed that piceatannol did not affect high fat diet-induced body weight gain or visceral fat gain in mice. However, piceatannol did reduce fasting blood glucose levels. Furthermore, to explore the potential of passion fruit seed extract containing piceatannol as a functional food, passion fruit seed extract was administered in a genetic diabetic mouse model (db/db mice). Single administration of passion fruit seed extract, as well as piceatannol reduced the blood glucose levels of these db/db mice. These results suggest that piceatannol and passion fruit seed extract may have potential application in the prevention of diabetes. PMID:25832644

  7. Obesity and diabetes in TNF-alpha receptor- deficient mice.

    PubMed Central

    Schreyer, S A; Chua, S C; LeBoeuf, R C

    1998-01-01

    TNF-alpha may play a role in mediating insulin resistance associated with obesity. This concept is based on studies of obese rodents and humans, and cell culture models. TNF elicits cellular responses via two receptors called p55 and p75. Our purpose was to test the involvement of TNF in glucose homeostasis using mice lacking one or both TNF receptors. C57BL/6 mice lacking p55 (p55(-)/-), p75, (p75(-)/-), or both receptors (p55(-)/-p75(-)/-) were fed a high-fat diet to induce obesity. Marked fasting hyperinsulinemia was seen for p55(-)/-p75(-)/- males between 12 and 16 wk of feeding the high-fat diet. Insulin levels were four times greater than wild-type mice. In contrast, p55(-)/- and p75(-)/- mice exhibited insulin levels that were similar or reduced, respectively, as compared with wild-type mice. In addition, high-fat diet-fed p75(-)/- mice had the lowest body weights and leptin levels, and improved insulin sensitivity. Obese (db/db) mice, which are not responsive to leptin, were used to study the role of p55 in severe obesity. Male p55(-)/-db/db mice exhibited threefold higher insulin levels and twofold lower glucose levels at 20 wk of age than control db/db expressing p55. All db/db mice remained severely insulin resistant based on fasting plasma glucose and insulin levels, and glucose and insulin tolerance tests. Our data do not support the concept that TNF, acting via its receptors, is a major contributor to obesity-associated insulin resistance. In fact, data suggest that the two TNF receptors work in concert to protect against diabetes. PMID:9664082

  8. Differential Expression of Long Noncoding RNAs between Sperm Samples from Diabetic and Non-Diabetic Mice.

    PubMed

    Jiang, Guang-Jian; Zhang, Teng; An, Tian; Zhao, Dan-Dan; Yang, Xiu-Yan; Zhang, Dong-Wei; Zhang, Yi; Mu, Qian-Qian; Yu, Na; Ma, Xue-Shan; Gao, Si-Hua

    2016-01-01

    To investigate the potential core reproduction-related genes associated with the development of diabetes, the expression profiles of long noncoding RNA (lncRNA) and messenger RNA (mRNA) in the sperm of diabetic mice were studied. We used microarray analysis to detect the expression of lncRNAs and coding transcripts in six diabetic and six normal sperm samples, and differentially expressed lncRNAs and mRNAs were identified through Volcano Plot filtering. The function of differentially expressed mRNA was determined by pathway and gene ontology (GO) analysis, and the function of lncRNAs was studied by subgroup analysis and their physical or functional relationships with corresponding mRNAs. A total of 7721 lncRNAs and 6097 mRNAs were found to be differentially expressed between the diabetic and normal sperm groups. The diabetic sperm exhibited aberrant expression profiles for lncRNAs and mRNAs, and GO and pathway analyses showed that the functions of differentially expressed mRNAs were closely related with many processes involved in the development of diabetes. Furthermore, potential core genes that might play important roles in the pathogenesis of diabetes-related low fertility were revealed by lncRNA- and mRNA-interaction studies, as well as coding-noncoding gene co-expression analysis based on the microarray expression profiles. PMID:27119337

  9. Differential Expression of Long Noncoding RNAs between Sperm Samples from Diabetic and Non-Diabetic Mice

    PubMed Central

    An, Tian; Zhao, Dan-Dan; Yang, Xiu-Yan; Zhang, Dong-Wei; Zhang, Yi; Mu, Qian-Qian; Yu, Na; Ma, Xue-Shan; Gao, Si-Hua

    2016-01-01

    To investigate the potential core reproduction-related genes associated with the development of diabetes, the expression profiles of long noncoding RNA (lncRNA) and messenger RNA (mRNA) in the sperm of diabetic mice were studied. We used microarray analysis to detect the expression of lncRNAs and coding transcripts in six diabetic and six normal sperm samples, and differentially expressed lncRNAs and mRNAs were identified through Volcano Plot filtering. The function of differentially expressed mRNA was determined by pathway and gene ontology (GO) analysis, and the function of lncRNAs was studied by subgroup analysis and their physical or functional relationships with corresponding mRNAs. A total of 7721 lncRNAs and 6097 mRNAs were found to be differentially expressed between the diabetic and normal sperm groups. The diabetic sperm exhibited aberrant expression profiles for lncRNAs and mRNAs, and GO and pathway analyses showed that the functions of differentially expressed mRNAs were closely related with many processes involved in the development of diabetes. Furthermore, potential core genes that might play important roles in the pathogenesis of diabetes-related low fertility were revealed by lncRNA- and mRNA-interaction studies, as well as coding-noncoding gene co-expression analysis based on the microarray expression profiles. PMID:27119337

  10. Galantamine Attenuates Type 1 Diabetes and Inhibits Anti-Insulin Antibodies in Nonobese Diabetic Mice

    PubMed Central

    Hanes, William M; Olofsson, Peder S; Kwan, Kevin; Hudson, LaQueta K; Chavan, Sangeeta S; Pavlov, Valentin A; Tracey, Kevin J

    2015-01-01

    Type 1 diabetes in mice is characterized by autoimmune destruction of insulin-producing pancreatic β-cells. Disease pathogenesis involves invasion of pancreatic islets by immune cells, including macrophages and T cells, and production of antibodies to self-antigens, including insulin. Activation of the inflammatory reflex, the neural circuit that inhibits inflammation, culminates on cholinergic receptor signals on immune cells to attenuate cytokine release and inhibit B-cell antibody production. Here, we show that galantamine, a centrally acting acetylcholinesterase inhibitor and an activator of the inflammatory reflex, attenuates murine experimental type 1 diabetes. Administration of galantamine to animals immunized with keyhole limpet hemocyanin (KLH) significantly suppressed splenocyte release of immunoglobulin G (IgG) and interleukin (IL)-4 and IL-6 during KLH challenge ex vivo. Administration of galantamine beginning at 1 month of age in nonobese diabetic (NOD) mice significantly delayed the onset of hyperglycemia, attenuated immune cell infiltration in pancreatic islets and decreased anti-insulin antibodies in serum. These observations indicate that galantamine attenuates experimental type 1 diabetes in mice and suggest that activation of the inflammatory reflex should be further studied as a potential therapeutic approach. PMID:26322849

  11. Impaired response of mature adipocytes of diabetic mice to hypoxia

    SciTech Connect

    Hong, Seok Jong Jin, Da P.; Buck, Donald W.; Galiano, Robert D.; Mustoe, Thomas A.

    2011-10-01

    Adipose tissue contains various cells such as infiltrated monocytes/macrophages, endothelial cells, preadipocytes, and adipocytes. Adipocytes have an endocrine function by secreting adipokines such as interleukin (IL)-6, tumor necrosis factor (TNF)-{alpha}, leptin, and adiponectin. Dysregulation of adipokines in adipose tissues leads to a chronic low-grade inflammation which could result in atherosclerosis, hypertension, and type 2 diabetes. A sustained inflammatory state, which is characterized by prolonged persistence of macrophages and neutrophils, is found in diabetic wounds. In addition, subcutaneous adipocytes are enormously increased in amount clinically in type 2 diabetes. However, the function of subcutaneous adipocytes, which play an important role in injured tissue subjected to hypoxia, has not been well characterized in vitro due to the difficulty of maintaining mature adipocytes in culture using conventional methods because of their buoyancy. In this study, we established a novel in vitro culture method of mature adipocytes by enclosing them in a hyaluronan (HA) based hydrogel to study their role in response to stress such as hypoxia. BrdU labeling and Ki67 immunostaining experiments showed that hydrogel enclosed mature adipocytes proliferate in vitro. Both mRNA and protein expression analyses for hypoxia regulated genes, such as vascular endothelial growth factor (VEGF) and heme oxygenase 1 (HO1), showed that mature adipocytes of wild type mice respond to hypoxia. In contrast, mature adipocytes of diabetic db/db and TallyHo mice did not efficiently respond to hypoxia. Our studies suggest that mature adipocytes are functionally active cells, and their abnormal function to hypoxia can be one of underlining mechanisms in type 2 diabetes.

  12. HoxD3 accelerates wound healing in diabetic mice

    SciTech Connect

    Hansen, Scott L.; Myers, Connie A.; Charboneau, Aubri; Young, David M.; and Boudreau, Nancy

    2003-12-01

    Poorly healing diabetic wounds are characterized by diminished collagen production and impaired angiogenesis. HoxD3, a homeobox transcription factor that promotes angiogenesis and collagen synthesis, is up-regulated during normal wound repair whereas its expression is diminished in poorly healing wounds of the genetically diabetic (db/db) mouse. To determine whether restoring expression of HoxD3 would accelerate diabetic wound healing, we devised a novel method of gene transfer, which incorporates HoxD3 plasmid DNA into a methylcellulose film that is placed on wounds created on db/db mice. The HoxD3 transgene was expressed in endothelial cells, fibroblasts, and keratinocytes of the wounds for up to 10 days. More importantly, a single application of HoxD3 to db/db mice resulted in a statistically significant acceleration of wound closure compared to control-treated wounds. Furthermore, we also observed that the HoxD3-mediated improvement in diabetic wound repair was accompanied by increases in mRNA expression of the HoxD3 target genes, Col1A1 and beta 3-integrin leading to enhanced angiogenesis and collagen deposition in the wounds. Although HoxD3-treated wounds also show improved re-epithelialization as compared to control db/db wounds, this effect was not due to direct stimulation of keratinocyte migration by HoxD3. Finally, we show that despite the dramatic increase in collagen synthesis and deposition in HoxD3-treated wounds, these wounds showed normal remodeling and we found no evidence of abnormal wound healing. These results indicate that HoxD3 may provide a means to directly improve collagen deposition, angiogenesis and closure in poorly healing diabetic wounds.

  13. Petalonia improves glucose homeostasis in streptozotocin-induced diabetic mice

    SciTech Connect

    Kang, Seong-Il; Jin, Young-Jun; Ko, Hee-Chul; Choi, Soo-Youn; Hwang, Joon-Ho; Whang, Ilson; Kim, Moo-Han; Shin, Hye-Sun; Jeong, Hyung-Bok; Kim, Se-Jae

    2008-08-22

    The anti-diabetic potential of Petalonia binghamiae extract (PBE) was evaluated in vivo. Dietary administration of PBE to streptozotocin (STZ)-induced diabetic mice significantly lowered blood glucose levels and improved glucose tolerance. The mode of action by which PBE attenuated diabetes was investigated in vitro using 3T3-L1 cells. PBE treatment stimulated 3T3-L1 adipocyte differentiation as evidenced by increased triglyceride accumulation. At the molecular level, peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) and terminal marker protein aP2, as well as the mRNA of GLUT4 were up-regulated by PBE. In mature adipocytes, PBE significantly stimulated the uptake of glucose and the expression of insulin receptor substrate-1 (IRS-1). Furthermore, PBE increased PPAR{gamma} luciferase reporter gene activity in COS-1 cells. Taken together, these results suggest that the in vivo anti-diabetic effect of PBE is mediated by both insulin-like and insulin-sensitizing actions in adipocytes.

  14. Increased Inner Ear Susceptibility to Noise Injury in Mice With Streptozotocin-Induced Diabetes

    PubMed Central

    Fujita, Takeshi; Yamashita, Daisuke; Katsunuma, Sayaka; Hasegawa, Shingo; Tanimoto, Hitoshi; Nibu, Ken-ichi

    2012-01-01

    We aimed to investigate the pathophysiology of diabetes-associated hearing impairment in type 1 diabetes using mice with streptozotocin-induced diabetes (C57BL/6J; male). Hearing function was evaluated 1, 3, and 5 months after induction of diabetes (five diabetic and five control animals per time point) using auditory-evoked brain stem responses (ABRs). Mice (four diabetic and four control) were exposed to loud noise (105 dB) 5 months after induction of diabetes. ABRs were measured before and after noise exposure. Cochlear blood flows were measured by laser-Doppler flowmeter. Spiral ganglion cells (SGCs) were counted. Vessel endothelial cells were observed by CD31 immunostaining. Chronologic changes in the ABR threshold shift were not significantly different between the diabetic and control groups. However, vessel walls in the modiolus of the cochleae were significantly thicker in the diabetic group than the control group. Additionally, recovery from noise-induced injury was significantly impaired in diabetic mice. Reduced cochlea blood flows and SGC loss were observed in diabetic mice cochleae after noise exposure. Our data suggest that diabetic cochleae are more susceptible than controls to loud noise exposure, and decreased cochlear blood flow due to sclerosis of the vessels and consequent loss of SGCs are possible mechanisms of hearing impairment in diabetic patients. PMID:22851574

  15. The dual role of scavenger receptor class A in development of diabetes in autoimmune NOD mice.

    PubMed

    Shimizu, Mami; Yasuda, Hisafumi; Hara, Kenta; Takahashi, Kazuma; Nagata, Masao; Yokono, Koichi

    2014-01-01

    Human type 1 diabetes is an autoimmune disease that results from the autoreactive destruction of pancreatic β cells by T cells. Antigen presenting cells including dendritic cells and macrophages are required to activate and suppress antigen-specific T cells. It has been suggested that antigen uptake from live cells by dendritic cells via scavenger receptor class A (SR-A) may be important. However, the role of SR-A in autoimmune disease is unknown. In this study, SR-A-/- nonobese diabetic (NOD) mice showed significant attenuation of insulitis, lower levels of insulin autoantibodies, and suppression of diabetes development compared with NOD mice. We also found that diabetes progression in SR-A-/- NOD mice treated with low-dose polyinosinic-polycytidylic acid (poly(I:C)) was significantly accelerated compared with that in disease-resistant NOD mice treated with low-dose poly(I:C). In addition, injection of high-dose poly(I: C) to mimic an acute RNA virus infection significantly accelerated diabetes development in young SR-A-/- NOD mice compared with untreated SR-A-/- NOD mice. Pathogenic cells including CD4+CD25+ activated T cells were increased more in SR-A-/- NOD mice treated with poly(I:C) than in untreated SR-A-/- NOD mice. These results suggested that viral infection might accelerate diabetes development even in diabetes-resistant subjects. In conclusion, our studies demonstrated that diabetes progression was suppressed in SR-A-/- NOD mice and that acceleration of diabetes development could be induced in young mice by poly(I:C) treatment even in SR-A-/- NOD mice. These results suggest that SR-A on antigen presenting cells such as dendritic cells may play an unfavorable role in the steady state and a protective role in a mild infection. Our findings imply that SR-A may be an important target for improving therapeutic strategies for type 1 diabetes. PMID:25343451

  16. Hyperglycemia and fight-flight behavior in nondiabetic and diabetic mice.

    PubMed

    Meehan, W P; Leedom, L J; Nagayama, T; Zeidler, A

    1987-01-01

    Glycemic responses to a resident-intruder encounter and to the drawing of blood from the retro-orbital sinus were studied in diabetic and normal male Swiss Webster mice. The diabetes induced with streptozotocin was either borderline, overt, or severe. The resident-intruder encounter consisted of a brief exposure to another male mouse trained to be aggressive. The blood collected was not sufficient (3% blood volume) to cause significant volume depletion. Behavior during the resident-intruder encounter was videotaped and later quantified. Borderline diabetic, overtly diabetic and nondiabetic mice responded to both procedures with significant increases in plasma glucose. The glycemic response to the resident-intruder encounter in these groups was significantly greater than that to the bleeding trial. The severely diabetic mice did not experience increases in plasma glucose in either test. Fight-flight behavior of nondiabetic mice was significantly correlated with increases in plasma glucose. Total activity was negatively correlated with change in plasma glucose in the borderline diabetic mice. In overtly diabetic mice no relationship between either measure and glucose increases was observed. These results indicate that plasma glucose elevation in overtly and severely diabetic mice is not as specific to behavior as in nondiabetic mice.

  17. Improvement of skin wound healing in diabetic mice by kinin B2 receptor blockade.

    PubMed

    Desposito, Dorinne; Chollet, Catherine; Taveau, Christopher; Descamps, Vincent; Alhenc-Gelas, François; Roussel, Ronan; Bouby, Nadine; Waeckel, Ludovic

    2016-01-01

    Impaired skin wound healing is a major medical problem in diabetic subjects. Kinins exert a number of vascular and other actions limiting organ damage in ischaemia or diabetes, but their role in skin injury is unknown. We investigated, through pharmacological manipulation of bradykinin B1 and B2 receptors (B1R and B2R respectively), the role of kinins in wound healing in non-diabetic and diabetic mice. Using two mouse models of diabetes (streptozotocin-induced and db/db mice) and non-diabetic mice, we assessed the effect of kinin receptor activation or inhibition by subtype-selective pharmacological agonists (B1R and B2R) and antagonist (B2R) on healing of experimental skin wounds. We also studied effects of agonists and antagonist on keratinocytes and fibroblasts in vitro. Levels of Bdkrb1 (encoding B1R) and Bdkrb2 (encoding B2R) mRNAs increased 1-2-fold in healthy and wounded diabetic skin compared with in non-diabetic skin. Diabetes delayed wound healing. The B1R agonist had no effect on wound healing. In contrast, the B2R agonist impaired wound repair in both non-diabetic and diabetic mice, inducing skin disorganization and epidermis thickening. In vitro, B2R activation unbalanced fibroblast/keratinocyte proliferation and increased keratinocyte migration. These effects were abolished by co-administration of B2R antagonist. Interestingly, in the two mouse models of diabetes, the B2R antagonist administered alone normalized wound healing. This effect was associated with the induction of Ccl2 (encoding monocyte chemoattractant protein 1)/Tnf (encoding tumour necrosis factor α) mRNAs. Thus stimulation of kinin B2 receptor impairs skin wound healing in mice. B2R activation occurs in the diabetic skin and delays wound healing. B2R blockade improves skin wound healing in diabetic mice and is a potential therapeutic approach to diabetic ulcers.

  18. Cardiac H2S Generation Is Reduced in Ageing Diabetic Mice.

    PubMed

    Jin, Sheng; Pu, Shi-Xin; Hou, Cui-Lan; Ma, Fen-Fen; Li, Na; Li, Xing-Hui; Tan, Bo; Tao, Bei-Bei; Wang, Ming-Jie; Zhu, Yi-Chun

    2015-01-01

    Aims. To examine whether hydrogen sulfide (H2S) generation changed in ageing diabetic mouse hearts. Results. Compared to mice that were fed tap water only, mice that were fed 30% fructose solution for 15 months exhibited typical characteristics of a severe diabetic phenotype with cardiac hypertrophy, fibrosis, and dysfunction. H2S levels in plasma, heart tissues, and urine were significantly reduced in these mice as compared to those in controls. The expression of the H2S-generating enzymes, cystathionine γ-lyase and 3-mercaptopyruvate sulfurtransferase, was significantly decreased in the hearts of fructose-fed mice, whereas cystathionine-β-synthase levels were significantly increased. Conclusion. Our results suggest that this ageing diabetic mouse model developed diabetic cardiomyopathy and that H2S levels were reduced in the diabetic heart due to alterations in three H2S-producing enzymes, which may be involved in the pathogenesis of diabetic cardiomyopathy. PMID:26078817

  19. Cardiac H2S Generation Is Reduced in Ageing Diabetic Mice

    PubMed Central

    Jin, Sheng; Pu, Shi-Xin; Hou, Cui-Lan; Ma, Fen-Fen; Li, Na; Li, Xing-Hui; Tan, Bo; Tao, Bei-Bei; Wang, Ming-Jie; Zhu, Yi-Chun

    2015-01-01

    Aims. To examine whether hydrogen sulfide (H2S) generation changed in ageing diabetic mouse hearts. Results. Compared to mice that were fed tap water only, mice that were fed 30% fructose solution for 15 months exhibited typical characteristics of a severe diabetic phenotype with cardiac hypertrophy, fibrosis, and dysfunction. H2S levels in plasma, heart tissues, and urine were significantly reduced in these mice as compared to those in controls. The expression of the H2S-generating enzymes, cystathionine γ-lyase and 3-mercaptopyruvate sulfurtransferase, was significantly decreased in the hearts of fructose-fed mice, whereas cystathionine-β-synthase levels were significantly increased. Conclusion. Our results suggest that this ageing diabetic mouse model developed diabetic cardiomyopathy and that H2S levels were reduced in the diabetic heart due to alterations in three H2S-producing enzymes, which may be involved in the pathogenesis of diabetic cardiomyopathy. PMID:26078817

  20. Anti-diabetic activity of peony seed oil, a new resource food in STZ-induced diabetic mice.

    PubMed

    Su, Jianhui; Wang, Hongxin; Ma, Caoyang; Lou, Zaixiang; Liu, Chengxiang; Tanver Rahman, MdRamim; Gao, Chuanzhong; Nie, Rongjing

    2015-09-01

    This study was conducted to investigate the components of a new resource food in China, peony seed oil (PSO) by GC-MS (gas chromatography-mass spectrometry), its inhibitory effects on carbohydrate hydrolyzing enzymes in vitro and its anti-diabetic effects on mice induced by streptozotocin (STZ). The results showed that peony seed oil showed weak anti-α-amylase activity; however, strong anti-α-glucosidase activity was noted. The GC-MS analysis of the oil showed 9 constituents of which α-linolenic acid was found to be the major component (38.66%), followed by linoleic acid (26.34%) and oleic acid (23.65%). The anti-diabetic potential of peony seed oil was tested in STZ induced diabetic mice. Administration of peony seed oil and glibenclamide reduced the blood glucose level and the area under curve (AUC) in STZ induced diabetic mice. There were significant increases in body weight, liver glycogen content, serum insulin level, high-density lipoprotein cholesterol (HDL-C) and decreases in glycosylated hemoglobin (HbA1C), total serum cholesterol (TC), and triglyceride (TG) in test groups as compared to the untreated diabetic groups. In vivo antioxidant studies on STZ induced diabetic mice revealed the reduction of malondialdehyde (MDA) and increase of glutathione peroxides (GSH-px), superoxide dismutase (SOD), and glutathione (GSH). The results provided a sound rationale for future clinical trials of oral administration of peony seed oil to alleviate postprandial hyperglycemia in streptozotocin-induced diabetic mice.

  1. Phenotypic Changes in Diabetic Neuropathy Induced by a High-Fat Diet in Diabetic C57Bl/6 Mice

    PubMed Central

    Guilford, B. L.; Ryals, J. M.; Wright, D. E.

    2011-01-01

    Emerging evidence suggests that dyslipidemia is an independent risk factor for diabetic neuropathy (DN) (reviewed by Vincent et al. 2009). To experimentally determine how dyslipidemia alters DN, we quantified neuropathic symptoms in diabetic mice fed a high-fat diet. Streptozotocin-induced diabetic C57BL/6 mice fed a high-fat diet developed dyslipidemia and a painful neuropathy (mechanical allodynia) instead of the insensate neuropathy (mechanical insensitivity) that normally develops in this strain. Nondiabetic mice fed a high-fat diet also developed dyslipidemia and mechanical allodynia. Thermal sensitivity was significantly reduced in diabetic compared to nondiabetic mice, but was not worsened by the high-fat diet. Moreover, diabetic mice fed a high-fat diet had significantly slower sensory and motor nerve conduction velocities compared to nondiabetic mice. Overall, dyslipidemia resulting from a high-fat diet may modify DN phenotypes and/or increase risk for developing DN. These results provide new insight as to how dyslipidemia may alter the development and phenotype of diabetic neuropathy. PMID:22144990

  2. Generating double knockout mice to model genetic intervention for diabetic cardiomyopathy in humans.

    PubMed

    Chavali, Vishalakshi; Nandi, Shyam Sundar; Singh, Shree Ram; Mishra, Paras Kumar

    2014-01-01

    Diabetes is a rapidly increasing disease that enhances the chances of heart failure twofold to fourfold (as compared to age and sex matched nondiabetics) and becomes a leading cause of morbidity and mortality. There are two broad classifications of diabetes: type1 diabetes (T1D) and type2 diabetes (T2D). Several mice models mimic both T1D and T2D in humans. However, the genetic intervention to ameliorate diabetic cardiomyopathy in these mice often requires creating double knockout (DKO). In order to assess the therapeutic potential of a gene, that specific gene is either overexpressed (transgenic expression) or abrogated (knockout) in the diabetic mice. If the genetic mice model for diabetes is used, it is necessary to create DKO with transgenic/knockout of the target gene to investigate the specific role of that gene in pathological cardiac remodeling in diabetics. One of the important genes involved in extracellular matrix (ECM) remodeling in diabetes is matrix metalloproteinase-9 (Mmp9). Mmp9 is a collagenase that remains latent in healthy hearts but induced in diabetic hearts. Activated Mmp9 degrades extracellular matrix (ECM) and increases matrix turnover causing cardiac fibrosis that leads to heart failure. Insulin2 mutant (Ins2+/-) Akita is a genetic model for T1D that becomes diabetic spontaneously at the age of 3-4 weeks and show robust hyperglycemia at the age of 10-12 weeks. It is a chronic model of T1D. In Ins2+/- Akita, Mmp9 is induced. To investigate the specific role of Mmp9 in diabetic hearts, it is necessary to create diabetic mice where Mmp9 gene is deleted. Here, we describe the method to generate Ins2+/-/Mmp9-/- (DKO) mice to determine whether the abrogation of Mmp9 ameliorates diabetic cardiomyopathy. PMID:25064116

  3. Generating double knockout mice to model genetic intervention for diabetic cardiomyopathy in humans.

    PubMed

    Chavali, Vishalakshi; Nandi, Shyam Sundar; Singh, Shree Ram; Mishra, Paras Kumar

    2014-01-01

    Diabetes is a rapidly increasing disease that enhances the chances of heart failure twofold to fourfold (as compared to age and sex matched nondiabetics) and becomes a leading cause of morbidity and mortality. There are two broad classifications of diabetes: type1 diabetes (T1D) and type2 diabetes (T2D). Several mice models mimic both T1D and T2D in humans. However, the genetic intervention to ameliorate diabetic cardiomyopathy in these mice often requires creating double knockout (DKO). In order to assess the therapeutic potential of a gene, that specific gene is either overexpressed (transgenic expression) or abrogated (knockout) in the diabetic mice. If the genetic mice model for diabetes is used, it is necessary to create DKO with transgenic/knockout of the target gene to investigate the specific role of that gene in pathological cardiac remodeling in diabetics. One of the important genes involved in extracellular matrix (ECM) remodeling in diabetes is matrix metalloproteinase-9 (Mmp9). Mmp9 is a collagenase that remains latent in healthy hearts but induced in diabetic hearts. Activated Mmp9 degrades extracellular matrix (ECM) and increases matrix turnover causing cardiac fibrosis that leads to heart failure. Insulin2 mutant (Ins2+/-) Akita is a genetic model for T1D that becomes diabetic spontaneously at the age of 3-4 weeks and show robust hyperglycemia at the age of 10-12 weeks. It is a chronic model of T1D. In Ins2+/- Akita, Mmp9 is induced. To investigate the specific role of Mmp9 in diabetic hearts, it is necessary to create diabetic mice where Mmp9 gene is deleted. Here, we describe the method to generate Ins2+/-/Mmp9-/- (DKO) mice to determine whether the abrogation of Mmp9 ameliorates diabetic cardiomyopathy.

  4. Autophagy ameliorates cognitive impairment through activation of PVT1 and apoptosis in diabetes mice.

    PubMed

    Li, Zhigui; Hao, Shuang; Yin, Hongqiang; Gao, Jing; Yang, Zhuo

    2016-05-15

    The underlying mechanisms of cognitive impairment in diabetes remain incompletely characterized. Here we show that the autophagic inhibition by 3-methyladenine (3-MA) aggravates cognitive impairment in streptozotocin-induced diabetic mice, including exacerbation of anxiety-like behaviors and aggravation in spatial learning and memory, especially the spatial reversal memory. Further neuronal function identification confirmed that both long term potentiation (LTP) and depotentiation (DPT) were exacerbated by autophagic inhibition in diabetic mice, which indicating impairment of synaptic plasticity. However, no significant change of pair-pulse facilitation (PPF) was recorded in diabetic mice with autophagic suppression compared with the diabetic mice, which indicated that presynaptic function was not affected by autophagic inhibition in diabetes. Subsequent hippocampal neuronal cell death analysis showed that the apoptotic cell death, but not the regulated necrosis, significantly increased in autophagic suppression of diabetic mice. Finally, molecular mechanism that may lead to cell death was identified. The long non-coding RNA PVT1 (plasmacytoma variant translocation 1) expression was analyzed, and data revealed that PVT1 was decreased significantly by 3-MA in diabetes. These findings show that PVT1-mediated autophagy may protect hippocampal neurons from impairment of synaptic plasticity and apoptosis, and then ameliorates cognitive impairment in diabetes. These intriguing findings will help pave the way for exciting functional studies of autophagy in cognitive impairment and diabetes that may alter the existing paradigms. PMID:26971628

  5. Protective effect of esculin on streptozotocin-induced diabetic renal damage in mice.

    PubMed

    Kang, Ki Sung; Lee, Woojung; Jung, Yujung; Lee, Ji Hwan; Lee, Seungyong; Eom, Dae-Woon; Jeon, Youngsic; Yoo, Hye Hyun; Jin, Ming Ji; Song, Kyung Il; Kim, Won Jun; Ham, Jungyeob; Kim, Hyoung Ja; Kim, Su-Nam

    2014-03-01

    The present study investigated the presence and mechanism of esculin-mediated renoprotection to assess its therapeutic potential. Esculin was orally administered at 20 mg/kg/day for 2 weeks to streptozotocin-induced diabetic mice, and its effects were compared with those of the vehicle in normal and diabetic mice. After oral administration of esculin to mice, the concentrations of esculin and esculetin in blood were 159.5 ± 29.8 and 9.7 ± 4.9 ng/mL at 30 min, respectively. Food and water intake were significantly increased in the diabetic mice compared to normal mice but attenuated in mice receiving esculin. The elevated blood glucose level and hepatic glucose-6-phosphatase expression were significantly reduced in esculin-treated diabetic mice, supporting the antidiabetic effect of esculin. Esculin also increased the uptake of glucose and induced the insulin-evoked phosphorylation of insulin receptor, Akt, and glycogen synthase kinase 3β in C2C12 myotubes, indicating a potential for improvement of insulin sensitivity. In addition, esculin lessened the elevated blood creatinine levels in diabetic mice and ameliorated diabetes-induced renal dysfunction by reducing caspase-3 activation in the kidney. Data support the beneficial effect of esculin against diabetes and oxidative stress-related inflammatory processes in the kidney.

  6. Lactobacillus salivarius reverse diabetes-induced intestinal defense impairment in mice through non-defensin protein.

    PubMed

    Chung, Pei-Hsuan; Wu, Ying-Ying; Chen, Pei-Hsuan; Fung, Chang-Phone; Hsu, Ching-Mei; Chen, Lee-Wei

    2016-09-01

    Altered intestinal microbiota and subsequent endotoxemia play pathogenic roles in diabetes. We aimed to study the mechanisms of intestinal defense impairment in type 1 diabetes and the effects of Lactobacillus salivarius as well as fructooligosaccharides (FOS) supplementation on diabetes-induced bacterial translocation. Alterations in the enteric microbiome, expression of mucosal antibacterial proteins and bacteria-killing activity of the intestinal mucosa in streptozotocin (STZ)-induced diabetic mice and Ins2(Akita) mice were investigated. The effects of dead L. salivarius (2×10(8)CFU/ml) and FOS (250 mg per day) supplementation for 1 week on endotoxin levels and Klebsiella pneumoniae translocation were also examined. Finally, germ-free mice were cohoused with wild-type or Ins2(Akita) mice for 2 weeks to examine the contribution of microbiota on the antibacterial protein expression. STZ-induced diabetic mice developed intestinal defense impairment as demonstrated by decreased mucosal bacteria-killing activity; reduction of non-defensin family proteins, such as Reg3β, Reg3γ, CRP-ductin and RELMβ, but not the defensin family proteins; and increased bacterial translocation. Intestinal bacteria overgrowth, enteric dysbiosis and increased intestinal bacterial translocation, particularly pathogenic K. pneumoniae in STZ-induced diabetic mice and Ins2(Akita) mice, were noted. Treating diabetic mice with dead L. salivarius or FOS reversed enteric dysbiosis, restored mucosal antibacterial protein and lessened endotoxin levels as well as K. pneumoniae translocation. Moreover, germ-free mice cohoused with wild-type mice demonstrated more intestinal Reg3β and RELMβ expression than those cohoused with Ins2(Akita) mice. These results indicate that hyperglycemia induces enteric dysbiosis, reduction of non-defensin proteins as well as bacteria-killing activity of the intestinal mucosa and intestinal defense impairment. Reversal of enteric dysbiosis with dead L. salivarius or

  7. Effect of Croatian propolis on diabetic nephropathy and liver toxicity in mice

    PubMed Central

    2012-01-01

    Background In the present study, we examined the antioxidant effect of water soluble derivative of propolis (WSDP) and ethanolic (EEP) extract of propolis on renal and liver function in alloxan-induced diabetic mice. In addition, we examined whether different extract of propolis could prevent diabetic nephropathy and liver toxicity by inhibiting lipid peroxidation in vivo. Methods Diabetes was induced in Swiss albino mice with a single intravenous injection of alloxan (75 mg kg-1). Two days after alloxan injection, propolis preparations (50 mg kg-1 per day) were given intraperitoneally for 7 days in diabetic mice. Survival analysis and body weights as well as hematological and biochemical parameters were measured. The renal and liver oxidative stress marker malonaldehyde levels and histopathological changes were monitored in the liver and kidney of treated and control mice. Results Administration of propolis to diabetic mice resulted in a significant increase of body weight, haematological and immunological parameters of blood as well as 100% survival of diabetic mice. Alloxan-injected mice showed a marked increase in oxidative stress in liver and kidney homogenate, as determined by lipid peroxidation. Histopathological observation of the liver sections of alloxan-induced diabetic mice showed several lesions including cellular vacuolization, cytoplasmic eosinophilia and lymphocyte infiltrations, but with individual variability.Treatment of diabetic mice with propolis extracts results in decreased number of vacuolized cells and degree of vacuolization; propolis treatment improve the impairment of fatty acid metabolism in diabetes. Renal histology showed corpuscular, tubular and interstitial changes in alloxan-induced diabetic mice. Test components did not improve renal histopathology in diabetic mice. Conclusions Propolis preparations are able to attenuate diabetic hepatorenal damage, probably through its anti-oxidative action and its detoxification

  8. ASK1 Inhibitor Halts Progression of Diabetic Nephropathy in Nos3-Deficient Mice.

    PubMed

    Tesch, Greg H; Ma, Frank Y; Han, Yingjie; Liles, John T; Breckenridge, David G; Nikolic-Paterson, David J

    2015-11-01

    p38 mitogen-activated protein kinase (MAPK) signaling promotes diabetic kidney injury. Apoptosis signal-regulating kinase (ASK)1 is one of the upstream kinases in the p38 MAPK-signaling pathway, which is activated by inflammation and oxidative stress, suggesting a possible role for ASK1 in diabetic nephropathy. In this study, we examined whether a selective ASK1 inhibitor can prevent the induction and progression of diabetic nephropathy in mice. Diabetes was induced in hypertensive endothelial nitric oxide synthase (Nos3)-deficient mice by five low-dose streptozotocin (STZ) injections. Groups of diabetic Nos3(-/-) mice received ASK1 inhibitor (GS-444217 delivered in chow) as an early intervention (2-8 weeks after STZ) or late intervention (weeks 8-15 after STZ). Control diabetic and nondiabetic Nos3(-/-) mice received normal chow. Treatment with GS-444217 abrogated p38 MAPK activation in diabetic kidneys but had no effect upon hypertension in Nos3(-/-) mice. Early intervention with GS-444217 significantly inhibited diabetic glomerulosclerosis and reduced renal dysfunction but had no effect on the development of albuminuria. Late intervention with GS-444217 improved renal function and halted the progression of glomerulosclerosis, renal inflammation, and tubular injury despite having no effect on established albuminuria. In conclusion, this study identifies ASK1 as a new therapeutic target in diabetic nephropathy to reduce renal inflammation and fibrosis independent of blood pressure control. PMID:26180085

  9. [Effects of cactus, alove veral, momorcica charantia on reducing the blood glucose of diabetic mice].

    PubMed

    Lin, X; Shen, X; Long, Z; Yang, Q

    2001-07-01

    The effects of cactus, alove veral and momorcica charantia on reducing the blood glucose level of mice were observed. The diabetic model with no symptom in mice was established by injection of streptozotocin(STZ) 80 mg/kg BW into abdominal cavity for 11 days. The diabetic mice were randomly divided into 8 groups: STZ diabetic model, diet A, diet B, cactus, alove veral, momordica charantia and glyburide groups. Cactus (60 g/kg BW), alove veral (60 g/kg BW), and momordica charantia (30 g/kg BW) were administrated orally each day to the diabetic mice for another 21 days. Serum glucose of mice fasting for 12 hours and 2 hours after meal was determined with the method of glucose-oxidase at the 21th day of the experiment. The results showed that serum glucose levels of diabetic mice were significantly higher than the normal control group (P < 0.01). After giving diet A, cactus, alove veral and momorcica charantia juice for 21 days, the serum glucose concentration of these diabetic mice were significantly lower than STZ diabetic model group (P < 0.01) but still higher than the normal control group.

  10. The IL-1β Receptor Antagonist SER140 Postpones the Onset of Diabetes in Female Nonobese Diabetic Mice

    PubMed Central

    Cucak, Helena; Hansen, Gitte; Vrang, Niels; Skarsfeldt, Torben; Steiness, Eva; Jelsing, Jacob

    2016-01-01

    The cytokine interleukin-1β (IL-1β) is known to stimulate proinflammatory immune responses and impair β-cell function and viability, all critical events in the pathogenesis of type 1 diabetes (T1D). Here we evaluate the effect of SER140, a small peptide IL-1β receptor antagonist, on diabetes progression and cellular pancreatic changes in female nonobese diabetic (NOD) mice. Eight weeks of treatment with SER140 reduced the incidence of diabetes by more than 50% compared with vehicle, decreased blood glucose, and increased plasma insulin. Additionally, SER140 changed the endocrine and immune cells dynamics in the NOD mouse pancreas. Together, the data suggest that SER140 treatment postpones the onset of diabetes in female NOD mice by interfering with IL-1β activated pathways. PMID:26953152

  11. Leptin treatment prevents type I diabetic marrow adiposity but not bone loss in mice.

    PubMed

    Motyl, Katherine J; McCabe, Laura R

    2009-02-01

    Leptin is a hormone secreted by adipocytes that is implicated in the regulation of bone density. Serum leptin levels are decreased in rodent models of type 1 (T1-) diabetes and in diabetic patients. Whether leptin mediates diabetic bone changes is unclear. Therefore, we treated control and T1-diabetic mice with chronic (28 days) subcutaneous infusion of leptin or saline to elucidate the therapeutic potential of leptin for diabetic osteoporosis. Leptin prevented the increase of marrow adipocytes and the increased aP2 expression that we observed in vehicle-treated diabetic mice. However, leptin did not prevent T1-diabetic decreases in trabecular bone volume fraction or bone mineral density in tibia or vertebrae. Consistent with this finding, markers of bone formation (osteocalcin RNA and serum levels) in diabetic mice were not restored to normal levels with leptin treatment. Interestingly, markers of bone resorption (TRAP5 RNA and serum levels) were decreased in diabetic mice by leptin treatment. In summary, we have demonstrated a link between low leptin levels in T1-diabetes and marrow adiposity. However, leptin treatment alone was not successful in preventing bone loss.

  12. Impact of experimental type 1 diabetes mellitus on systemic and coagulation vulnerability in mice acutely exposed to diesel exhaust particles

    PubMed Central

    2013-01-01

    Background Epidemiological evidence indicates that diabetic patients have increased susceptibility to adverse cardiovascular outcomes related to acute increases in exposures to particulate air pollution. However, mechanisms underlying these effects remain unclear. Methods To evaluate the possible mechanisms underlying these actions, we assessed the systemic effects of diesel exhaust particles (DEP) in control mice, and mice with streptozotocin–induced type 1 diabetes. Four weeks following induction of diabetes, the animals were intratracheally instilled (i.t.) with DEP (0.4 mg/kg) or saline, and several cardiovascular endpoints were measured 24 h thereafter. Results DEP caused leukocytosis and a significant increase in plasma C-reactive protein and 8-isoprostane concentrations in diabetic mice compared to diabetic mice exposed to saline or non-diabetic mice exposed to DEP. The arterial PO2 as well as the number of platelets and the thrombotic occlusion time in pial arterioles assessed in vivo were significantly decreased following the i.t. instillation of DEP in diabetic mice compared to diabetic mice exposed to saline or non-diabetic mice exposed to DEP. Both alanine aminotransferase and aspartate transaminase activities, as well as the plasma concentrations of plasminogen activator inhibitor and von Willebrand factor were significantly increased in DEP-exposed diabetic mice compared to diabetic mice exposed to saline or DEP-exposed non-diabetic mice. The in vitro addition of DEP (0.25-1 μg/ml) to untreated mouse blood significantly and dose-dependently induced in vitro platelet aggregation, and these effects were exacerbated in blood of diabetic mice. Conclusion This study has shown that systemic and coagulation events are aggravated by type 1 diabetes in mice, acutely exposed to DEP and has described the possible mechanisms for these actions that may also be relevant to the exacerbation of cardiovascular morbidity accompanying particulate air pollution in

  13. Tadalafil Promotes the Recovery of Peripheral Neuropathy in Type II Diabetic Mice.

    PubMed

    Wang, Lei; Chopp, Michael; Szalad, Alexandra; Lu, XueRong; Jia, LongFei; Lu, Mei; Zhang, Rui Lan; Zhang, Zheng Gang

    2016-01-01

    We previously demonstrated that treatment of diabetic peripheral neuropathy with the short (4 hours) half-life phosphodiesterase 5 (PDE5) inhibitor, sildenafil, improved functional outcome in diabetic db/db mice. To further examine the effect of PDE5 inhibition on diabetic peripheral neuropathy, we investigated the effect of another potent PDE5 inhibitor, tadalafil, on diabetic peripheral neuropathy. Tadalafil is pharmacokinetically distinct from sildenafil and has a longer half-life (17+hours) than sildenafil. Diabetic mice (BKS.Cg-m+/+Leprdb/J, db/db) at age 20 weeks were treated with tadalafil every 48 hours for 8 consecutive weeks. Compared with diabetic mice treated with saline, tadalafil treatment significantly improved motor and sensory conduction velocities in the sciatic nerve and peripheral thermal sensitivity. Tadalafil treatment also markedly increased local blood flow and the density of FITC-dextran perfused vessels in the sciatic nerve concomitantly with increased intraepidermal nerve fiber density. Moreover, tadalafil reversed the diabetes-induced reductions of axon diameter and myelin thickness and reversed the diabetes-induced increased g-ratio in the sciatic nerve. Furthermore, tadalafil enhanced diabetes-reduced nerve growth factor (NGF) and platelet-derived growth factor-C (PDGF-C) protein levels in diabetic sciatic nerve tissue. The present study demonstrates that tadalafil increases regional blood flow in the sciatic nerve tissue, which may contribute to the improvement of peripheral nerve function and the amelioration of diabetic peripheral neuropathy.

  14. Tadalafil Promotes the Recovery of Peripheral Neuropathy in Type II Diabetic Mice.

    PubMed

    Wang, Lei; Chopp, Michael; Szalad, Alexandra; Lu, XueRong; Jia, LongFei; Lu, Mei; Zhang, Rui Lan; Zhang, Zheng Gang

    2016-01-01

    We previously demonstrated that treatment of diabetic peripheral neuropathy with the short (4 hours) half-life phosphodiesterase 5 (PDE5) inhibitor, sildenafil, improved functional outcome in diabetic db/db mice. To further examine the effect of PDE5 inhibition on diabetic peripheral neuropathy, we investigated the effect of another potent PDE5 inhibitor, tadalafil, on diabetic peripheral neuropathy. Tadalafil is pharmacokinetically distinct from sildenafil and has a longer half-life (17+hours) than sildenafil. Diabetic mice (BKS.Cg-m+/+Leprdb/J, db/db) at age 20 weeks were treated with tadalafil every 48 hours for 8 consecutive weeks. Compared with diabetic mice treated with saline, tadalafil treatment significantly improved motor and sensory conduction velocities in the sciatic nerve and peripheral thermal sensitivity. Tadalafil treatment also markedly increased local blood flow and the density of FITC-dextran perfused vessels in the sciatic nerve concomitantly with increased intraepidermal nerve fiber density. Moreover, tadalafil reversed the diabetes-induced reductions of axon diameter and myelin thickness and reversed the diabetes-induced increased g-ratio in the sciatic nerve. Furthermore, tadalafil enhanced diabetes-reduced nerve growth factor (NGF) and platelet-derived growth factor-C (PDGF-C) protein levels in diabetic sciatic nerve tissue. The present study demonstrates that tadalafil increases regional blood flow in the sciatic nerve tissue, which may contribute to the improvement of peripheral nerve function and the amelioration of diabetic peripheral neuropathy. PMID:27438594

  15. Tadalafil Promotes the Recovery of Peripheral Neuropathy in Type II Diabetic Mice

    PubMed Central

    Wang, Lei; Chopp, Michael; Szalad, Alexandra; Lu, XueRong; Jia, LongFei; Lu, Mei; Zhang, Rui Lan; Zhang, Zheng Gang

    2016-01-01

    We previously demonstrated that treatment of diabetic peripheral neuropathy with the short (4 hours) half-life phosphodiesterase 5 (PDE5) inhibitor, sildenafil, improved functional outcome in diabetic db/db mice. To further examine the effect of PDE5 inhibition on diabetic peripheral neuropathy, we investigated the effect of another potent PDE5 inhibitor, tadalafil, on diabetic peripheral neuropathy. Tadalafil is pharmacokinetically distinct from sildenafil and has a longer half-life (17+hours) than sildenafil. Diabetic mice (BKS.Cg-m+/+Leprdb/J, db/db) at age 20 weeks were treated with tadalafil every 48 hours for 8 consecutive weeks. Compared with diabetic mice treated with saline, tadalafil treatment significantly improved motor and sensory conduction velocities in the sciatic nerve and peripheral thermal sensitivity. Tadalafil treatment also markedly increased local blood flow and the density of FITC-dextran perfused vessels in the sciatic nerve concomitantly with increased intraepidermal nerve fiber density. Moreover, tadalafil reversed the diabetes-induced reductions of axon diameter and myelin thickness and reversed the diabetes-induced increased g-ratio in the sciatic nerve. Furthermore, tadalafil enhanced diabetes-reduced nerve growth factor (NGF) and platelet-derived growth factor-C (PDGF-C) protein levels in diabetic sciatic nerve tissue. The present study demonstrates that tadalafil increases regional blood flow in the sciatic nerve tissue, which may contribute to the improvement of peripheral nerve function and the amelioration of diabetic peripheral neuropathy. PMID:27438594

  16. Evaluation of the Effects of Novel Nafimidone Derivatives on Thermal Hypoalgesia in Mice with Diabetic Neuropathy

    PubMed Central

    Kamışlı, Suat; Karakurt, Arzu; Uyumlu, Ayşe B.; Satılmış, Basri; Alagöz, Abdullah; Genç, Metin F.; Batcıoğlu, Kadir

    2013-01-01

    Objective: Diabetic neuropathy (DN) is a common complication in Diabetes Mellitus. The streptozotocin-induced diabetic rodent is the most commonly used animal model of diabetes and increased sodium channel expression and activity were revealed in this model. At this study, we evaluated the effect of three different nafimidone derivatives which have possible anticonvulsant activity on disorders of thermal pain sensation in diabetic mice. Study Design: Randomized animal experiment. Material and Methods: Mice were divided randomly into five groups (5 mice per group): Control, Diabetes, Dibetes+C1, Diabetes+C2, Diabetes+C3. We used hot and cold plate, and tail-immersion tests for assessment of thermal nociceptive responses. Results: Compared with the control group, the hot-plate response time and the number of paw liftings on cold plate as important indicators of loss of sensation increased, but no significant difference (p>0.05) was found in tail-immersion response time test in diabetes group. C3 compound moved it back to control group levels in the all of three tests. C1 and C2 compounds were effective only in cold-plate test. Conclusion: Nafimidone derivatives may be effective in the cases where epilepsy and diabetes occur together since it has shown efficacy against “loss of sensation” which evolves in diabetic neuropathy over time as well as its antiepileptic effect. PMID:25207077

  17. Antidepressant effects of insulin in streptozotocin induced diabetic mice: Modulation of brain serotonin system.

    PubMed

    Gupta, Deepali; Kurhe, Yeshwant; Radhakrishnan, Mahesh

    2014-04-22

    Diabetes is a persistent metabolic disorder, which often leads to depression as a result of the impaired neurotransmitter function. Insulin is believed to have antidepressant effects in depression associated with diabetes; however, the mechanism underlying the postulated effect is poorly understood. In the present study, it is hypothesized that insulin mediates an antidepressant effect in streptozotocin (STZ) induced diabetes in mice through modulation of the serotonin system in the brain. Therefore, the current study investigated the antidepressant effect of insulin in STZ induced diabetes in mice and insulin mediated modulation in the brain serotonin system. In addition, the possible pathways that lead to altered serotonin levels as a result of insulin administration were examined. Experimentally, Swiss albino mice of either sex were rendered diabetic by a single intraperitoneal (i.p.) injection of STZ. After one week, diabetic mice received a single dose of either insulin or saline or escitalopram for 14days. Thereafter, behavioral studies were conducted to test the behavioral despair effects using forced swim test (FST) and tail suspension test (TST), followed by biochemical estimations of serotonin concentrations and monoamine oxidase (MAO) activity in the whole brain content. The results demonstrated that, STZ treated diabetic mice exhibited an increased duration of immobility in FST and TST as compared to non-diabetic mice, while insulin treatment significantly reversed the effect. Biochemical assays revealed that administration of insulin attenuated STZ treated diabetes induced neurochemical alterations as indicated by elevated serotonin levels and decreased MAO-A and MAO-B activities in the brain. Collectively, the data indicate that insulin exhibits antidepressant effects in depression associated with STZ induced diabetes in mice through the elevation of the brain serotonin levels.

  18. O-GlcNAcase overexpression reverses coronary endothelial cell dysfunction in type 1 diabetic mice.

    PubMed

    Makino, Ayako; Dai, Anzhi; Han, Ying; Youssef, Katia D; Wang, Weihua; Donthamsetty, Reshma; Scott, Brian T; Wang, Hong; Dillmann, Wolfgang H

    2015-11-01

    Cardiovascular disease is the primary cause of morbidity and mortality in diabetes, and endothelial dysfunction is commonly seen in these patients. Increased O-linked N-acetylglucosamine (O-GlcNAc) protein modification is one of the central pathogenic features of diabetes. Modification of proteins by O-GlcNAc (O-GlcNAcylation) is regulated by two key enzymes: β-N-acetylglucosaminidase [O-GlcNAcase (OGA)], which catalyzes the reduction of protein O-GlcNAcylation, and O-GlcNAc transferase (OGT), which induces O-GlcNAcylation. However, it is not known whether reducing O-GlcNAcylation can improve endothelial dysfunction in diabetes. To examine the effect of endothelium-specific OGA overexpression on protein O-GlcNAcylation and coronary endothelial function in diabetic mice, we generated tetracycline-inducible, endothelium-specific OGA transgenic mice, and induced OGA by doxycycline administration in streptozotocin-induced type 1 diabetic mice. OGA protein expression was significantly decreased in mouse coronary endothelial cells (MCECs) isolated from diabetic mice compared with control MCECs, whereas OGT protein level was markedly increased. The level of protein O-GlcNAcylation was increased in diabetic compared with control mice, and OGA overexpression significantly decreased the level of protein O-GlcNAcylation in MCECs from diabetic mice. Capillary density in the left ventricle and endothelium-dependent relaxation in coronary arteries were significantly decreased in diabetes, while OGA overexpression increased capillary density to the control level and restored endothelium-dependent relaxation without changing endothelium-independent relaxation. We found that connexin 40 could be the potential target of O-GlcNAcylation that regulates the endothelial functions in diabetes. These data suggest that OGA overexpression in endothelial cells improves endothelial function and may have a beneficial effect on coronary vascular complications in diabetes.

  19. Optical cryo-imaging of kidney mitochondrial redox state in diabetic mice models

    NASA Astrophysics Data System (ADS)

    Maleki, S.; Sepehr, R.; Staniszewski, K.; Sheibani, N.; Sorenson, C. M.; Ranji, M.

    2012-03-01

    Oxidative stress (OS), which increases during diabetes, exacerbates the development and progression of diabetes complications including renal vascular and proximal tubule cell dysfunction. The objective of this study was to investigate the changes in the metabolic state of the tissue in diabetic mice kidneys using fluorescence imaging. Mitochondrial metabolic coenzymes NADH (Nicotinamide Adenine Dinucleotide), and FADH-2 (Flavin Adenine Dinucleotide) are autofluorescent and can be monitored without exogenous labels by optical techniques. The ratio of the fluorescence intensity of these fluorophores, (NADH/FAD), called the NADH redox ratio (RR), is a marker of metabolic state of a tissue. We examined mitochondrial redox states of kidneys from diabetic mice, Akita/+ and its control wild type (WT) for a group of 8- and 12-week-old mice. Average intensity and histogram of maximum projected images of FAD, NADH, and NADH RR were calculated for each kidney. Our results indicated a 17% decrease in the mean NADH RR of the kidney from 8-week-old mice compared with WT mice and, a 30% decrease in the mean NADH RR of kidney from12-week-old mice compared with WT mice. These results indicated an increase in OS in diabetic animals and its progression over time. Thus, NADH RR can be used as a hallmark of OS in diabetic kidney allowing temporal identification of oxidative state.

  20. Breviscapine attenuatted contrast medium-induced nephropathy via PKC/Akt/MAPK signalling in diabetic mice

    PubMed Central

    Jiang, Wenbin; Li, Zhengwei; Zhao, Wei; Chen, Hao; Wu, Youyang; Wang, Yi; Shen, Zhida; He, Jialin; Chen, Shengyu; Zhang, Jiefang; Fu, Guosheng

    2016-01-01

    Contrast medium-induced nephropathy (CIN) remains a major cause of iatrogenic, drug-induced renal injury. Recent studies reveal that Breviscapine can ameliorate diabetic nephropathy in mice. Yet it remains unknown if Breviscapine could reduce CIN in diabetic mice. In this study, male C57/BL6J mice were randomly divided into 7 groups: control, diabetes mellitus, CIN, diabetes mellitus+CIN, diabetes mellitus+Breviscapine, CIN+Breviscapine and diabetes mellitus+CIN+Breviscapine. Model of CIN was induced by tail intravenous administration of iopromide and model of diabetes mellitus was induced by Streptozotocin intraperitoneally. Breviscapine was administered intragastrically for 4 weeks. Renal function parameters, kidney histology, markers of renal fibrosis, phosphorylation of protein kinase C/Akt/mitogen activated protein kinases were measured by western blot. We found out that diabetes mellitus aggravated CIN damage. Renal histological analysis showed Breviscapine reduced of renal fibrosis and tubular damage. Breviscapine was also shown markedly to ameliorate CIN fibrotic markers expression, reduced proteinuria and serum creatinine. Furthermore, Breviscapine decreased phosphorylation of PKCβII, Akt, JNK1/2 and p38. Therefore, Breviscapine treatment could ameliorate the development of CIN in diabetic mice, which was partly attributed to its suppression of renal fibrosis via phosphorylation of PKCβII/Akt/JNK1/2/p38 signalling. PMID:27158329

  1. Breviscapine attenuatted contrast medium-induced nephropathy via PKC/Akt/MAPK signalling in diabetic mice.

    PubMed

    Jiang, Wenbin; Li, Zhengwei; Zhao, Wei; Chen, Hao; Wu, Youyang; Wang, Yi; Shen, Zhida; He, Jialin; Chen, Shengyu; Zhang, Jiefang; Fu, Guosheng

    2016-01-01

    Contrast medium-induced nephropathy (CIN) remains a major cause of iatrogenic, drug-induced renal injury. Recent studies reveal that Breviscapine can ameliorate diabetic nephropathy in mice. Yet it remains unknown if Breviscapine could reduce CIN in diabetic mice. In this study, male C57/BL6J mice were randomly divided into 7 groups: control, diabetes mellitus, CIN, diabetes mellitus+CIN, diabetes mellitus+Breviscapine, CIN+Breviscapine and diabetes mellitus+CIN+Breviscapine. Model of CIN was induced by tail intravenous administration of iopromide and model of diabetes mellitus was induced by Streptozotocin intraperitoneally. Breviscapine was administered intragastrically for 4 weeks. Renal function parameters, kidney histology, markers of renal fibrosis, phosphorylation of protein kinase C/Akt/mitogen activated protein kinases were measured by western blot. We found out that diabetes mellitus aggravated CIN damage. Renal histological analysis showed Breviscapine reduced of renal fibrosis and tubular damage. Breviscapine was also shown markedly to ameliorate CIN fibrotic markers expression, reduced proteinuria and serum creatinine. Furthermore, Breviscapine decreased phosphorylation of PKCβII, Akt, JNK1/2 and p38. Therefore, Breviscapine treatment could ameliorate the development of CIN in diabetic mice, which was partly attributed to its suppression of renal fibrosis via phosphorylation of PKCβII/Akt/JNK1/2/p38 signalling.

  2. Dental caries and caries-related periodontitis in type 2 diabetic mice.

    PubMed

    Sano, T; Matsuura, T; Ozaki, K; Narama, I

    2011-03-01

    Diabetic patients are predisposed to periodontal disease as well as dental caries; however, there are contradictory reports about the possible association between dental caries and diabetes. Thus, the authors set out to determine whether diabetes affects onset of dental caries and periodontal disease and to clarify whether dental caries and periodontal disease are associated with each other in diabetic db/db mice. Oral tissue was examined from 68 male mice (diabetic db/db and nondiabetic db/+; aged 20, 30, 40, and 50 weeks) and 20 female mice (db/db and db/+; aged 50 weeks). Macroscopically, caries were seen developing in the diabetic mice by 20 weeks of age. The number of teeth with dental lesions increased with age in the db/db mice at a significantly higher incidence than that of db/+ mice. Histologically, dental caries were detected in 30 of 120 molars in 17 of 20 db/db mice at 50 weeks of age and in 4 of 108 molars in 4 of 18 db/+ mice of the same age. The severity of dental caries in db/db mice was significantly higher than it was in db/+ mice. Dental caries were a primary change that led to bacterial gingivitis and pulpitis. These lesions spread to the dental root and periodontal connective tissue through the apical foramen. Apical periodontitis was more frequent and severe when occurring in close association with dental caries. In conclusion, there is a strong relationship between diabetes and dental caries, but in this model, it is highly probable that the onset of periodontal disease was a secondary change resulting from dental caries.

  3. Double transgenic mice with type 1 diabetes mellitus develop somatic, metabolic and vascular disorders.

    PubMed

    Radu, D L; Georgescu, Adriana; Stavaru, Crina; Carale, Alina; Popov, Doina

    2004-01-01

    The double transgenic mice (dTg) were obtained by mating: (i) transgenic mice expressing the hemagglutinin of influenza virus under the insulin promoter with (ii) transgenic mice expressing specific T lymphocytes with receptor for the immunodominant epitope of the same virus. In this study we show that dTg mice developed type 1 diabetes mellitus associated with hyperglycemia, low level of plasma insulin, glucosuria, weight loss and approximately 90% mortality (at 3 months biological age). The membrane of red blood cells was more sensitive to osmotic shock in diabetic mice, compared to non-diabetic mice, assessing systemic oxidative stress. Both vasoconstriction and vasorelaxation of the renal arteries decreased significantly in diabetic mice (compared to the control group of non-diabetic mice) related to the phenotypic change of endothelium and smooth muscle cells within the artery wall. This animal model, may be used in developing various strategies to study pancreatic beta-cell function, as well as for a better metabolic control conducting to a reduced risk of vascular complications. PMID:15491510

  4. Arsenic induces diabetic effects through beta-cell dysfunction and increased gluconeogenesis in mice

    NASA Astrophysics Data System (ADS)

    Liu, Su; Guo, Xuechao; Wu, Bing; Yu, Haiyan; Zhang, Xuxiang; Li, Mei

    2014-11-01

    Arsenic as a potential risk factor for type 2 diabetes has been received attention recently. However, the roles of arsenic on development of diabetes are unclear. In this study, we compared the influences of inorganic arsenic (iAs) on normal and diabetic mice by systems toxicology approaches. Although iAs exposure did not change glucose tolerance in normal mice, it caused the pancreatic β-cell dysfunction and increased gluconeogenesis and oxidative damages in liver. However, iAs exposure worsened the glucose tolerance in diabetic mice, which might be due to increased gluconeogenesis and impairment of pancreatic β-cell function. It is interesting that iAs exposure could improve the insulin sensitivity based on the insulin tolerance testing by the activation of glucose uptake-related genes and enzymes in normal and diabetic individuals. Our data suggested that iAs exposure could cause pre-diabetic effects by altering the lipid metabolism, gluconeogenesis and insulin secretion in normal individual, and worsen diabetic effects in diabetes individual by these processes. Insulin resistance might be not the reason of diabetic effects caused by iAs, indicating that mechanism of the diabetogenic effects of iAs exposure is different from the mechanism associated with traditional risk factors (such as obesity)-reduced type 2 diabetes.

  5. In vivo targeted molecular magnetic resonance imaging of free radicals in diabetic cardiomyopathy within mice.

    PubMed

    Towner, R A; Smith, N; Saunders, D; Carrizales, J; Lupu, F; Silasi-Mansat, R; Ehrenshaft, M; Mason, R P

    2015-01-01

    Free radicals contribute to the pathogenesis of diabetic cardiomyopathy. We present a method for in vivo observation of free radical events within murine diabetic cardiomyopathy. This study reports on in vivo imaging of protein/lipid radicals using molecular MRI (mMRI) and immuno-spin trapping (IST) in diabetic cardiac muscle. To detect free radicals in diabetic cardiomyopathy, streptozotocin (STZ)-exposed mice were given 5,5-dimethyl-pyrroline-N-oxide (DMPO) and administered an anti-DMPO probe (biotin-anti-DMPO antibody-albumin-Gd-DTPA). For controls, non-diabetic mice were given DMPO (non-disease control), and administered an anti-DMPO probe; or diabetic mice were given DMPO but administered a non-specific IgG contrast agent instead of the anti-DMPO probe. DMPO administration started at 7 weeks following STZ treatment for 5 days, and the anti-DMPO probe was administered at 8 weeks for MRI detection. MRI was used to detect a significant increase (p < 0.001) in MRI signal intensity (SI) from anti-DMPO nitrone adducts in diabetic murine left-ventricular (LV) cardiac tissue, compared to controls. Regional increases in MR SI in the LV were found in the apical and upper-left areas (p < 0.01 for both), compared to controls. The biotin moiety of the anti-DMPO probe was targeted with fluorescently-labeled streptavidin to locate the anti-DMPO probe in excised cardiac tissues, which indicated elevated fluorescence only in cardiac muscle of mice administered the anti-DMPO probe. Oxidized lipids and proteins were also found to be significantly elevated (p < 0.05 for both) in diabetic cardiac muscle compared to controls. It can be concluded that diabetic mice have more heterogeneously distributed radicals in cardiac tissue than non-diabetic mice.

  6. Flos Puerariae Extract Ameliorates Cognitive Impairment in Streptozotocin-Induced Diabetic Mice

    PubMed Central

    Liu, Zhong-he; Chen, Hong-guang; Wu, Pan-feng; Yao, Qing; Cheng, Hong-ke; Yu, Wei; Liu, Chao

    2015-01-01

    Objective. The effects of Flos Puerariae extract (FPE) on cognitive impairment associated with diabetes were assessed in C57BL/6J mice. Methods. Experimental diabetic mice model was induced by one injection of 50 mg/kg streptozotocin (STZ) for 5 days consecutively. FPE was orally administrated at the dosages of 50, 100, or 200 mg/kg/day, respectively. The learning and memory ability was assessed by Morris water maze test. Body weight, blood glucose, free fatty acid (FFA) and total cholesterol (TCH) in serum, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and acetylcholinesterase (AChE) activities in cerebral cortex and hippocampus were also measured. Results. Oral administration of FPE significantly improved cognitive deficits in STZ-induced diabetic mice. FPE treatment also maintained body weight and ameliorated hyperglycemia and dyslipidemia in diabetic mice. Additionally, decreased MDA level, enhanced CAT, and GSH-Px activities in cerebral cortex or hippocampus, as well as alleviated AChE activity in cerebral cortex, were found in diabetic mice supplemented with FPE. Conclusion. This study suggests that FPE ameliorates memory deficits in experimental diabetic mice, at least partly through the normalization of metabolic abnormalities, ameliorated oxidative stress, and AChE activity in brain. PMID:26060502

  7. Urtica dioica leaves modulates muscarinic cholinergic system in the hippocampus of streptozotocin-induced diabetic mice.

    PubMed

    Patel, Sita Sharan; Parashar, Arun; Udayabanu, Malairaman

    2015-06-01

    Diabetes mellitus is a chronic metabolic disorder and has been associated with cognitive dysfunction. In our earlier study, chronic Urtica dioica (UD) treatment significantly ameliorated diabetes induced associative and spatial memory deficit in mice. The present study was designed to explore the effect of UD leaves extract on muscarinic cholinergic system, which has long been known to be involved in cognition. Streptozotocin (STZ) (50 mg/kg, i.p., consecutively for 5 days) was used to induce diabetes followed by treatment with UD extract (50 mg/kg, oral) or rosiglitazone (5 mg/kg, oral) for 8 weeks. STZ-induced diabetic mice showed significant reduction in hippocampal muscarinic acetylcholine receptor-1 and choline acetyltransferase expressions. Chronic diabetes significantly up-regulated the protein expression of acetylcholinesterase associated with oxidative stress in hippocampus. Besides, STZ-induced diabetic mice showed hypolocomotion with up-regulation of muscarinic acetylcholine receptor-4 expression in striatum. Chronic UD treatment significantly attenuated the cholinergic dysfunction and oxidative stress in the hippocampus of diabetic mice. UD had no effect on locomotor activity and muscarinic acetylcholine receptor-4 expression in striatum. In conclusion, UD leaves extract has potential to reverse diabetes mediated alteration in muscarinic cholinergic system in hippocampus and thereby improve memory functions. PMID:25514862

  8. Effect of Tongxinluo on nerve regeneration in mice with diabetic peripheral neuropathy.

    PubMed

    Li, X; Zhang, J; Zhao, W; Yang, H; Ma, J; Qi, Y; Wu, S

    2015-01-01

    Diabetic peripheral neuropathy (DPN) is a common complication of diabetes. This study aims to investigate the effects of Tongxinluo on the nerve regeneration in diabetic peripheral neuropathy mice. Forty Specefic Pathogen Free (SPF) male KK/Upj—Ay mice were divided into diabetes group, diabetes with high dose Tongxinluo (4g/kg) (D+H), diabetes with mid dose Tongxinluo (2g/kg) (D+M), and diabetes with low dose Tongxinluo (1g/kg) (D+L) groups. Fasting blood glucose (FPG), heat pain threshold, motor nerve conduction velocity (MNCV), insulin—like growth factor—1 (IGF1), activator protein 1 (c—fos), nerve growth factor (NGF), and basic fibroblast growth factor (BFGF) were measured. Results indicated that FPG of diabetes group was significantly higher than that of control group. Heat pain threshold and MNCV were significantly lowered in diabetes group. Expression levels of IGF1, NGF and BFGF were significantly lower than that of control, whereas c—fos expression was significantly higher than that of control group. Tongxinluo treatment (D+M and D+H) significantly up—regulated heat pain threshold, MNCV, and IGF1, NGF and BFGF expression, but decreased c—fos expresson when compared to that of diabetes group. In conclusion, Tongxinluo can ameliorate diabetic peripheral neuropathy, improve MNCV, and promote nerve regeneration. The underlying mechanism needs to be further elucidated. PMID:26522065

  9. Protective Effects of Red Guava on Inflammation and Oxidative Stress in Streptozotocin-Induced Diabetic Mice.

    PubMed

    Li, Pei-Ying; Hsu, Cheng-Chin; Yin, Mei-Chin; Kuo, Yueh-Hsiung; Tang, Feng-Yao; Chao, Che-Yi

    2015-12-12

    Diabetes is an important chronic disease and the 4th leading cause of death in Taiwan. Hyperglycemia-induced oxidative and inflammatory damage are the main causes of chronic complications in diabetic patients. The red guava (red-fleshed guava cultivar of Psidium guajava L.) is a tropical fruit belonging to the Myrtaceae family and an important commercial crop in Taiwan. In this study, the protective effects of a diet containing red guava on inflammation and oxidative stress in streptozotocin (STZ)-induced diabetic mice were examined. The experimental group was divided into seven subgroups: normal (N), diabetes mellitus (DM), diabetes + red guava 1% (L), 2% (M), and 5% (H), diabetes + 5% red guava + anti-diabetic rosiglitazone (HR), and diabetes + anti-diabetic rosiglitazone (R). The mice were fed for 8 weeks and sacrificed by decapitation. Compared with the DM group, the experimental groups with diets containing red guava as well as rosiglitazone all showed significant improvements in blood glucose control, insulin resistance, creatinine, blood urea nitrogen, triglycerides, non-esterified fatty acids, cholesterol, c-reactive protein, TNF-α, and IL-10. Furthermore, the expression of inflammatory proteins, such as iNOS and NF-κB, was suppressed via activated PPARγ, and the expression levels of GPx3 and ACO increased. In summary, red guava can significantly suppress inflammatory and oxidative damage caused by diabetes and alleviate diabetic symptoms; thus, it exerts protective effects and has potential applications for the development of a dietary supplement.

  10. Protective Effects of Red Guava on Inflammation and Oxidative Stress in Streptozotocin-Induced Diabetic Mice.

    PubMed

    Li, Pei-Ying; Hsu, Cheng-Chin; Yin, Mei-Chin; Kuo, Yueh-Hsiung; Tang, Feng-Yao; Chao, Che-Yi

    2015-01-01

    Diabetes is an important chronic disease and the 4th leading cause of death in Taiwan. Hyperglycemia-induced oxidative and inflammatory damage are the main causes of chronic complications in diabetic patients. The red guava (red-fleshed guava cultivar of Psidium guajava L.) is a tropical fruit belonging to the Myrtaceae family and an important commercial crop in Taiwan. In this study, the protective effects of a diet containing red guava on inflammation and oxidative stress in streptozotocin (STZ)-induced diabetic mice were examined. The experimental group was divided into seven subgroups: normal (N), diabetes mellitus (DM), diabetes + red guava 1% (L), 2% (M), and 5% (H), diabetes + 5% red guava + anti-diabetic rosiglitazone (HR), and diabetes + anti-diabetic rosiglitazone (R). The mice were fed for 8 weeks and sacrificed by decapitation. Compared with the DM group, the experimental groups with diets containing red guava as well as rosiglitazone all showed significant improvements in blood glucose control, insulin resistance, creatinine, blood urea nitrogen, triglycerides, non-esterified fatty acids, cholesterol, c-reactive protein, TNF-α, and IL-10. Furthermore, the expression of inflammatory proteins, such as iNOS and NF-κB, was suppressed via activated PPARγ, and the expression levels of GPx3 and ACO increased. In summary, red guava can significantly suppress inflammatory and oxidative damage caused by diabetes and alleviate diabetic symptoms; thus, it exerts protective effects and has potential applications for the development of a dietary supplement. PMID:26703532

  11. Acute Versus Progressive Onset of Diabetes in NOD Mice: Potential Implications for Therapeutic Interventions in Type 1 Diabetes.

    PubMed

    Mathews, Clayton E; Xue, Song; Posgai, Amanda; Lightfoot, Yaima L; Li, Xia; Lin, Andrea; Wasserfall, Clive; Haller, Michael J; Schatz, Desmond; Atkinson, Mark A

    2015-11-01

    Most natural history models for type 1 diabetes (T1D) propose that overt hyperglycemia results after a progressive loss of insulin-secreting β-cell mass and/or function. To experimentally address this concept, we prospectively determined morning blood glucose measurements every other day in multiple cohorts (total n = 660) of female NOD/ShiLtJ mice starting at 8 weeks of age until diabetes onset or 26 weeks of age. Consistent with this notion, a majority of mice that developed diabetes (354 of 489 [72%]) displayed a progressive increase in blood glucose with transient excursions >200 mg/dL, followed by acute and persistent hyperglycemia at diabetes onset. However, 135 of the 489 (28%) diabetic animals demonstrated normal glucose values followed by acute (i.e., sudden) hyperglycemia. Interestingly, diabetes onset occurred earlier in mice with acute versus progressive disease onset (15.37 ± 0.3207 vs. 17.44 ± 0.2073 weeks of age, P < 0.0001). Moreover, the pattern of onset (i.e., progressive vs. acute) dramatically influenced the ability to achieve reversal of T1D by immunotherapeutic intervention, with increased effectiveness observed in situations of a progressive deterioration in euglycemia. These studies highlight a novel natural history aspect in this animal model, one that may provide important guidance for the selection of subjects participating in human trials seeking disease reversal. PMID:26216853

  12. Adipose-derived stem cells from diabetic mice show impaired vascular stabilization in a murine model of diabetic retinopathy.

    PubMed

    Cronk, Stephen M; Kelly-Goss, Molly R; Ray, H Clifton; Mendel, Thomas A; Hoehn, Kyle L; Bruce, Anthony C; Dey, Bijan K; Guendel, Alexander M; Tavakol, Daniel N; Herman, Ira M; Peirce, Shayn M; Yates, Paul A

    2015-05-01

    Diabetic retinopathy is characterized by progressive vascular dropout with subsequent vision loss. We have recently shown that an intravitreal injection of adipose-derived stem cells (ASCs) can stabilize the retinal microvasculature, enabling repair and regeneration of damaged capillary beds in vivo. Because an understanding of ASC status from healthy versus diseased donors will be important as autologous cellular therapies are developed for unmet clinical needs, we took advantage of the hyperglycemic Akimba mouse as a preclinical in vivo model of diabetic retinopathy in an effort aimed at evaluating therapeutic efficacy of adipose-derived stem cells (mASCs) derived either from healthy, nondiabetic or from diabetic mice. To these ends, Akimba mice received intravitreal injections of media conditioned by mASCs or mASCs themselves, subsequent to development of substantial retinal capillary dropout. mASCs from healthy mice were more effective than diabetic mASCs in protecting the diabetic retina from further vascular dropout. Engrafted ASCs were found to preferentially associate with the retinal vasculature. Conditioned medium was unable to recapitulate the vasoprotection seen with injected ASCs. In vitro diabetic ASCs showed decreased proliferation and increased apoptosis compared with healthy mASCs. Diabetic ASCs also secreted less vasoprotective factors than healthy mASCs, as determined by high-throughput enzyme-linked immunosorbent assay. Our findings suggest that diabetic ASCs are functionally impaired compared with healthy ASCs and support the utility of an allogeneic injection of ASCs versus autologous or conditioned media approaches in the treatment of diabetic retinopathy.

  13. Cilostazol improves the response to ischemia in diabetic mice by a mechanism dependent on PPARγ.

    PubMed

    Biscetti, Federico; Pecorini, Giovanni; Arena, Vincenzo; Stigliano, Egidio; Angelini, Flavia; Ghirlanda, Giovanni; Ferraccioli, Gianfranco; Flex, Andrea

    2013-12-01

    Cilostazol is effective for the treatment of peripheral ischemia. This compound has several beneficial effects on platelet aggregation, serum lipids and endothelial cells, and we recently found that it enhances collateral blood flow in the ischemic hind limbs of mice. Peroxisome proliferator-activated receptor (PPAR)γ, a receptor for thiazolidinediones, plays a role in angiogenesis. The aim of this work was to investigate the underlying molecular mechanisms and effects of cilostazol in a model of peripheral ischemia in diabetic mice. We induced diabetes in mice by streptozotocin (STZ) administration and studied ischemia-induced angiogenesis in the ischemic hind limbs of cilostazol-treated and untreated control mice. We found that perfusion recovery was significantly improved in treated compared with control diabetic mice. Interestingly, we found that the expression of PPARγ is reduced in ischemic tissues of diabetic mice. Furthermore, we discovered that local inhibition of the activity of this nuclear receptor decreased the angiogenic response to cilostazol treatment. Finally, we noted that this phenomenon is dependent on VEGF and modulated by PPARγ. Cilostazol administration enhances collateral blood flow in the ischemic hind limbs of STZ-induced diabetic mice through a PPARγ-dependent mechanism.

  14. Improvement of skin wound healing in diabetic mice by kinin B2 receptor blockade.

    PubMed

    Desposito, Dorinne; Chollet, Catherine; Taveau, Christopher; Descamps, Vincent; Alhenc-Gelas, François; Roussel, Ronan; Bouby, Nadine; Waeckel, Ludovic

    2016-01-01

    Impaired skin wound healing is a major medical problem in diabetic subjects. Kinins exert a number of vascular and other actions limiting organ damage in ischaemia or diabetes, but their role in skin injury is unknown. We investigated, through pharmacological manipulation of bradykinin B1 and B2 receptors (B1R and B2R respectively), the role of kinins in wound healing in non-diabetic and diabetic mice. Using two mouse models of diabetes (streptozotocin-induced and db/db mice) and non-diabetic mice, we assessed the effect of kinin receptor activation or inhibition by subtype-selective pharmacological agonists (B1R and B2R) and antagonist (B2R) on healing of experimental skin wounds. We also studied effects of agonists and antagonist on keratinocytes and fibroblasts in vitro. Levels of Bdkrb1 (encoding B1R) and Bdkrb2 (encoding B2R) mRNAs increased 1-2-fold in healthy and wounded diabetic skin compared with in non-diabetic skin. Diabetes delayed wound healing. The B1R agonist had no effect on wound healing. In contrast, the B2R agonist impaired wound repair in both non-diabetic and diabetic mice, inducing skin disorganization and epidermis thickening. In vitro, B2R activation unbalanced fibroblast/keratinocyte proliferation and increased keratinocyte migration. These effects were abolished by co-administration of B2R antagonist. Interestingly, in the two mouse models of diabetes, the B2R antagonist administered alone normalized wound healing. This effect was associated with the induction of Ccl2 (encoding monocyte chemoattractant protein 1)/Tnf (encoding tumour necrosis factor α) mRNAs. Thus stimulation of kinin B2 receptor impairs skin wound healing in mice. B2R activation occurs in the diabetic skin and delays wound healing. B2R blockade improves skin wound healing in diabetic mice and is a potential therapeutic approach to diabetic ulcers. PMID:26443866

  15. Lactoferrin stimulates killing and clearance of bacteria but does not prevent mortality of diabetic mice.

    PubMed

    Zagulski, T; Jarzabek, Z; Zagulska, A; Jaszczak, M; Kochanowska, I E; Zimecki, M

    2001-01-01

    We have previously shown that bovine lactoferrin (BLF) given intravenously (i.v.) protected mice against a lethal dose of Escherichia coli and strongly stimulated both the clearing and killing activities in liver, lungs, spleen and kidney. Since some studies indicated a reduction of the manifestation of experimental pancreatitis with lactoferrin (LF), we decided to examine the protective activity of BLF against lethal E. coli infection in animals with alloxan (Alx)-induced diabetes. It appeared that 48 h diabetes substantially lowered the killing activity in all four organs as well as the clearing rate of E. coli from the circulation. BLF given i.v. reduced this undesirable effect of diabetes. However, in 10- and 20-day diabetic animals, the diabetes alone stimulated the killing activity in the organs investigated, and upregulated the clearing rate of E. coli from the circulation. Lactoferrin significantly increased both the killing and the clearing activity in these long-term diabetic animals. In some cases the stimulating effect of BLF was very high, suggesting a concerted action of BLF and diabetes in that category of mice. Despite these beneficial effects of BLF and diabetes on the killing process in the investigated organs, the survival time of animals from all the diabetic groups (48 h, 10 and 20 days) was not prolonged by BLF. The protective properties of BLF did not depend on the blood glucose levels in the diabetic animals. BLF partly delayed the development of experimental Alx-induced diabetes, measured by the glucose level, but only if administered shortly after Alx injection. In conclusion, we demonstrated that the state of diabetes alone could increase killing of bacteria in the investigated organs and LF enhanced this process. However, LF had no protective effect against the mortality of diabetic mice infected with a lethal dose of E. coli.

  16. Activation of endothelial NAD(P)H oxidase accelerates early glomerular injury in diabetic mice

    PubMed Central

    Nagasu, Hajime; Satoh, Minoru; Kiyokage, Emi; Kidokoro, Kengo; Toida, Kazunori; Channon, Keith M; Kanwar, Yashpal S; Sasaki, Tamaki; Kashihara, Naoki

    2016-01-01

    Increased generation of reactive oxygen species (ROS) is a common denominative pathogenic mechanism underlying vascular and renal complications in diabetes mellitus. Endothelial NAD(P)H oxidase is a major source of vascular ROS, and it has an important role in endothelial dysfunction. We hypothesized that activation of endothelial NAD(P)H oxidase initiates and worsens the progression of diabetic nephropathy, particularly in the development of albuminuria. We used transgenic mice with endothelial-targeted overexpression of the catalytic subunit of NAD(P)H oxidase, Nox2 (NOX2TG). NOX2TG mice were crossed with Akita insulin-dependent diabetic (Akita) mice that develop progressive hyperglycemia. We compared the progression of diabetic nephropathy in Akita versus NOX2TG-Akita mice. NOX2TG-Akita mice and Akita mice developed significant albuminuria above the baseline at 6 and 10 weeks of age, respectively. Compared with Akita mice, NOX2TG-Akita mice exhibited higher levels of NAD(P)H oxidase activity in glomeruli, developed glomerular endothelial perturbations, and attenuated expression of glomerular glycocalyx. Moreover, in contrast to Akita mice, the NOX2TG-Akita mice had numerous endothelial microparticles (blebs), as detected by scanning electron microscopy, and increased glomerular permeability. Furthermore, NOX2TG-Akita mice exhibited distinct phenotypic changes in glomerular mesangial cells expressing α-smooth muscle actin, and in podocytes expressing increased levels of desmin, whereas the glomeruli generated increased levels of ROS. In conclusion, activation of endothelial NAD(P)H oxidase in the presence of hyperglycemia initiated and exacerbated diabetic nephropathy characterized by the development of albuminuria. Moreover, ROS generated in the endothelium compounded glomerular dysfunctions by altering the phenotypes of mesangial cells and compromising the integrity of the podocytes. PMID:26552047

  17. Improvement of cognitive impairment in female type 2 diabetes mellitus mice by spironolactone.

    PubMed

    Sakata, Akiko; Mogi, Masaki; Iwanami, Jun; Tsukuda, Kana; Min, Li-Juan; Jing, Fei; Ohshima, Kousei; Ito, Masaharu; Horiuchi, Masatsugu

    2012-03-01

    Patients with type 2 diabetes mellitus (T2DM) exhibit more severe cognitive decline in females compared with males; however, the preventive approach to this gender-specific cognitive decline is still an enigma. Spironolactone is a potassium-sparing diuretic that also acts as an androgen receptor antagonist. Here, we investigated whether spironolactone attenuates cognitive impairment observed in female T2DM mice. Adult wild-type (WT) mice and an obese T2DM model, KKAy mice, were employed in this study. Cognitive function was evaluated by the shuttle avoidance test and Morris water maze test. Administration of spironolactone (50 mg/kg per day in chow) had no significant effect on blood pressure, glucose tolerance or insulin resistance. In WT mice, no significant sex difference in cognitive function was observed; however, treatment with spironolactone improved spatial memory in the water maze, especially in female WT mice. Administration of spironolactone markedly improved the cognitive decline in female KKAy mice up to the level in male KKAy mice. Spironolactone treatment also improved cognitive function in ovariectomized-KKAy mice, but failed to improve it in those with administration of estradiol (200 µg/kg per day). In diabetic mice, spironolactone improved impaired cognitive function observed in female mice, suggesting that spironolactone may prevent cognitive impairment associated with diabetes in females clinically.

  18. Defective CD8+ T cell peripheral tolerance in nonobese diabetic mice.

    PubMed

    Kreuwel, H T; Biggs, J A; Pilip, I M; Pamer, E G; Lo, D; Sherman, L A

    2001-07-15

    Nonobese diabetic (NOD) mice develop spontaneous autoimmune diabetes that involves participation of both CD4+ and CD8+ T cells. Previous studies have demonstrated spontaneous reactivity to self-Ags within the CD4+ T cell compartment in this strain. Whether CD8+ T cells in NOD mice achieve and maintain tolerance to self-Ags has not previously been evaluated. To investigate this issue, we have assessed the extent of tolerance to a model pancreatic Ag, the hemagglutinin (HA) molecule of influenza virus, that is transgenically expressed by pancreatic islet beta cells in InsHA mice. Previous studies have demonstrated that BALB/c and B10.D2 mice that express this transgene exhibit tolerance of HA and retain only low-avidity CD8+ T cells specific for the dominant peptide epitope of HA. In this study, we present data that demonstrate a deficiency in peripheral tolerance within the CD8+ T cell repertoire of NOD-InsHA mice. CD8+ T cells can be obtained from NOD-InsHA mice that exhibit high avidity for HA, as measured by tetramer (K(d)HA) binding and dose titration analysis. Significantly, these autoreactive CD8+ T cells can cause diabetes very rapidly upon adoptive transfer into NOD-InsHA recipient mice. The data presented demonstrate a retention in the repertoire of CD8+ T cells with high avidity for islet Ags that could contribute to autoimmune diabetes in NOD mice.

  19. Diabetes-Associated Dry Eye Syndrome in a New Humanized Transgenic Model of Type 1 Diabetes

    PubMed Central

    Imam, Shahnawaz; Elagin, Raya B.

    2013-01-01

    Purpose Patients with Type 1 Diabetes (T1D) are at high risk of developing lacrimal gland dysfunction. We have developed a new model of human T1D using double-transgenic mice carrying HLA-DQ8 diabetes-susceptibility haplotype instead of mouse MHC-class II and expressing the human beta cell autoantigen Glutamic Acid Decarboxylase in pancreatic beta cells. We report here the development of dry eye syndrome (DES) after diabetes induction in our humanized transgenic model. Methods Double-transgenic mice were immunized with DNA encoding human GAD65, either naked or in adenoviral vectors, to induce T1D. Mice monitored for development of diabetes developed lacrimal gland dysfunction. Results Animals developed lacrimal gland disease (classically associated with diabetes in Non Obese Diabetic [NOD] mice and with T1D in humans) as they developed glucose intolerance and diabetes. Animals manifested obvious clinical signs of dry eye syndrome (DES), from corneal erosions to severe keratitis. Histological studies of peri-bulbar areas revealed lymphocytic infiltration of glandular structures. Indeed, infiltrative lesions were observed in lacrimal/Harderian glands within weeks following development of glucose intolerance. Lesions ranged from focal lymphocytic infiltration to complete acinar destruction. We observed a correlation between the severity of the pancreatic infiltration and the severity of the ocular disease. Conclusions Our results demonstrate development of DES in association with antigen-specific insulitis and diabetes following immunization with clinically relevant human autoantigen concomitantly expressed in pancreatic beta cells of diabetes-susceptible mice. As in the NOD mouse model and as in human T1D, our animals developed diabetes-associated DES. This specific finding stresses the relevance of our model for studying these human diseases. We believe our model will facilitate studies to prevent/treat diabetes-associated DES as well as human diabetes. PMID

  20. Erythropoietin restores C-fiber function and prevents pressure ulcer formation in diabetic mice.

    PubMed

    Demiot, Claire; Sarrazy, Vincent; Javellaud, James; Gourloi, Loriane; Botelle, Laurent; Oudart, Nicole; Achard, Jean-Michel

    2011-11-01

    Pressure-induced vasodilatation (PIV), a cutaneous physiological neurovascular (C-fiber/endothelium) mechanism, is altered in diabetes and could possibly contribute to pressure ulcer development. We wanted to determine whether recombinant human erythropoietin (rhEPO), which has protective neurovascular effects, could prevent PIV alteration and pressure ulcer formation. We developed a skin pressure ulcer model in mice by applying two magnetic plates to the dorsal skin. This induced significant stage 2 ulcers (assessed visually and histologically) in streptozotocin-treated mice with 8 weeks of diabetes compared with very few in controls. Control and streptozotocin mice received either no treatment or systematic rhEPO (3,000 UI kg(-1) intraperitoneally, twice a week) during the last 2 weeks of diabetes. After 8 weeks of diabetes, we assessed ulcer development, PIV, endothelium-dependent vasodilation, C-fiber-mediated nociception threshold, and skin innervation density. Pretreatment with rhEPO fully prevented ulcer development in streptozotocin mice and also fully restored C-fiber nociception, skin innervation density, and significantly improved PIV, but had no effect on endothelium-dependent vasodilation. Our finding that rhEPO treatment protects the skin against pressure-induced ulcers in diabetic mice encourages evaluation of the therapeutic potential for non-hematopoietic analogs of EPO in preventing neuropathic diabetic ulcers.

  1. Antihyperglycemic Effect of Ganoderma Lucidum Polysaccharides on Streptozotocin-Induced Diabetic Mice

    PubMed Central

    Li, Fenglin; Zhang, Yiming; Zhong, Zhijian

    2011-01-01

    The current study evaluated the glucose-lowering effect of ganoderma lucidum polysaccharides (Gl-PS) in streptozotocin (STZ)-induced diabetic mice. The diabetic mice were randomly divided into four groups (8 mice per group): diabetic control group, low-dose Gl-PS treated group (50 mg/kg, Gl-PS), high-dose Gl-PS treated group (150 mg/kg, Gl-PS) and positive drug control treated group (glibenclamide, 4 mg/kg), with normal mice used as the control group. Body weights, fasting blood glucose (FBG), serum insulin and blood lipid levels of mice were measured. After 28 days of treatment with Gl-PS, body weights and serum insulin levels of the Gl-PS treated groups was significantly higher than that of the diabetic control group, whereas FBG levels was significantly lower. Moreover, total cholesterol (TC), triglyceride (TG) and low density lipoprotein cholesterol (LDL-C) levels of the Gl-PS treated groups had dropped, whereas the high density lipoprotein cholesterol (HDL-C) levels had increased. In addition, according to acute toxicity studies, Gl-PS did not cause behavioral changes and any death of mice. These data suggest that Gl-PS has an antihyperglycemic effect. Furthermore, considering the Gl-PS effects on lipid profile, it may be a potential hypolipidaemic agent, which will be a great advantage in treating diabetic conditions associated with atherosclerosis or hyperlipidemia. PMID:22016649

  2. Pseudomonas aeruginosa biofilms perturb wound resolution and antibiotic tolerance in diabetic mice.

    PubMed

    Watters, Chase; DeLeon, Katrina; Trivedi, Urvish; Griswold, John A; Lyte, Mark; Hampel, Ken J; Wargo, Matthew J; Rumbaugh, Kendra P

    2013-04-01

    Diabetic patients are more susceptible to the development of chronic wounds than non-diabetics. The impaired healing properties of these wounds, which often develop debilitating bacterial infections, significantly increase the rate of lower extremity amputation in diabetic patients. We hypothesize that bacterial biofilms, or sessile communities of bacteria that reside in a complex matrix of exopolymeric material, contribute to the severity of diabetic wounds. To test this hypothesis, we developed an in vivo chronic wound, diabetic mouse model to determine the ability of the opportunistic pathogen, Pseudomonas aeruginosa, to cause biofilm-associated infections. Utilizing this model, we observed that diabetic mice with P. aeruginosa-infected chronic wounds displayed impaired bacterial clearing and wound closure in comparison with their non-diabetic littermates. While treating diabetic mice with insulin improved their overall health, it did not restore their ability to resolve P. aeruginosa wound infections or speed healing. In fact, the prevalence of biofilms and the tolerance of P. aeruginosa to gentamicin treatment increased when diabetic mice were treated with insulin. Insulin treatment was observed to directly affect the ability of P. aeruginosa to form biofilms in vitro. These data demonstrate that the chronically wounded diabetic mouse appears to be a useful model to study wound healing and biofilm infection dynamics, and suggest that the diabetic wound environment may promote the formation of biofilms. Further, this model provides for the elucidation of mechanistic factors, such as the ability of insulin to influence antimicrobial effectiveness, which may be relevant to the formation of biofilms in diabetic wounds.

  3. Chromium, selenium, and zinc multimineral enriched yeast supplementation ameliorates diabetes symptom in streptozocin-induced mice.

    PubMed

    Liu, Jun; Bao, Wei; Jiang, Man; Zhang, Yan; Zhang, Xiping; Liu, Liegang

    2012-05-01

    Chromium, selenium, and zinc malnutrition has been implicated in the pathogenesis of diabetic mellitus. This study aims to investigate the effects of novel multiminerals-enriched yeast (MMEY) which are minerals supplementation containing elevated levels of chromium, selenium, and zinc simultaneously in a diabetic animal model. Streptozocin-induced diabetic male Balb/c mice (n = 80) were randomly divided into diabetes control group and three treatment groups. They were administrated oral gavages with low, medium, or high doses of MMEY, respectively. Meanwhile, healthy male Balb/c mice (n = 40) of the same body weight were randomly assigned into normal control group and high dose of MMEY control group. After 8 weeks duration of treatment, the animals were sacrificed by cervical dislocation. Serum glucose concentrations, lipid profiles, oxidative/antioxidant, and immunity status were determined. No significant adverse effects were observed in the high-dose MMEY control group. Treatment of the diabetic mice with medium- or high-dose MMEY significantly decreased serum glucose, triglyceride, total cholesterol, and malondialdehyde and increased high-density lipoprotein cholesterol, glutathione, and the activities of superoxide dismutase and glutathione peroxidase. In addition, MMEY ameliorated the pathological damage of the pancreatic islets, elevated the thymus or spleen coefficient, and increased the expressions of interleukin-2 and -4 in spleen lymphocytes compared with unsupplemented diabetic mice. In conclusion, these results indicate that supplemental MMEY inhibits hyperglycemia, abates oxidative stress, modulates disorders of lipid metabolism, and reduces the impairment of immune function in diabetic mice; especially notable are the protective effects of medium doses of MMEY on the islet cells of diabetic mice.

  4. Fibroblast Cell-Based Therapy for Experimental Autoimmune Diabetes.

    PubMed

    Jalili, Reza B; Zhang, Yun; Hosseini-Tabatabaei, Azadeh; Kilani, Ruhangiz T; Khosravi Maharlooei, Mohsen; Li, Yunyuan; Salimi Elizei, Sanam; Warnock, Garth L; Ghahary, Aziz

    2016-01-01

    Type 1 diabetes (T1D) results from autoimmune destruction of insulin producing β cells of the pancreatic islets. Curbing autoimmunity at the initiation of T1D can result in recovery of residual β cells and consequently remission of diabetes. Here we report a cell-based therapy for autoimmune diabetes in non-obese diabetic (NOD) mice using dermal fibroblasts. This was achieved by a single injection of fibroblasts, expressing the immunoregulatory molecule indoleamine 2,3 dioxygenase (IDO), into peritoneal cavity of NOD mice shortly after the onset of overt hyperglycemia. Mice were then monitored for reversal of hyperglycemia and changes in inflammatory/regulatory T cell profiles. Blood glucose levels dropped into the normal range in 82% of NOD mice after receiving IDO-expressing fibroblasts while all control mice remained diabetic. We found significantly reduced islet inflammation, increased regulatory T cells, and decreased T helper 17 cells and β cell specific autoreactive CD8+ T cells following IDO cell therapy. We further showed that some of intraperitoneal injected fibroblasts migrated to local lymph nodes and expressed co-inhibitory molecules. These findings suggest that IDO fibroblasts therapy can reinstate self-tolerance and alleviate β cell autoreactivity in NOD mice, resulting in remission of autoimmune diabetes. PMID:26765526

  5. Inner Retinal Oxygen Delivery, Metabolism, and Extraction Fraction in Ins2Akita Diabetic Mice

    PubMed Central

    Blair, Norman P.; Wanek, Justin; Felder, Anthony E.; Brewer, Katherine C.; Joslin, Charlotte E.; Shahidi, Mahnaz

    2016-01-01

    Purpose Retinal nonperfusion and hypoxia are important factors in human diabetic retinopathy, and these presumably inhibit energy production and lead to cell death. The purpose of this study was to elucidate the effect of diabetes on inner retinal oxygen delivery and metabolism in a mouse model of diabetes. Methods Phosphorescence lifetime and blood flow imaging were performed in spontaneously diabetic Ins2Akita (n = 22) and nondiabetic (n = 22) mice at 12 and 24 weeks of age to measure retinal arterial (O2A) and venous (O2V) oxygen contents and total retinal blood flow (F). Inner retinal oxygen delivery (DO2) and metabolism (MO2) were calculated as F ∗ O2A and F ∗ (O2A − O2V), respectively. Oxygen extraction fraction (OEF), which equals MO2/DO2, was calculated. Results DO2 at 12 weeks were 112 ± 40 and 97 ± 29 nL O2/min in nondiabetic and diabetic mice, respectively (NS), and 148 ± 31 and 85 ± 37 nL O2/min at 24 weeks, respectively (P < 0.001). MO2 were 65 ± 31 and 66 ± 27 nL O2/min in nondiabetic and diabetic mice at 12 weeks, respectively, and 79 ± 14 and 54 ± 28 nL O2/min at 24 weeks, respectively (main effects = NS). At 12 weeks OEF were 0.57 ± 0.17 and 0.67 ± 0.09 in nondiabetic and diabetic mice, respectively, and 0.54 ± 0.07 and 0.63 ± 0.08 at 24 weeks, respectively (main effect of diabetes: P < 0.01). Conclusions Inner retinal MO2 was maintained in diabetic Akita mice indicating that elevation of the OEF adequately compensated for reduced DO2 and prevented oxidative metabolism from being limited by hypoxia. PMID:27802520

  6. Anti-diabetic effects of rice hull smoke extract on glucose-regulating mechanism in type 2 diabetic mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The aim of this study is to determine the protective effect of a liquid rice hull smoke extract (RHSE) against type 2 diabetes induced by a high fat diet administered to mice. Dietary administration of 0.5% or 1% RHSE for 7 weeks results in significantly reduced blood glucose and triglyceride and to...

  7. Suppression of streptozotocin-induced type-1 diabetes in mice by radon inhalation.

    PubMed

    Nishiyama, Y; Kataoka, T; Teraoka, J; Sakoda, A; Tanaka, H; Ishimori, Y; Mitsunobu, F; Taguchi, T; Yamaoka, K

    2013-01-01

    We examined the protective effect of radon inhalation on streptozotocin (STZ)-induced type-1 diabetes in mice. Mice inhaled radon at concentrations of 1000, 2500, and 5500 Bq/m3 for 24 hours before STZ administration. STZ administration induced characteristics of type-1 diabetes such as hyperglycemia and hypoinsulinemia; however, radon inhalation at doses of 1000 and 5500 Bq/m3 significantly suppressed the elevation of blood glucose in diabetic mice. Serum insulin was significantly higher in mice pre-treated with radon at a dose of 1000 Bq/m3 than in mice treated with a sham. In addition, superoxide dismutase activities and total glutathione contents were significantly higher and lipid peroxide was significantly lower in mice pre-treated with radon at doses of 1000 and 5500 Bq/m3 than in mice treated with a sham. These results were consistent with the result that radon inhalation at 1000 and 5500 Bq/m3 suppressed hyperglycemia. These findings suggested that radon inhalation suppressed STZ-induced type-1 diabetes through the enhancement of antioxidative functions in the pancreas.

  8. Anti-diabetic activity of cassava cross-linked octenyl succinic maltodextrin in STZ-induced diabetic mice.

    PubMed

    Wang, Li; Zheng, Maoqiang; Wang, Yingyao; Zhang, Ying; Qian, Haifeng; Zhang, Hui; Qi, Xiguang

    2014-03-01

    The effect of cassava cross-linked octenyl succinic maltodextrin (CCOMD) on diabetic mice was investigated in this study. For CCOMD-L (low dose) and CCOMD-H (high dose) groups, the body weights were recovered by 14.9% and 18.5%, respectively, which were significantly higher than that of model control group. It was also found that the blood glucose and insulin levels were ameliorated in the diabetic mice by the CCOMD diet. Moreover, the CCOMD diet decreased the plasma total cholesterol level (8.1-9.1%) and LDL cholesterol level (28.9-39.4%), and improved the plasma HDL cholesterol level (13.8-15.3%) and intestine short chain fatty acid content. The results indicated that CCOMD administration may be helpful for treating and preventing hyperlipidemia and hyperglycemia in diabetes.

  9. Unacylated ghrelin restores insulin and autophagic signaling in skeletal muscle of diabetic mice.

    PubMed

    Tam, Bjorn T; Pei, Xiao M; Yung, Benjamin Y; Yip, Shea P; Chan, Lawrence W; Wong, Cesar S; Siu, Parco M

    2015-12-01

    Impairment of insulin signaling in skeletal muscle detrimentally affects insulin-stimulated disposal of glucose. Restoration of insulin signaling in skeletal muscle is important as muscle is one of the major sites for disposal of blood glucose. Recently, unacylated ghrelin (UnAG) has received attention in diabetic research due to its favorable actions on improving glucose tolerance, glycemic control, and insulin sensitivity. The investigation of UnAG has entered phase Ib clinical trial in type 2 diabetes and phase II clinical trial in hyperphagia in Prader-Willi syndrome. Nonetheless, the precise mechanisms responsible for the anti-diabetic actions of UnAG remain incompletely understood. In this study, we examined the effects of UnAG on restoring the impaired insulin signaling in skeletal muscle of db/db diabetic mice. Our results demonstrated that UnAG effectively restored the impaired insulin signaling in diabetic muscle. UnAG decreased insulin receptor substrate (IRS) phosphorylation, increased protein kinase B (Akt) phosphorylation, and, hence, suppressed mTOR signaling. Consequently, UnAG enhanced Glut4 localization and increased PDH activity in the diabetic skeletal muscle. Intriguingly, our data indicated that UnAG normalized the suppressed autophagic signaling in diabetic muscle. In conclusion, our findings illustrated that UnAG restored the impaired insulin and autophagic signaling in skeletal muscle of diabetic mice, which are valuable to understand the underlying mechanisms of the anti-diabetic action of UnAG at peripheral skeletal muscle level. PMID:26228926

  10. Urtica dioica modulates hippocampal insulin signaling and recognition memory deficit in streptozotocin induced diabetic mice.

    PubMed

    Patel, Sita Sharan; Gupta, Sahil; Udayabanu, Malairaman

    2016-06-01

    Diabetes mellitus has been associated with functional abnormalities in the hippocampus and performance of cognitive function. Urtica dioica (UD) has been used in the treatment of diabetes. In our previous report we observed that UD extract attenuate diabetes mediated associative and spatial memory dysfunction. The present study aimed to evaluate the effect of UD extract on mouse model of diabetes-induced recognition memory deficit and explore the possible mechanism behind it. Streptozotocin (STZ) (50 mg/kg, i.p. consecutively for 5 days) was used to induce diabetes followed by UD extract (50 mg/kg, oral) or rosiglitazone (ROSI) (5 mg/kg, oral) administration for 8 weeks. STZ induced diabetic mice showed significant decrease in hippocampal insulin signaling and translocation of glucose transporter type 4 (GLUT4) to neuronal membrane resulting in cognitive dysfunction and hypolocomotion. UD treatment effectively improved hippocampal insulin signaling, glucose tolerance and recognition memory performance in diabetic mice, which was comparable to ROSI. Further, diabetes mediated oxidative stress and inflammation was reversed by chronic UD or ROSI administration. UD leaves extract acts via insulin signaling pathway and might prove to be effective for the diabetes mediated central nervous system complications. PMID:26767366

  11. Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide.

    PubMed Central

    Janson, J; Soeller, W C; Roche, P C; Nelson, R T; Torchia, A J; Kreutter, D K; Butler, P C

    1996-01-01

    The islet in non-insulin-dependent diabetes mellitus (NIDDM) is characterized by loss of beta cells and large local deposits of amyloid derived from the 37-amino acid protein, islet amyloid polypeptide (IAPP). We have hypothesized that IAPP amyloid forms intracellularly causing beta-cell destruction under conditions of high rates of expression. To test this we developed a homozygous transgenic mouse model with high rates of expression of human IAPP. Male transgenic mice spontaneously developed diabetes mellitus by 8 weeks of age, which was associated with selective beta-cell death and impaired insulin secretion. Small intra- and extracellular amorphous IAPP aggregates were present in islets of transgenic mice during the development of diabetes mellitus. However, IAPP derived amyloid deposits were found in only a minority of islets at approximately 20 weeks of age, notably after development of diabetes mellitus in male transgenic mice. Approximately 20% of female transgenic mice spontaneously developed diabetes mellitus at 30+ weeks of age, when beta-cell degeneration and both amorphous and amyloid deposits of IAPP were present. We conclude that overexpression of human IAPP causes beta-cell death, impaired insulin secretion, and diabetes mellitus. Large deposits of IAPP derived amyloid do not appear to be important in this cytotoxicity, but early, small amorphous intra- and extracellular aggregates of human IAPP were consistently present at the time of beta-cell death and therefore may be the most cytotoxic form of IAPP. Images Fig. 1 Fig. 3 Fig. 4 Fig. 5 PMID:8692984

  12. Protective effects of macrophage-derived interferon against encephalomyocarditis virus-induced diabetes mellitus in mice.

    PubMed

    Hirasawa, K; Ogiso, Y; Takeda, M; Lee, M J; Itagaki, S; Doi, K

    1995-12-01

    The involvement of macrophages in protection against diabetes mellitus in mice of BALB/c (susceptible) and C57BL (resistant) strains infected with the B (non-diabetogenic) or D (highly diabetogenic) variant of encephalomyocarditis (EMC) virus was examined. Pretreatment with the B variant of EMC virus (EMC-B), avirulent interferon (IFN) inducer, or Corynebacterium parvum inhibited diabetes in BALB/c mice infected with the D variant of EMC virus (EMC-D). Treatment of C57BL mice with carrageenan to compromise macrophage function rendered C57BL mice susceptible to EMC-D-induced diabetes. In macrophage culture for BALB/c mice, EMC-B induced IFN at an earlier stage than did EMC-D. The C57BL mouse-derived macrophages produced more IFN than did BALB/c mouse-derived macrophages after stimulation with EMC-D. Moreover, C. parvum increased IFN production in macrophage cultures from BALB/c mice, whereas carrageenan inhibited that in macrophage cultures from C57BL mice. These results suggest that IFN derived from macrophages may have an important role in protecting mice against EMC virus infection. PMID:8746525

  13. Exendin-4 improves resistance to Listeria monocytogenes infection in diabetic db/db mice

    PubMed Central

    Liu, Hsien Yueh; Chung, Chih-Yao; Yang, Wen-Chin; Liang, Chih-Lung; Wang, Chi-Young; Chang, Chih-Yu

    2012-01-01

    The incidence of diabetes mellitus is increasing among companion animals. This disease has similar characteristics in both humans and animals. Diabetes is frequently identified as an independent risk factor for infections associated with increased mortality. In the present study, homozygous diabetic (db/db) mice were infected with Listeria (L.) monocytogenes and then treated with the anti-diabetic drug exendin-4, a glucagon-like peptide 1 analogue. In aged db/db mice, decreased CD11b+ macrophage populations with higher lipid content and lower phagocytic activity were observed. Exendin-4 lowered high lipid levels and enhanced phagocytosis in macrophages from db/db mice infected with L. monocytogenes. Exendin-4 also ameliorated obesity and hyperglycemia, and improved ex vivo bacteria clearance by macrophages in the animals. Liver histology examined during L. monocytogenes infection indicated that abscess formation was much milder in exendin-4-treated db/db mice than in the control animals. Moreover, mechanistic studies demonstrated that expression of ATP binding cassette transporter 1, a sterol transporter, was higher in macrophages isolated from the exendin-4-treated db/db mice. Overall, our results suggest that exendin-4 decreases the risk of infection in diabetic animals by modifying the interaction between intracellular lipids and phagocytic macrophages. PMID:23000581

  14. Inhibition of inflammasome activation improves the impaired pattern of healing in genetically diabetic mice

    PubMed Central

    Bitto, Alessandra; Altavilla, Domenica; Pizzino, Gabriele; Irrera, Natasha; Pallio, Giovanni; Colonna, Michele R; Squadrito, Francesco

    2014-01-01

    Background and Purpose Type 2 diabetes impairs the healing process because of an exaggerated and persistent inflammatory response, and an altered expression pattern of angiogenic molecules. We investigated the effects of inflammasome blockade in diabetes-related wound-healings defects, in genetically diabetic mice. Experimental Approach An incisional skin wound model was produced on the back of female diabetic C57BL/KsJ-m +/+ Leptdb mice (db+/db+) and their normal littermates (db+/m+). Animals were treated daily with two inflammasome blocking agents, BAY 11-7082 (20 mg·kg−1 i.p.), or Brilliant Blue G (BBG, 45.5 mg·kg−1 i.p.), or vehicle. Mice were killed on 3, 6 and 12 days after skin injury to measure expression of the NOD-like receptor NLRP3, caspase-1, VEGF, the inflammasome adapter protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and the chemokine CXCL12. Wound levels of IL-1β and IL-18 were also measured, along with histological assessments of wound tissue and the time to complete wound closure. Key Results During healing, the diabetic mice exhibited increased activation of NLRP3, caspase-1, ASC, IL-1β and IL-18. They also showed a reduced expression of VEGF and CXCL12.Treatment with BAY 11-7082 or BBG, to block activation of the inflammasome, decreased the levels of pro-inflammatory molecules. Histological evaluation indicated that inflammasome blockade improved the impaired healing pattern, at day 12 in diabetic mice, along with a decreased time to complete skin healing. Conclusions and Implications These data strongly suggest that activation of the NLRP3 inflammasome is one of the key contributors to the delayed healing of wounds in diabetic mice. PMID:24329484

  15. Intranasal delivery of nanomicelle curcumin promotes corneal epithelial wound healing in streptozotocin-induced diabetic mice.

    PubMed

    Guo, Chuanlong; Li, Mengshuang; Qi, Xia; Lin, Guiming; Cui, Fenghua; Li, Fengjie; Wu, Xianggen

    2016-01-01

    Corneal nerves are mainly derived from the ophthalmic branch of the trigeminal ganglion (TG). Corneal neuropathy contributes to epithelial degenerative changes in diabetic keratopathy. Efficient drug delivery to TG may be beneficial for the treatment of diabetic keratopathy. This article described intranasal delivery of nanomicelle curcumin to correct pathophysiological conditions in TG to promote corneal epithelial/nerve wound healing in streptozotocin-induced diabetic mice. A diabetic mice model with corneal epithelium abrasion was established. Ocular topical and/or intranasal nanomicelle curcumin treatments were performed, and treatment efficacy and mechanisms of action were explored. Results showed that intranasal nanomicelle curcumin treatment promoted corneal epithelial wound healing and recovery of corneal sensation. Enhanced accumulation of reactive oxygen species, reduced free radical scavengers, increased mRNA expressions of inflammatory cytokines, and decreased mRNA expressions of neurotrophic factors in the cornea and TG neuron were observed in diabetic mice with corneal epithelium abrasions. Intranasal nanomicelle curcumin treatment effectively recovered these pathophysiological conditions, especially that of the TG neuron, and a strengthened recovery was observed with ocular topical combined with intranasal treatment. These findings indicated that intranasal curcumin treatment effectively helped promote diabetic corneal epithelial/nerve wound healing. This novel treatment might be a promising strengthened therapy for diabetic keratopathy. PMID:27405815

  16. Endothelin Receptor-A Antagonist Attenuates Retinal Vascular and Neuroretinal Pathology in Diabetic Mice

    PubMed Central

    Chou, Jonathan C.; Rollins, Stuart D.; Ye, Minghao; Batlle, Daniel; Fawzi, Amani A.

    2014-01-01

    Purpose. We sought to determine the effects of atrasentan, a selective endothelin-A receptor antagonist, on the retinal vascular and structural integrity in a db/db mouse, an animal model of type 2 diabetes and diabetic retinopathy. Methods. Diabetic mice, 23 weeks old, were given either atrasentan or vehicle treatment in drinking water for 8 weeks. At the end of the treatment period, eyes underwent trypsin digest to assess the retinal vascular pathology focusing on capillary degeneration, endothelial cell, and pericyte loss. Paraffin-embedded retinal cross sections were used to evaluate retinal sublayer thickness both near the optic nerve and in the retinal periphery. Immunohistochemistry and TUNEL assay were done to evaluate retinal cellular and vascular apoptosis. Results. Compared with untreated db/db mice, atrasentan treatment was able to ameliorate the retinal vascular pathology by reducing pericyte loss (29.2% ± 0.4% vs. 44.4% ± 2.0%, respectively, P < 0.05) and capillary degeneration as determined by the percentage of acellular capillaries (8.6% ± 0.3% vs. 3.3% ± 0.41%, respectively, P < 0.05). A reduction in inner retinal thinning both at the optic nerve and at the periphery in treated diabetic mice was also observed in db/db mice treated with atrasentan as compared with untreated db/db mice (P < 0.05). TUNEL assay suggested that atrasentan may decrease enhanced apoptosis in neuroretinal layers and vascular pericytes in the db/db mice. Conclusions. Endothelin-A receptor blockade using atrasentan significantly reduces the vascular and neuroretinal complications in diabetic mice. Endothelin-A receptor blockade is a promising therapeutic target in diabetic retinopathy. PMID:24644048

  17. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice

    PubMed Central

    Kriegel, Martin A.; Sefik, Esen; Hill, Jonathan A.; Wu, Hsin-Jung; Benoist, Christophe; Mathis, Diane

    2011-01-01

    Vertebrates typically harbor a rich gastrointestinal microbiota, which has coevolved with the host over millennia and is essential for several host physiological functions, in particular maturation of the immune system. Recent studies have highlighted the importance of a single bacterial species, segmented filamentous bacteria (SFB), in inducing a robust T-helper cell type 17 (Th17) population in the small-intestinal lamina propria (SI-LP) of the mouse gut. Consequently, SFB can promote IL-17–dependent immune and autoimmune responses, gut-associated as well as systemic, including inflammatory arthritis and experimental autoimmune encephalomyelitis. Here, we exploit the incomplete penetrance of SFB colonization of NOD mice in our animal facility to explore its impact on the incidence and course of type 1 diabetes in this prototypical, spontaneous model. There was a strong cosegregation of SFB positivity and diabetes protection in females, but not in males, which remained relatively disease-free regardless of the SFB status. In contrast, insulitis did not depend on SFB colonization. SFB-positive, but not SFB-negative, females had a substantial population of Th17 cells in the SI-LP, which was the only significant, repeatable difference in the examined T-cell compartments of the gut, pancreas, or systemic lymphoid tissues. Th17-signature transcripts dominated the very limited SFB-induced molecular changes detected in SI-LP CD4+ T cells. Thus, a single bacterium, and the gut immune system alterations associated with it, can either promote or protect from autoimmunity in predisposed mouse models, probably reflecting their variable dependence on different Th subsets. PMID:21709219

  18. Flos Puerariae Extract Prevents Myocardial Apoptosis via Attenuation Oxidative Stress in Streptozotocin-Induced Diabetic Mice

    PubMed Central

    Guo, Shuang; Cheng, Hongke; Wu, Jiliang; Liu, Chao

    2014-01-01

    Background Diabetic cardiomyopathy (DCM) suggests a direct cellular insult to myocardium. Apoptosis is considered as one of the hallmarks of DCM. Oxidative stress plays a key role in the pathogenesis of DCM. In this study, we explored the prevention of myocardial apoptosis by crude extract from Flos Puerariae (FPE) in experimental diabetic mice. Methods Experimental diabetic model was induced by intraperitoneally injection of streptozotocin (STZ, 50 mg/kg/day) for five consecutive days in C57BL/6J mice. FPE (100, 200 mg/kg) was orally administrated once a day for ten weeks. Cardiac structure changes, apoptosis, superoxide production, NADPH oxidase subunits expression (gp91phox, p47phox, and p67phox), and related regulatory factors were assessed in the heart of mice. Results Diabetic mice were characterized by high blood glucose (≥11.1 mmol/L) and reduced body weight. In the end of the experiment, aberrant myofilament structure, as well as TUNEL positive cardiac cells coupled with increased Bax/Bcl-2 ratio and Caspase-3 expression was found in diabetic mice. Moreover, ROS formation, the ratio of NADP+/NADPH and NADPH oxidase subunits expression of gp91phox and p47phox, lipid peroxidation level was significantly increased, while antioxidant enzyme SOD and GSH-Px activity were reduced in the myocardial tissue of diabetic mice. In contrast, treatment with FPE resulted in a normalized glucose and weight profile. FPE administration also preserved myocardial structure and reduced apoptotic cardiac cell death in diabetic mice. The elevated markers of oxidative stress were significantly reversed by FPE supplementation. Further, FPE treatment markedly inhibited the increased Bax/Bcl-2 ratio and Caspase-3 expression, as well as suppressed JNK and P38 MAPK activation in the heart of diabetic mice. Conclusions Our data demonstrate for the first time that FPE may have therapeutic potential for STZ-induced diabetic cardiomyopathy through preventing myocardial apoptosis via

  19. Activation of spinal cannabinoid CB2 receptors inhibits neuropathic pain in streptozotocin-induced diabetic mice.

    PubMed

    Ikeda, H; Ikegami, M; Kai, M; Ohsawa, M; Kamei, J

    2013-10-10

    The role of spinal cannabinoid systems in neuropathic pain of streptozotocin (STZ)-induced diabetic mice was studied. In normal mice, injection of the cannabinoid receptor agonist WIN-55,212-2 (1 and 3μg, i.t.) dose-dependently prolonged the tail-flick latency, whereas there were no changes with the injection of either cannabinoid CB1 (AM 251, 1 μg, i.t.) or CB2 (AM 630, 4 μg, i.t.) receptor antagonists. AM 251 (1 μg, i.t.), but not AM 630 (4 μg, i.t.), significantly inhibited the prolongation of the tail-flick latency induced by WIN-55,212-2 (3 μg, i.t.). In STZ-induced diabetic mice, the tail-flick latency was significantly shorter than that in normal mice. A low dose of WIN-55,212-2 (1 μg, i.t.) significantly recovered the tail-flick latency in STZ-induced diabetic mice. The effect of WIN-55,212-2 (1 μg, i.t.) in STZ-induced diabetic mice was significantly inhibited by AM 630 (4 μg, i.t.), but not AM 251 (1 μg). The selective cannabinoid CB2 receptor agonist L-759,656 (19 and 38 μg, i.t.) also dose-dependently recovered the tail-flick latency in STZ-induced diabetic mice, and this recovery was inhibited by AM 630 (4 μg, i.t.). The protein levels of cannabinoid CB1 receptors, CB2 receptors and diacylglycerol lipase α (DGL-α), the enzyme that synthesizes endocannabinoid 2-arachidonoylglycerol, in the spinal cord were examined using Western blotting. The protein levels of both cannabinoid CB1 and CB2 receptors were increased in STZ-induced diabetic mice, whereas the protein level of DGL-α was significantly decreased. These results indicate that spinal cannabinoid systems are changed in diabetic mice and suggest that cannabinoid CB2 receptor agonists might have an ability to recover diabetic neuropathic pain.

  20. Coronary arterial BK channel dysfunction exacerbates ischemia/reperfusion-induced myocardial injury in diabetic mice.

    PubMed

    Lu, Tong; Jiang, Bin; Wang, Xiao-Li; Lee, Hon-Chi

    2016-09-01

    The large conductance Ca(2+)-activated K(+) (BK) channels, abundantly expressed in coronary artery smooth muscle cells (SMCs), play a pivotal role in regulating coronary circulation. A large body of evidence indicates that coronary arterial BK channel function is diminished in both type 1 and type 2 diabetes. However, the consequence of coronary BK channel dysfunction in diabetes is not clear. We hypothesized that impaired coronary BK channel function exacerbates myocardial ischemia/reperfusion (I/R) injury in streptozotocin-induced diabetic mice. Combining patch-clamp techniques and cellular biological approaches, we found that diabetes facilitated the colocalization of angiotensin II (Ang II) type 1 receptors and BK channel α-subunits (BK-α), but not BK channel β1-subunits (BK-β1), in the caveolae of coronary SMCs. This caveolar compartmentation in vascular SMCs not only enhanced Ang II-mediated inhibition of BK-α but also produced a physical disassociation between BK-α and BK-β1, leading to increased infarct size in diabetic hearts. Most importantly, genetic ablation of caveolae integrity or pharmacological activation of coronary BK channels protected the cardiac function of diabetic mice from experimental I/R injury in both in vivo and ex vivo preparations. Our results demonstrate a vascular ionic mechanism underlying the poor outcome of myocardial injury in diabetes. Hence, activation of coronary BK channels may serve as a therapeutic target for cardiovascular complications of diabetes. PMID:27574914

  1. Administration of Danhong Injection to diabetic db/db mice inhibits the development of diabetic retinopathy and nephropathy.

    PubMed

    Liu, Mengyang; Pan, Quan; Chen, Yuanli; Yang, Xiaoxiao; Zhao, Buchang; Jia, Lifu; Zhu, Yan; Zhang, Boli; Gao, Xiumei; Li, Xiaoju; Han, Jihong; Duan, Yajun

    2015-06-10

    Danhong Injection (DHI), a Chinese medicine for treatment of patients with coronary heart disease, inhibits primary abdominal aortic aneurysms in apoE deficient (apoE(-/-)) mice. Formation of microaneurysms plays an important role in the development of diabetic retinopathy and nephropathy. It remains unknown if DHI can reduce these diabetic complications. In this study, diabetic db/db mice in two groups were injected with saline and DHI, respectively, for 14 weeks. Blood and tissue samples were collected to determine serum glucose, lipids and tissue structure. DHI reduced diabetes-induced body weight gain, serum cholesterol and glucose levels. In retinas, DHI blocked the shrink of whole retina and retinal sub-layers by inhibiting expression of caspase 3, matrix metalloproteinase 2 (MMP-2) and MMP-9, accumulation of carbohydrate macromolecules and formation of acellular capillaries. DHI improved renal functions by inhibiting mesangial matrix expansion, expression of vascular endothelial growth factor A, fibronectin and advanced glycation end products in kidneys. Mechanistically, DHI induced expression of glucokinase, AMPKα/phosphorylated AMPKα, insulin receptor substrate 1, fibroblast growth factor 21 and peroxisome proliferator-activated γ. Expression of genes responsible for energy expenditure was also activated by DHI. Therefore, DHI inhibits diabetic retinopathy and nephropathy by ameliorating glucose metabolism and demonstrates a potential application in clinics.

  2. Pivotal role of oxidative stress in tumor metastasis under diabetic conditions in mice.

    PubMed

    Ikemura, Mai; Nishikawa, Makiya; Kusamori, Kosuke; Fukuoka, Miho; Yamashita, Fumiyoshi; Hashida, Mitsuru

    2013-09-10

    Diabetic patients are reported to have a high incidence and mortality of cancer, but little is known about the linkage. In this study, we investigated whether high oxidative stress is involved in the acceleration of tumor metastasis in diabetic mice. Murine melanoma B16-BL6 cells stably labeled with firefly luciferase (B16-BL6/Luc) were inoculated into the tail vein of streptozotocin (STZ)-treated or untreated mice. A luciferase assay demonstrated that tumor cells were present largely in the lung of untreated mice, whereas large numbers of tumor cells were detected in both the lung and liver of STZ-treated mice. Repeated injections of polyethylene glycol-conjugated catalase (PEG-catalase), a long-circulating derivative, reduced the elevated fasting blood glucose levels and plasma lipoperoxide levels of STZ-treated mice, but had no significant effects on these parameters in untreated mice. In addition, the injections significantly reduced the number of tumor cells in the lung and liver in both untreated and STZ-treated mice. Culture of B16-BL6/Luc cells in medium containing over 45 mg/dl glucose hardly affected the proliferation of the cells, whereas the addition of plasma of STZ-treated mice to the medium significantly increased the number of cells. Plasma samples of STZ-treated mice receiving PEG-catalase exhibited no such effect on proliferation. These findings indicate that a hyperglycemia-induced increase in oxidative stress is involved in the acceleration of tumor metastasis, and the removal of systemic hydrogen peroxide by PEG-catalase can inhibit the progression of diabetic conditions and tumor metastasis in diabetes. PMID:23735571

  3. Attenuation of hepatotoxicity and oxidative stress in diabetes STZ-induced type 1 by biotin in Swiss albino mice.

    PubMed

    Aldahmash, Badr Abdullah; El-Nagar, Doaa Mohamed; Ibrahim, Khalid Elfakki

    2016-03-01

    Diabetes mellitus is one of the major health problems. This study was designed to investigate the effect of biotin to regulate blood glucose level, reduced toxicity and oxidative stress in liver of diabetic mice STZ-induced type 1. Male mice were divided into three groups, the first one served as the control group, the second and the third groups received single ip dose of 150 mg/kg of STZ, the second group served as the untreated diabetic group, the third group received daily oral dose of 15 mg/kg of biotin, livers and liver index showed insignificant difference among groups. Blood glucose level showed a significant decrease in treated diabetic mice compared to untreated diabetic mice. Biochemical analysis showed a significant decrease in liver enzymes AST and ALT compared to the control group. Histopathological examination showed severe changes in untreated diabetic liver tissue manifested by dilated portal vein, leukocytic infiltration, fatty degeneration and moderate to severe histopathological score, whereas, treated diabetic mice with biotin showed reduction in hepatotoxicity represented by appearance of relative healthy hepatocytes and normal histopathological score. Immunohistochemistry of acrolein showed intense immunoreactions in liver section of untreated diabetic mice and faint immunoreactions in treated diabetic mice with biotin as evidence to oxidative stress reduction. PMID:26981014

  4. Attenuation of hepatotoxicity and oxidative stress in diabetes STZ-induced type 1 by biotin in Swiss albino mice

    PubMed Central

    Aldahmash, Badr Abdullah; El-Nagar, Doaa Mohamed; Ibrahim, Khalid Elfakki

    2015-01-01

    Diabetes mellitus is one of the major health problems. This study was designed to investigate the effect of biotin to regulate blood glucose level, reduced toxicity and oxidative stress in liver of diabetic mice STZ-induced type 1. Male mice were divided into three groups, the first one served as the control group, the second and the third groups received single ip dose of 150 mg/kg of STZ, the second group served as the untreated diabetic group, the third group received daily oral dose of 15 mg/kg of biotin, livers and liver index showed insignificant difference among groups. Blood glucose level showed a significant decrease in treated diabetic mice compared to untreated diabetic mice. Biochemical analysis showed a significant decrease in liver enzymes AST and ALT compared to the control group. Histopathological examination showed severe changes in untreated diabetic liver tissue manifested by dilated portal vein, leukocytic infiltration, fatty degeneration and moderate to severe histopathological score, whereas, treated diabetic mice with biotin showed reduction in hepatotoxicity represented by appearance of relative healthy hepatocytes and normal histopathological score. Immunohistochemistry of acrolein showed intense immunoreactions in liver section of untreated diabetic mice and faint immunoreactions in treated diabetic mice with biotin as evidence to oxidative stress reduction. PMID:26981014

  5. Defects in dermal Vγ4 γ δ T cells result in delayed wound healing in diabetic mice.

    PubMed

    Liu, Zhongyang; Xu, Yingbin; Zhang, Xiaorong; Liang, Guangping; Chen, Lei; Xie, Julin; Tang, Jinming; Zhao, Jingling; Shu, Bin; Qi, Shaohai; Chen, Jian; Luo, Gaoxing; Wu, Jun; He, Weifeng; Liu, Xusheng

    2016-01-01

    The skin serves as a physical and chemical barrier to provide an initial line of defense against environmental threats; however, this function is impaired in diabetes. Vγ4 γ δ T cells in the dermis are an important part of the resident cutaneous immunosurveillance program, but these cells have yet to be explored in the context of diabetes. In this study, we observed that the impaired maintenance of dermal Vγ4 γ δ T cells is caused by reduced production of IL-7 in the skin of diabetic mice, which was closely associated with weakened activation of the mTOR pathway in the epidermis of diabetic mice. Weakened CCL20/CCR6 chemokine signaling resulted in the impaired recruitment of dermal Vγ4 γ δ T cells following wounding in diabetic mice. Meanwhile, reduced levels of IL-23 and IL-1β in the dermis around the wounds of diabetic mice resulted in the impaired production of IL-17 by dermal Vγ4 γ δ T cells. Therefore, diminished dermal Vγ4 γ δ T cells and impaired IL-17 production by these cells were important factors in the markedly reduced IL-17 levels in the skin around the wounds of diabetic mice. Because reduced IL-17 levels at the wound edge have been closely associated with delayed wound closure in diabetic mice, defects in dermal Vγ4 γ δ T cells may be an important mechanism underlying delayed wound healing in diabetic mice. PMID:27398150

  6. Defects in dermal Vγ4 γ δ T cells result in delayed wound healing in diabetic mice.

    PubMed

    Liu, Zhongyang; Xu, Yingbin; Zhang, Xiaorong; Liang, Guangping; Chen, Lei; Xie, Julin; Tang, Jinming; Zhao, Jingling; Shu, Bin; Qi, Shaohai; Chen, Jian; Luo, Gaoxing; Wu, Jun; He, Weifeng; Liu, Xusheng

    2016-01-01

    The skin serves as a physical and chemical barrier to provide an initial line of defense against environmental threats; however, this function is impaired in diabetes. Vγ4 γ δ T cells in the dermis are an important part of the resident cutaneous immunosurveillance program, but these cells have yet to be explored in the context of diabetes. In this study, we observed that the impaired maintenance of dermal Vγ4 γ δ T cells is caused by reduced production of IL-7 in the skin of diabetic mice, which was closely associated with weakened activation of the mTOR pathway in the epidermis of diabetic mice. Weakened CCL20/CCR6 chemokine signaling resulted in the impaired recruitment of dermal Vγ4 γ δ T cells following wounding in diabetic mice. Meanwhile, reduced levels of IL-23 and IL-1β in the dermis around the wounds of diabetic mice resulted in the impaired production of IL-17 by dermal Vγ4 γ δ T cells. Therefore, diminished dermal Vγ4 γ δ T cells and impaired IL-17 production by these cells were important factors in the markedly reduced IL-17 levels in the skin around the wounds of diabetic mice. Because reduced IL-17 levels at the wound edge have been closely associated with delayed wound closure in diabetic mice, defects in dermal Vγ4 γ δ T cells may be an important mechanism underlying delayed wound healing in diabetic mice.

  7. Inactivation of arf-bp1 induces p53 activation and diabetic phenotypes in mice.

    PubMed

    Kon, Ning; Zhong, Jiayun; Qiang, Li; Accili, Domenico; Gu, Wei

    2012-02-10

    It is well accepted that the Mdm2 ubiquitin ligase acts as a major factor in controlling p53 stability and activity in vivo. Although several E3 ligases have been reported to be involved in Mdm2-independent p53 degradation, the roles of these ligases in p53 regulation in vivo remain largely unknown. To elucidate the physiological role of the ubiquitin ligase ARF-BP1, we generated arf-bp1 mutant mice. We found that inactivation of arf-bp1 during embryonic development in mice resulted in p53 activation and embryonic lethality, but the mice with arf-bp1 deletion specifically in the pancreatic β-cells (arf-bp1(FL/Y)/RIP-cre) were viable and displayed no obvious abnormality after birth. Interestingly, these mice showed dramatic loss of β-cells as mice aged, and >50% of these mice died of severe diabetic symptoms before reaching 1 year of age. Notably, the diabetic phenotype of these mice was largely reversed by concomitant deletion of p53, and the life span of the mice was significantly extended (p53(LFL/FL)/arf-bp1(FL/Y)/RIP-cre). These findings underscore an important role of ARF-BP1 in maintaining β-cell homeostasis in aging mice and reveal that the stability of p53 is critically regulated by ARF-BP1 in vivo.

  8. The protective effects of oral low-dose quercetin on diabetic nephropathy in hypercholesterolemic mice

    PubMed Central

    Gomes, Isabele B. S.; Porto, Marcella L.; Santos, Maria C. L. F. S.; Campagnaro, Bianca P.; Gava, Agata L.; Meyrelles, Silvana S.; Pereira, Thiago M. C.; Vasquez, Elisardo C.

    2015-01-01

    Aims: Diabetic nephropathy (DN) is one of the most important causes of chronic renal disease, and the incidence of DN is increasing worldwide. Considering our previous report (Gomes et al., 2014) indicating that chronic treatment with oral low-dose quercetin (10 mg/Kg) demonstrated anti-oxidative, anti-apoptotic and renoprotective effects in the C57BL/6J model of DN, we investigated whether this flavonoid could also have beneficial effects in concurrent DN and spontaneous atherosclerosis using the apolipoprotein E-deficient mouse (apoE−/−). Methods: Streptozotocin was used to induce diabetes (100 mg/kg/day, 3 days) in male apoE−/− mice (8 week-old). After 6 weeks, the mice were randomly separated into DQ: diabetic apoE−/− mice treated with quercetin (10 mg/kg/day, 4 weeks, n = 8), DV: diabetic ApoE−/− mice treated with vehicle (n = 8) and ND: non-treated non-diabetic mice (n = 8). Results: Quercetin treatment diminished polyuria (~30%; p < 0.05), glycemia (~25%, p < 0.05), normalized the hypertriglyceridemia. Moreover, this bioflavonoid diminished creatininemia (~30%, p < 0.01) and reduced proteinuria but not to normal levels. We also observed protective effects on the renal structural changes, including normalization of the index of glomerulosclerosis and kidney weight/body weight. Conclusions: Our data revealed that quercetin treatment significantly reduced DN in hypercholesterolemic mice by inducing biochemical changes (decrease in glucose and triglycerides serum levels) and reduction of glomerulosclerosis. Thus, this study highlights the relevance of quercetin as an alternative therapeutic option for DN, including in diabetes associated with dyslipidemia. PMID:26388784

  9. Low TGFβ1 expression prevents and high expression exacerbates diabetic nephropathy in mice

    PubMed Central

    Hathaway, Catherine K.; Gasim, Adil M. H.; Grant, Ruriko; Chang, Albert S.; Kim, Hyung-Suk; Madden, Victoria J.; Bagnell, C. Robert; Jennette, J. Charles; Smithies, Oliver; Kakoki, Masao

    2015-01-01

    Nephropathy develops in many but not all patients with long-standing type 1 diabetes. Substantial efforts to identify genotypic differences explaining this differential susceptibility have been made, with limited success. Here, we show that the expression of the transforming growth factor β1 gene (Tgfb1) affects the development of diabetic nephropathy in mice. To do this we genetically varied Tgfb1 expression in five steps, 10%, 60%, 100%, 150%, and 300% of normal, in mice with type 1 diabetes caused by the Akita mutation in the insulin gene (Ins2Akita). Although plasma glucose levels were not affected by Tgfb1 genotype, many features of diabetic nephropathy (mesangial expansion, elevated plasma creatinine and urea, decreased creatinine clearance and albuminuria) were progressively ameliorated as Tgfb1 expression decreased and were progressively exacerbated when expression was increased. The diabetic 10% hypomorphs had comparable creatinine clearance and albumin excretion to wild-type mice and no harmful changes in renal morphology. The diabetic 300% hypermorphs had ∼1/3 the creatinine clearance of wild-type mice, >20× their albumin excretion, ∼3× thicker glomerular basement membranes and severe podocyte effacement, matching human diabetic nephropathy. Switching Tgfb1 expression from low to high in the tubules of the hypomorphs increased their albumin excretion more than 10-fold but creatinine clearance remained high. Switching Tgfb1 expression from low to high in the podocytes markedly decreased creatinine clearance, but minimally increased albumin excretion. Decreasing expression of Tgfb1 could be a promising option for preventing loss of renal function in diabetes. PMID:25902541

  10. High fat-fed diabetic mice present with profound alterations of the osteocyte network.

    PubMed

    Mabilleau, Guillaume; Perrot, Rodolphe; Flatt, Peter R; Irwin, Nigel; Chappard, Daniel

    2016-09-01

    Diabetes mellitus is considered to be an independent risk factor for bone fragility fractures. Reductions in bone mass, observed only with type 1 diabetes mellitus, as well as modifications of bone microarchitectures and tissue material properties are landmarks of diabetes-related bone alterations. An interesting feature observed in type 2 diabetes mellitus (T2DM) is the augmented concentration in circulating sclerostin. This observation prompts us to hypothesize that modifications of osteocyte network and perilacunar mineralization occur in T2DM. As such, the aims of the present study were to ascertain by quantitative backscattered electron imaging, confocal microscopy and image analysis, modifications of perilacunar tissue mineral density, osteocyte morphology and osteocyte network topology in a mouse model of high fat-induced type 2 diabetes. As compared with lean control animals, diabetic mice exhibited a significant 48% decrease in perilacunar mineralization heterogeneity although mean perilacunar mineralization was unchanged. Furthermore, in diabetic animals, osteocyte volume was significantly augmented by 34% with no change in the overall number of dendrite processes. Finally, the network topology was profoundly modified in diabetic mice with increases in the mean node degree, mean node volume and hub numbers whilst the mean link length was reduced. Overall, it appeared that in diabetic animals, the dendritic network exhibited features of a scale-free network as opposed to the single-scale characteristic observed in lean controls. However, it is important to ascertain whether diabetic patients exhibit such modifications of the osteocyte network and whether anti-diabetic drugs could restore normal osteocyte and network parameters, thereby improving bone quality and protecting against fragility fractures. PMID:27312542

  11. Gene expression profiling in hearts of diabetic mice uncovers a potential role of estrogen-related receptor γ in diabetic cardiomyopathy.

    PubMed

    Lasheras, Jaime; Vilà, Maria; Zamora, Mònica; Riu, Efrén; Pardo, Rosario; Poncelas, Marcos; Cases, Ildefonso; Ruiz-Meana, Marisol; Hernández, Cristina; Feliu, Juan E; Simó, Rafael; García-Dorado, David; Villena, Josep A

    2016-07-15

    Diabetic cardiomyopathy is characterized by an abnormal oxidative metabolism, but the underlying mechanisms remain to be defined. To uncover potential mechanisms involved in the pathophysiology of diabetic cardiomyopathy, we performed a gene expression profiling study in hearts of diabetic db/db mice. Diabetic hearts showed a gene expression pattern characterized by the up-regulation of genes involved in lipid oxidation, together with an abnormal expression of genes related to the cardiac contractile function. A screening for potential regulators of the genes differentially expressed in diabetic mice found that estrogen-related receptor γ (ERRγ) was increased in heart of db/db mice. Overexpression of ERRγ in cultured cardiomyocytes was sufficient to promote the expression of genes involved in lipid oxidation, increase palmitate oxidation and induce cardiomyocyte hypertrophy. Our findings strongly support a role for ERRγ in the metabolic alterations that underlie the development of diabetic cardiomyopathy. PMID:27062900

  12. Emetine Di-HCl Attenuates Type 1 Diabetes Mellitus in Mice

    PubMed Central

    Hudson, LaQueta K; Dancho, Meghan E; Li, Jianhua; Bruchfeld, Johanna B; Ragab, Ahmed A; He, Mingzhu M; Bragg, Meaghan; Lenaghan, Delaney; Quinn, Michael D; Fritz, Jason R; Tanzi, Matthew V; Silverman, Harold A; Hanes, William M; Levine, Yaakov A; Pavlov, Valentin A; Olofsson, Peder S; Roth, Jesse; Al-Abed, Yousef; Andersson, Ulf; Tracey, Kevin J; Chavan, Sangeeta S

    2016-01-01

    Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by β cell destruction, insulin deficiency and hyperglycemia. Activated macrophages and autoimmune T cells play a crucial role in the pathogenesis of hyperglycemia in NOD murine diabetes models, but the molecular mechanisms of macrophage activation are unknown. We recently identified pigment epithelium-derived factor (PEDF) as an adipocyte-derived factor that activates macrophages and mediates insulin resistance. Reasoning that PEDF might participate as a proinflammatory mediator in murine diabetes, we measured PEDF levels in NOD mice. PEDF levels are significantly elevated in pancreas, in parallel with pancreatic TNF levels in NOD mice. To identify experimental therapeutics, we screened 2,327 compounds in two chemical libraries (the NIH Clinical Collection and Pharmakon-1600) for leads that inhibit PEDF mediated TNF release in macrophage cultures. The lead molecule selected, “emetine” is a widely used emetic. It inhibited PEDF-mediated macrophage activation with an EC50 or 146 nmol/L. Administration of emetine to NOD mice and to C57Bl6 mice subjected to streptozotocin significantly attenuated hyperglycemia, reduced TNF levels in pancreas and attenuated insulitis. Together, these results suggest that targeting PEDF with emetine may attenuate TNF release and hyperglycemia in murine diabetes models. This suggests that further investigation of PEDF and emetine in the pathogenesis of human diabetes is warranted. PMID:27341452

  13. Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice.

    PubMed

    Franko, Andras; Huypens, Peter; Neschen, Susanne; Irmler, Martin; Rozman, Jan; Rathkolb, Birgit; Neff, Frauke; Prehn, Cornelia; Dubois, Guillaume; Baumann, Martina; Massinger, Rebecca; Gradinger, Daniel; Przemeck, Gerhard K H; Repp, Birgit; Aichler, Michaela; Feuchtinger, Annette; Schommers, Philipp; Stöhr, Oliver; Sanchez-Lasheras, Carmen; Adamski, Jerzy; Peter, Andreas; Prokisch, Holger; Beckers, Johannes; Walch, Axel K; Fuchs, Helmut; Wolf, Eckhard; Schubert, Markus; Wiesner, Rudolf J; Hrabě de Angelis, Martin

    2016-09-01

    Bezafibrate (BEZ), a pan activator of peroxisome proliferator-activated receptors (PPARs), has been generally used to treat hyperlipidemia for decades. Clinical trials with type 2 diabetes patients indicated that BEZ also has beneficial effects on glucose metabolism, although the underlying mechanisms of these effects remain elusive. Even less is known about a potential role for BEZ in treating type 1 diabetes. Here we show that BEZ markedly improves hyperglycemia and glucose and insulin tolerance in mice with streptozotocin (STZ)-induced diabetes, an insulin-deficient mouse model of type 1 diabetes. BEZ treatment of STZ mice significantly suppressed the hepatic expression of genes that are annotated in inflammatory processes, whereas the expression of PPAR and insulin target gene transcripts was increased. Furthermore, BEZ-treated mice also exhibited improved metabolic flexibility as well as an enhanced mitochondrial mass and function in the liver. Finally, we show that the number of pancreatic islets and the area of insulin-positive cells tended to be higher in BEZ-treated mice. Our data suggest that BEZ may improve impaired glucose metabolism by augmenting hepatic mitochondrial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity and metabolic flexibility. Thus, BEZ treatment might also be useful for patients with impaired glucose tolerance or diabetes. PMID:27284107

  14. Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease

    PubMed Central

    Ruberte, Jesús; Ayuso, Eduard; Navarro, Marc; Carretero, Ana; Nacher, Víctor; Haurigot, Virginia; George, Mónica; Llombart, Cristina; Casellas, Alba; Costa, Cristina; Bosch, Assumpció; Bosch, Fatima

    2004-01-01

    IGF-1 has been associated with the pathogenesis of diabetic retinopathy, although its role is not fully understood. Here we show that normoglycemic/normoinsulinemic transgenic mice overexpressing IGF-1 in the retina developed most alterations seen in human diabetic eye disease. A paracrine effect of IGF-1 in the retina initiated vascular alterations that progressed from nonproliferative to proliferative retinopathy and retinal detachment. Eyes from 2-month-old transgenic mice showed loss of pericytes and thickening of basement membrane of retinal capillaries. In mice 6 months and older, venule dilatation, intraretinal microvascular abnormalities, and neovascularization of the retina and vitreous cavity were observed. Neovascularization was consistent with increased IGF-1 induction of VEGF expression in retinal glial cells. In addition, IGF-1 accumulated in aqueous humor, which may have caused rubeosis iridis and subsequently adhesions between the cornea and iris that hampered aqueous humor drainage and led to neovascular glaucoma. Furthermore, all transgenic mice developed cataracts. These findings suggest a role of IGF-1 in the development of ocular complications in long-term diabetes. Thus, these transgenic mice may be used to study the mechanisms that lead to diabetes eye disease and constitute an appropriate model in which to assay new therapies. PMID:15085194

  15. Glucagon Receptor Blockade With a Human Antibody Normalizes Blood Glucose in Diabetic Mice and Monkeys.

    PubMed

    Okamoto, Haruka; Kim, Jinrang; Aglione, JohnPaul; Lee, Joseph; Cavino, Katie; Na, Erqian; Rafique, Ashique; Kim, Jee Hae; Harp, Joyce; Valenzuela, David M; Yancopoulos, George D; Murphy, Andrew J; Gromada, Jesper

    2015-08-01

    Antagonizing glucagon action represents an attractive therapeutic option for reducing hepatic glucose production in settings of hyperglycemia where glucagon excess plays a key pathophysiological role. We therefore generated REGN1193, a fully human monoclonal antibody that binds and inhibits glucagon receptor (GCGR) signaling in vitro. REGN1193 administration to diabetic ob/ob and diet-induced obese mice lowered blood glucose to levels observed in GCGR-deficient mice. In diet-induced obese mice, REGN1193 reduced food intake, adipose tissue mass, and body weight. REGN1193 increased circulating levels of glucagon and glucagon-like peptide 1 and was associated with reversible expansion of pancreatic α-cell area. Hyperglucagonemia and α-cell hyperplasia was observed in fibroblast growth factor 21-deficient mice treated with REGN1193. Single administration of REGN1193 to diabetic cynomolgus monkeys normalized fasting blood glucose and glucose tolerance and increased circulating levels of glucagon and amino acids. Finally, administration of REGN1193 for 8 weeks to normoglycemic cynomolgus monkeys did not cause hypoglycemia or increase pancreatic α-cell area. In summary, the GCGR-blocking antibody REGN1193 normalizes blood glucose in diabetic mice and monkeys but does not produce hypoglycemia in normoglycemic monkeys. Thus, REGN1193 provides a potential therapeutic modality for diabetes mellitus and acute hyperglycemic conditions. PMID:26020795

  16. Cannabinoid functions in the amygdala contribute to conditioned fear memory in streptozotocin-induced diabetic mice: Interaction with glutamatergic functions.

    PubMed

    Ikeda, Hiroko; Ikegami, Megumi; Kai, Misa; Kamei, Junzo

    2015-07-01

    The role of cannabinoid systems in conditioned fear memory was investigated in streptozotocin (STZ)-induced diabetic mice. The cannabinoid receptor agonist WIN-55,212-2 (1mg/kg, i.p.), when injected into normal mice after conditioning, significantly prolonged the duration of freezing behavior. This effect was significantly inhibited by the cannabinoid CB1 receptor antagonist AM 251 (3mg/kg, s.c.), but not by the cannabinoid CB2 receptor antagonist AM 630 (1mg/kg, s.c.). The duration of freezing in STZ-induced diabetic mice was significantly longer than that in non-diabetic mice. The injection of WIN-55,212-2 (1mg/kg, i.p.) after conditioning significantly prolonged the duration of freezing in non-diabetic mice, but not in STZ-induced diabetic mice. In contrast, the injection of AM 251 (3mg/kg, s.c.) after conditioning significantly shortened the duration of freezing in STZ-induced diabetic mice, but not in non-diabetic mice. The injection of AM 251 (3mg/kg, s.c.) before conditioning or before testing did not significantly affect the duration of freezing in STZ-induced diabetic mice. The protein levels of cannabinoid CB1 receptors in the amygdala were increased in STZ-induced diabetic mice. In contrast, the protein levels of cannabinoid CB2 receptors and diacylglycerol lipase α, the enzyme that synthesizes endocannabinoid 2-arachidonoylglycerol, in the amygdala did not differ between non-diabetic and STZ-induced diabetic mice. None of these proteins in the hippocampus was different between non-diabetic and STZ-induced diabetic mice. The injection of AM 251 (50 ng/side) into the basolateral amygdala significantly inhibited the duration of freezing in STZ-induced diabetic mice. Since endocannabinoid is controlled by glutamatergic function, we further examined the role of glutamatergic function in the increased fear memory in STZ-induced diabetic mice. The amounts of glutamine and glutamic acid in the amygdala of STZ-induced diabetic mice were significantly increased

  17. Cinnamic acid exerts anti-diabetic activity by improving glucose tolerance in vivo and by stimulating insulin secretion in vitro.

    PubMed

    Hafizur, Rahman M; Hameed, Abdul; Shukrana, Mishkat; Raza, Sayed Ali; Chishti, Sidra; Kabir, Nurul; Siddiqui, Rehan A

    2015-02-15

    Although the anti-diabetic activity of cinnamic acid, a pure compound from cinnamon, has been reported but its mechanism(s) is not yet clear. The present study was designed to explore the possible mechanism(s) of anti-diabetic activity of cinnamic acid in in vitro and in vivo non-obese type 2 diabetic rats. Non-obese type 2 diabetes was developed by injecting 90 mg/kg streptozotocin in 2-day-old Wistar pups. Cinnamic acid and cinnamaldehyde were administered orally to diabetic rats for assessing acute blood glucose lowering effect and improvement of glucose tolerance. Additionally, insulin secretory activity of cinnamic acid and cinnamaldehyde was evaluated in isolated mice islets. Cinnamic acid, but not cinnamaldehyde, decreased blood glucose levels in diabetic rats in a time- and dose-dependent manner. Oral administration of cinnamic acid with 5 and 10 mg/kg doses to diabetic rats improved glucose tolerance in a dose-dependent manner. The improvement by 10 mg/kg cinnamic acid was comparable to that of standard drug glibenclamide (5 mg/kg). Further in vitro studies showed that cinnamaldehyde has little or no effect on glucose-stimulated insulin secretion; however, cinnamic acid significantly enhanced glucose-stimulated insulin secretion in isolated islets. In conclusion, it can be said that cinnamic acid exerts anti-diabetic activity by improving glucose tolerance in vivo and stimulating insulin secretion in vitro.

  18. Human embryonic stem cell-derived pancreatic endoderm alleviates diabetic pathology and improves reproductive outcome in C57BL/KsJ-Lep(db/+) gestational diabetes mellitus mice.

    PubMed

    Xing, Baoheng; Wang, Lili; Li, Qin; Cao, Yalei; Dong, Xiujuan; Liang, Jun; Wu, Xiaohua

    2015-07-01

    Gestational diabetes mellitus is a condition commonly encountered during mid to late pregnancy with pathologic manifestations including hyperglycemia, hyperinsulinemia, insulin resistance, and fetal maldevelopment. The cause of gestational diabetes mellitus can be attributed to both genetic and environmental factors, hence complicating its diagnosis and treatment. Pancreatic progenitors derived from human embryonic stem cells were shown to be able to effectively treat diabetes in mice. In this study, we have developed a system of treating diabetes using human embryonic stem cell-derived pancreatic endoderm in a mouse model of gestational diabetes mellitus. Human embryonic stem cells were differentiated in vitro into pancreatic endoderm, which were then transplanted into db/+ mice suffering from gestational diabetes mellitus. The transplant greatly improved glucose metabolism and reproductive outcome of the females compared with the control groups. Our findings support the feasibility of using differentiated human embryonic stem cells for treating gestational diabetes mellitus patients.

  19. NaoXinTong Inhibits the Development of Diabetic Retinopathy in db/db Mice

    PubMed Central

    Liu, Mengyang; Pan, Quan; Chen, Yuanli; Yang, Xiaoxiao; Zhao, Buchang; Jia, Lifu; Zhu, Yan; Han, Jihong; Li, Xiaoju; Duan, Yajun

    2015-01-01

    Buchang NaoXinTong capsule (NXT) is a Chinese Materia Medica standardized product extracted from 16 Chinese traditional medical herbs and widely used for treatment of patients with cerebrovascular and cardiovascular diseases in China. Formation of microaneurysms plays an important role in the development of diabetic retinopathy. In this study, we investigated if  NXT can protect diabetic mice against the development of diabetic retinopathy. The db/db mice (~6 weeks old), a diabetic animal model, were divided into two groups and fed normal chow or plus NXT for 14 weeks. During the treatment, fasting blood glucose levels were monthly determined. After treatment, retinas were collected to determine retinal thickness, accumulation of carbohydrate macromolecules, and caspase-3 (CAS-3) expression. Our results demonstrate that administration of NXT decreased fasting blood glucose levels. Associated with the decreased glucose levels, NXT blocked the diabetes-induced shrink of multiple layers, such as photoreceptor layer and outer nuclear/plexiform layers, in the retina. NXT also inhibited the diabetes-induced expression of CAS-3 protein and mRNA, MMP-2/9 and TNFα mRNA, accumulation of carbohydrate macromolecules, and formation of acellular capillaries in the retina. Taken together, our study shows that NXT can inhibit the development of diabetic retinopathy and suggests a new potential application of NXT in clinic. PMID:25821481

  20. Edaravone protect against retinal damage in streptozotocin-induced diabetic mice.

    PubMed

    Yuan, Dongqing; Xu, Yidan; Hang, Hui; Liu, Xiaoyi; Chen, Xi; Xie, Ping; Yuan, Songtao; Zhang, Weiwei; Lin, Xiaojun; Liu, Qinghuai

    2014-01-01

    Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, is used for the clinical treatment of retinal injury. In this study, we investigated the protective effects of edaravone against diabetic retinal damage in the mouse. Diabetic retinopathy in the mouse was induced by injection of streptozotocin. Edaravone was given once-daily and was intraperitoneally (i.p.) treated at a dose of 3 mg/kg from streptozotocin injection to 4 weeks after onset of diabetes. Retinal ganglion cells (RGCs) damage was evaluated by recording the pattern electroretinogram (ERG). RGCs damage was also detected by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and the levels of reactive oxygen species (ROS) were determined fluorometrically. The expressions of phosporylated-ERK1/2, BDNF, and caspase-3 were determined by Western blot analysis. Retinal levels of ROS, phosphorylated ERK1/2, and cleaved caspase-3 were significantly increased, whereas the expression of BDNF was significantly decreased in the retinas of diabetic mice, compared to nondiabetic mice. Administration of edaravone significantly attenuated diabetes induced RGCs death, upregulation of ROS, ERK1/2 phosphorylation, and cleaved caspase-3 and downregulation of BDNF. These findings suggest that oxidative stress plays a pivotal role in diabetic retinal damage and that systemic administration of edaravone may slow the progression of retinal neuropathy induced by diabetes.

  1. MicroRNA-29b Inhibits Diabetic Nephropathy in db/db Mice

    PubMed Central

    Chen, Hai-Yong; Zhong, Xiang; Huang, Xiao R; Meng, Xiao-Ming; You, Yongke; Chung, Arthur CK; Lan, Hui Y

    2014-01-01

    Inflammation and its consequent fibrosis are two main features of diabetic nephropathy (DN), but target therapy on these processes for DN remains yet ineffective. We report here that miR-29b is a novel therapeutic agent capable of inhibiting progressive renal inflammation and fibrosis in type 2 diabetes in db/db mice. Under diabetic conditions, miR-29b was largely downregulated in response to advanced glycation end (AGE) product, which was associated with upregulation of collagen matrix in mesangial cells via the transforming growth factor-β (TGF-β)/Smad3-dependent mechanism. These pathological changes were reversed by overexpressing miR-29b, but enhanced by knocking-down miR-29b. Similarly, loss of renal miR-29b was associated with progressive diabetic kidney injury, including microalbuminuria, renal fibrosis, and inflammation. Restored renal miR-29b by the ultrasound-based gene therapy was capable of attenuating diabetic kidney disease. Further studies revealed that inhibition of Sp1 expression, TGF-β/Smad3-dependent renal fibrosis, NF-κB–driven renal inflammation, and T-bet/Th1-mediated immune response may be mechanisms associated with miR-29b treatment in db/db mice. In conclusion, miR-29b may play a protective role in diabetic kidney disease and may have therapeutic potential for diabetic kidney complication. PMID:24445937

  2. Adverse Effects of Diabetes Mellitus on the Skeleton of Aging Mice.

    PubMed

    Portal-Núñez, Sergio; Ardura, Juan Antonio; Lozano, Daniel; Bolívar, Oskarina Hernández; López-Herradón, Ana; Gutiérrez-Rojas, Irene; Proctor, Alexander; van der Eerden, Bram; Schreuders-Koedam, Marijke; van Leeuwen, Johannes; Alcaraz, María José; Mulero, Francisca; de la Fuente, Mónica; Esbrit, Pedro

    2016-03-01

    In the present study, the possibility that a diabetic (DM) status might worsen age-related bone deterioration was explored in mice. Male CD-1 mice aged 2 (young control group) or 16 months, nondiabetic or made diabetic by streptozotocin injections, were used. DM induced a decrease in bone volume, trabecular number, and eroded surface, and in mineral apposition and bone formation rates, but an increased trabecular separation, in L1-L3 vertebrae of aged mice. Three-point bending and reference point indentation tests showed slight changes pointing to increased frailty and brittleness in the mouse tibia of diabetic old mice. DM was related to a decreased expression of both vascular endothelial growth factor and its receptor 2, which paralleled that of femoral vasculature, and increased expression of the pro-adipogenic gene peroxisome proliferator-activated receptor γ and adipocyte number, without affecting β-catenin pathway in old mouse bone. Concomitant DM in old mice failed to affect total glutathione levels or activity of main anti-oxidative stress enzymes, although xanthine oxidase was slightly increased, in the bone marrow, but increased the senescence marker caveolin-1 gene. In conclusion, DM worsens bone alterations of aged mice, related to decreased bone turnover and bone vasculature and increased senescence, independently of the anti-oxidative stress machinery. PMID:26386012

  3. Adverse Effects of Diabetes Mellitus on the Skeleton of Aging Mice.

    PubMed

    Portal-Núñez, Sergio; Ardura, Juan Antonio; Lozano, Daniel; Bolívar, Oskarina Hernández; López-Herradón, Ana; Gutiérrez-Rojas, Irene; Proctor, Alexander; van der Eerden, Bram; Schreuders-Koedam, Marijke; van Leeuwen, Johannes; Alcaraz, María José; Mulero, Francisca; de la Fuente, Mónica; Esbrit, Pedro

    2016-03-01

    In the present study, the possibility that a diabetic (DM) status might worsen age-related bone deterioration was explored in mice. Male CD-1 mice aged 2 (young control group) or 16 months, nondiabetic or made diabetic by streptozotocin injections, were used. DM induced a decrease in bone volume, trabecular number, and eroded surface, and in mineral apposition and bone formation rates, but an increased trabecular separation, in L1-L3 vertebrae of aged mice. Three-point bending and reference point indentation tests showed slight changes pointing to increased frailty and brittleness in the mouse tibia of diabetic old mice. DM was related to a decreased expression of both vascular endothelial growth factor and its receptor 2, which paralleled that of femoral vasculature, and increased expression of the pro-adipogenic gene peroxisome proliferator-activated receptor γ and adipocyte number, without affecting β-catenin pathway in old mouse bone. Concomitant DM in old mice failed to affect total glutathione levels or activity of main anti-oxidative stress enzymes, although xanthine oxidase was slightly increased, in the bone marrow, but increased the senescence marker caveolin-1 gene. In conclusion, DM worsens bone alterations of aged mice, related to decreased bone turnover and bone vasculature and increased senescence, independently of the anti-oxidative stress machinery.

  4. Antidiabetic efficacy of bradykinin antagonist R-954 on glucose tolerance test in diabetic type 1 mice.

    PubMed

    Catanzaro, Orlando L; Dziubecki, Damian; Obregon, Pablo; Rodriguez, Ricardo R; Sirois, Pierre

    2010-04-01

    Insulin-dependent diabetes mellitus (type 1 diabetes) is an inflammatory autoimmune disease associated with many complications including nephropathy, retinopathy, neuropathy and hyperalgesia. Experimental evidence has shown that the bradykinin B1 receptor (BKB1-R) is involved in the development of type 1 diabetes and found to be upregulated alongside the disease. In the present study the effects of the selective BKB1-R antagonist the R-954 (Ac-Orn-[Oic(2), alpha-MePhe(5), D-beta Nal(7), Ile(8) ]des-Arg(9)-BK and the BKB1-R agonist des Arg(9)-BK (DBK) were studied on diabetic hyperglycemia. Diabetic type 1 was induced in C57 BL/KsJ mdb male mice by five consecutives doses of STZ (45mg/kg i.p.). A glucose tolerance test (GTT) was performed by an intraperitoneal administration of glucose, 8, 12 and 18days after the diabetes induction. The induction of type 1 diabetes provoked a significant hyperglycemia levels in diabetic mice at 12 and 18days after STZ. The administration of R-954 (400microg/kg i.p.) at 12 and 18days after STZ returned the glycemia levels of this animals to normal values. In addition the administration of DKB (300microg/kg i.p.) significantly potentiated the diabetes-induced hyperglycemia; this effect that was totally reversed by R-954. These results provide further evidence for the implication of BKB1-R in the type 1 diabetes mellitus (insulitis). PMID:20092893

  5. Ursolic Acid Protects Diabetic Mice Against Monocyte Dysfunction and Accelerated Atherosclerosis

    PubMed Central

    Ullevig, Sarah L.; Zhao, Qingwei; Zamora, Debora; Asmis, Reto

    2011-01-01

    Aims Accelerated atherosclerosis is a major diabetic complication initiated by the enhanced recruitment of monocytes into the vasculature. In this study, we examined the therapeutic potential of the phytonutrients ursolic acid (UA) and resveratrol (RES) in preventing monocyte recruitment and accelerated atherosclerosis. Methods and Results Dietary supplementation with either RES or UA (0.2%) protected against accelerated atherosclerosis induced by streptozotocin in high-fat diet-fed LDL receptor-deficient mice. However, mice that received dietary UA for 11 weeks were significantly better protected and showed a 53% reduction in lesion formation while mice fed a RES-supplemented diet showed only a 31% reduction in lesion size. Importantly, UA was also significantly more effective in preventing the appearance of proinflammatory GR-1high monocytes induced by these diabetic conditions and reducing monocyte recruitment into MCP-1-loaded Matrigel plugs implanted into these diabetic mice. Oxidatively-stressed THP-1 monocytes mimicked the behavior of blood monocytes in diabetic mice and showed enhanced responsiveness to monocyte chemoattractant protein-1 (MCP-1) without changing MCP-1 receptor (CCR2) surface expression. Pretreatment of THP-1 monocytes with RES or UA (0.3 – 10 μM) for 15 h resulted in the dose-dependent inhibition of H2O2-accelerated chemotaxis in response to MCP-1, but with an IC50 of 0.4 μM, UA was 2.7-fold more potent than RES. Conclusion Dietary UA is a potent inhibitor of monocyte dysfunction and accelerated atherosclerosis induced by diabetes. These studies identify ursolic acid as a potential therapeutic agent for the treatment of diabetic complications, including accelerated atherosclerosis, and provide a novel mechanism for the anti-atherogenic properties of ursolic acid. PMID:21752377

  6. Synaptic transmission at parasympathetic neurons of the major pelvic ganglion from normal and diabetic male mice.

    PubMed

    Tompkins, John D; Vizzard, Margaret A; Parsons, Rodney L

    2013-02-01

    Bladder and erectile dysfunction are common urologic complications of diabetes and are associated with reduced parasympathetic autonomic control. To determine whether disruption of ganglionic neurotransmission contributes to the loss of function, we investigated synaptic transmission at parasympathetic, major pelvic ganglion (MPG) neurons in control and chronically (20 wk) diabetic mice. In contrast to what has been reported for sympathetic neurons, diabetes did not cause an interruption of synaptic transmission at parasympathetic MPG neurons from streptozotocin-treated C57BL/6J (STZ) or db/db mice. Cholinergically mediated excitatory postsynaptic potentials (EPSPs) were suprathreshold during 5-s trains of 5-, 10-, and 20-Hz stimuli. Asynchronous neurotransmitter release, observed as miniature EPSPs (mEPSPs) during and after stimulation, permitted quantitative assessment of postganglionic, cholinergic receptor sensitivity. mEPSP amplitude following tetanic stimulation (recorded at -60 mV) was reduced in STZ (4.95 ± 0.4 vs. 3.71 ± 0.3 mV, P = 0.03), but not db/db mice. The number of posttetanic mEPSPs was significantly greater in db/db mice at all frequencies tested. Assessment of basic electrophysiological properties revealed that parasympathetic MPG neurons from db/db mice had less negative membrane potentials, lower input resistances, and shorter afterhyperpolarizations relative to their control. MPG neurons from STZ had longer afterhyperpolarizations but were otherwise similar to controls. Membrane excitability, measured by the membrane responsiveness to long-duration (1 s), suprathreshold depolarizing pulses, was unchanged in either model. The present study indicates that, while parasympathetic neurotransmission at the MPG is intact in chronically diabetic mice, obese, type 2 diabetic animals exhibit an altered presynaptic regulation of neurotransmitter release.

  7. A minor subset of Batf3-dependent antigen presenting cells in islets of Langerhans is essential for the development of autoimmune diabetes

    PubMed Central

    Ferris, Stephen T.; Carrero, Javier A.; Mohan, James F.; Calderon, Boris; Murphy, Kenneth M.; Unanue, Emil R.

    2014-01-01

    Summary Autoimmune diabetes is characterized by inflammatory infiltration; however the initiating events are poorly understood. We found that the islets of Langerhans in young non-obese diabetic (NOD) mice contained two antigen presenting cell (APC) populations: a major macrophage and a minor CD103+ dendritic cell (DC) population. By four weeks of age, CD4+ T cells entered islets coincident with an increase of CD103+ DCs. In order to examine the role of the CD103+ DCs in diabetes, we examined Batf3-deficient NOD mice that lacked the CD103+ DCs in islets and pancreatic lymph nodes. This led to a lack of autoreactive T cells in islets and, importantly, no incidence of diabetes. Additional examination revealed that presentation of major histocompatibility complex (MHC) class I epitopes in the pancreatic lymph nodes was absent with a partial impairment of MHC class II presentation. Altogether, this study reveals that CD103+ DCs were essential for autoimmune diabetes development. PMID:25367577

  8. The Altered Renal and Hepatic Expression of Solute Carrier Transporters (SLCs) in Type 1 Diabetic Mice

    PubMed Central

    Xu, Chenghao; Zhu, Ling; Chan, Ting; Lu, Xiaoxi; Shen, Weiyong; Gillies, Mark C.; Zhou, Fanfan

    2015-01-01

    Diabetes mellitus is a chronic metabolic disorder that significantly affects human health and well-being. The Solute carrier transporters (SLCs), particularly the Organic anion/cation transporters (Oats/Octs/Octns), Organic anion transporting polypeptides (Oatps) and Oligopeptide transporters (Pepts) are essential membrane proteins responsible for cellular uptake of many endogenous and exogenous substances such as clinically important drugs. They are widely expressed in mammalian key organs especially the kidney and liver, in which they facilitate the influx of various drug molecules, thereby determining their distribution and elimination in body. The altered expression of SLCs in diabetes mellitus could have a profound and clinically significant influence on drug therapies. In this study, we extensively investigated the renal and hepatic expression of twenty essential SLCs in the type 1 diabetic Ins2Akita murine model that develops both hyperglycemia and diabetes-related complications using real-time PCR and immunoblotting analysis. We found that the renal expression of mOatp1a1, mOatp1a6, mOat1, mOat3, mOat5, mOct2 and mPept2 was decreased; while that of mPept1 was increased at the mRNA level in the diabetic mice compared with non-diabetic controls. We found up-regulated mRNA expression of mOatp1a4, mOatp1c1, mOctn2, mOct3 and mPept1 as well as down-regulation of mOatp1a1 in the livers of diabetic mice. We confirmed the altered protein expression of several SLCs in diabetic mice, especially the decreased renal and hepatic expression of mOatp1a1. We also found down-regulated protein expression of mOat3 and mOctn1 in the kidneys as well as increased protein expression of mOatp1a4 and mOct3 in the livers of diabetic mice. Our findings contribute to better understanding the modulation of SLC transporters in type 1 diabetes mellitus, which is likely to affect the pharmacokinetic performance of drugs that are transported by these transporters and therefore, forms the

  9. Ceruletide decreases food intake in non-obese man.

    PubMed

    Stacher, G; Steinringer, H; Schmierer, G; Schneider, C; Winklehner, S

    1982-01-01

    Cholecystokinin decreases food intake in animals and in man. This study investigated whether the structurally related ceruletide reduces food intake in healthy non-obese man. Twelve females and 12 males participated, after an over-night fast, in each of two experiments. During the basal 40 min, saline was infused IV. Thereafter, the infusion was, in random double blind fashion, either continued with saline or switched to 60 or 120 ng/kg b. wt/hr ceruletide. Butter was melted in a pan and scrambled eggs with ham were prepared in front of the subjects, who were instructed to eat, together with bread and mallow tea, as much as they wanted. With 120 ng/kg/hr ceruletide, the subjects ate significantly less (16.8 percent) than with saline (3725 kJ +/- 489 SEM and 4340 kJ +/- 536, respectively; p less than 0.025). They also reported less hunger (p less than 0.005) and activation (p less than 0.005) and activation (p less than 0.01), and had longer reaction times (p less than 0.01) and a weaker psychomotor performance (p less than 0.025). 60 ng/kg/hr ceruletide decreased food intake only slightly (6.6%; 3089 kJ +/- 253 and 3292 kJ +/- 300 respectively) and no significant changes in the above measures occurred. In conclusion, ceruletide reduces food intake in man, thus resembling the effects of cholecystokinin.

  10. Gene expression microarray analysis of the sciatic nerve of mice with diabetic neuropathy.

    PubMed

    Zhang, Lei; Qu, Shen; Liang, Aibin; Jiang, Hong; Wang, Hao

    2015-02-01

    The present study aimed to explore novel target genes that regulate the development of diabetic neuropathy (DN) by analyzing gene expression profiles in the sciatic nerve of infected mice. The GSE11343 microarray dataset, which was downloaded from Gene Expression Omnibus, included data on 4 control samples and 5 samples from mice with diabetes induced by streptozotocin (STZ), 5 samples from normal mice treated with rosiglitazone (Rosi) and 5 samples from mice with diabetes induced by STZ and treated with Rosi. Differentially expressed genes (DEGs) between the different groups were identified using the substitution augmentation modification redefinition (SAMR) model. The Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Regulatory and protein‑protein interaction networks were searched using BioCarta and STRING, respectively. The protein structures of potential regulatory genes were predicted using the SYBYL program. Compared with the controls, 1,384 DEGs were identified in the mice with STZ-induced diabetes and 7 DEGs were identified in the mice treated with Rosi. There were 518 DEGs identified between the mice in the STZ + Rosi and STZ groups. We identified 45 GO items, and the calmodulin nerve phosphatase and chemokine signaling pathways were identified as the main pathways. Three genes [myristoylated alanine-rich protein kinase C substrate (Marcks), GLI pathogenesis-related 2 (Glipr2) and centrosomal protein 170 kDa (Cep170)] were found to be co-regulated by both STZ and Rosi, the protein structure of which was predicted and certain binding activity to Rosi was docked. Our study demonstrates that the Marcks, Glipr2 and Cep170 genes may be underlying drug targets in the treatment of DN. PMID:25435094

  11. Gene expression microarray analysis of the sciatic nerve of mice with diabetic neuropathy

    PubMed Central

    ZHANG, LEI; QU, SHEN; LIANG, AIBIN; JIANG, HONG; WANG, HAO

    2015-01-01

    The present study aimed to explore novel target genes that regulate the development of diabetic neuropathy (DN) by analyzing gene expression profiles in the sciatic nerve of infected mice. The GSE11343 microarray dataset, which was downloaded from Gene Expression Omnibus, included data on 4 control samples and 5 samples from mice with diabetes induced by streptozotocin (STZ), 5 samples from normal mice treated with rosiglitazone (Rosi) and 5 samples from mice with diabetes induced by STZ and treated with Rosi. Differentially expressed genes (DEGs) between the different groups were identified using the substitution augmentation modification redefinition (SAMR) model. The Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Regulatory and protein-protein interaction networks were searched using BioCarta and STRING, respectively. The protein structures of potential regulatory genes were predicted using the SYBYL program. Compared with the controls, 1,384 DEGs were identified in the mice with STZ-induced diabetes and 7 DEGs were identified in the mice treated with Rosi. There were 518 DEGs identified between the mice in the STZ + Rosi and STZ groups. We identified 45 GO items, and the calmodulin nerve phosphatase and chemokine signaling pathways were identified as the main pathways. Three genes [myristoylated alanine-rich protein kinase C substrate (Marcks), GLI pathogenesis-related 2 (Glipr2) and centrosomal protein 170 kDa (Cep170)] were found to be co-regulated by both STZ and Rosi, the protein structure of which was predicted and certain binding activity to Rosi was docked. Our study demonstrates that the Marcks, Glipr2 and Cep170 genes may be underlying drug targets in the treatment of DN. PMID:25435094

  12. Impaired adiponectin signaling contributes to disturbed catabolism of branched-chain amino acids in diabetic mice.

    PubMed

    Lian, Kun; Du, Chaosheng; Liu, Yi; Zhu, Di; Yan, Wenjun; Zhang, Haifeng; Hong, Zhibo; Liu, Peilin; Zhang, Lijian; Pei, Haifeng; Zhang, Jinglong; Gao, Chao; Xin, Chao; Cheng, Hexiang; Xiong, Lize; Tao, Ling

    2015-01-01

    The branched-chain amino acids (BCAA) accumulated in type 2 diabetes are independent contributors to insulin resistance. The activity of branched-chain α-keto acid dehydrogenase (BCKD) complex, rate-limiting enzyme in BCAA catabolism, is reduced in diabetic states, which contributes to elevated BCAA concentrations. However, the mechanisms underlying decreased BCKD activity remain poorly understood. Here, we demonstrate that mitochondrial phosphatase 2C (PP2Cm), a newly identified BCKD phosphatase that increases BCKD activity, was significantly downregulated in ob/ob and type 2 diabetic mice. Interestingly, in adiponectin (APN) knockout (APN(-/-)) mice fed with a high-fat diet (HD), PP2Cm expression and BCKD activity were significantly decreased, whereas BCKD kinase (BDK), which inhibits BCKD activity, was markedly increased. Concurrently, plasma BCAA and branched-chain α-keto acids (BCKA) were significantly elevated. APN treatment markedly reverted PP2Cm, BDK, BCKD activity, and BCAA and BCKA levels in HD-fed APN(-/-) and diabetic animals. Additionally, increased BCKD activity caused by APN administration was partially but significantly inhibited in PP2Cm knockout mice. Finally, APN-mediated upregulation of PP2Cm expression and BCKD activity were abolished when AMPK was inhibited. Collectively, we have provided the first direct evidence that APN is a novel regulator of PP2Cm and systematic BCAA levels, suggesting that targeting APN may be a pharmacological approach to ameliorating BCAA catabolism in the diabetic state. PMID:25071024

  13. Effect of Potentilla fulgens on lipid peroxidation and antioxidant status in alloxan-induced diabetic mice

    PubMed Central

    Saio, Valrielyn; Syiem, Donkupar; Sharma, Ramesh

    2012-01-01

    Potentilla fulgens (Rosaceae) root traditionally used as a folk remedy by local health practitioners of Khasi Hills, Meghalaya was investigated for its effects on lipid peroxidation and antioxidant status in alloxan-induced diabetic mice. Significant increase in levels of thiobarbituric acid reactive substances (TBARS) and decrease in activities of glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) were observed under diabetic condition. Intraperitoneal administration of methanol extract of P. fulgens roots at a dose of 250 mg/kg body weight to male swiss albino diabetic mice for 14 days caused significant reduction in the elevated TBARS level, while increasing the activities of the antioxidant enzymes in diabetic mice. Maximum reduction in TBARS level was observed in liver tissue (75%, p<0.001). Kidney exhibited the highest elevation in the activity for catalase (68%, p<0.001) and superoxide dismutase (29%, p<0.001) while maximum increase in glutathione peroxidase activity was seen in brain (50%, p<0.001). The effects of P. fulgens was compared against known antioxidant, vitamin C. Results indicate that Potentilla fulgens methanolic root extract can reduce free radical mediated oxidative stress in experimental diabetes mellitus. PMID:24826032

  14. INFLUENCE OF TYPE II DIABETES AND OBESITY ON THE DISPOSITION AND ELIMINATION OF TCDD IN MICE

    EPA Science Inventory

    INFLUENCE OF TYPE II DIABETES AND OBESITY ON THE DISPOSTION AND ELIMINATION OF TCDD IN MICE. MJ DeVito', JJ Diliberto', DG Ross', C Emond2, VM Richardson', and LS Birnbaum', 'ETD, NHEERL, ORD, US EPA, RTP, NC, 27711, USA, 2National Research Council.
    One possible explanation fo...

  15. Chloroquine improves left ventricle diastolic function in streptozotocin-induced diabetic mice

    PubMed Central

    Yuan, Xun; Xiao, Yi-Chuan; Zhang, Gui-Ping; Hou, Ning; Wu, Xiao-Qian; Chen, Wen-Liang; Luo, Jian-Dong; Zhang, Gen-Shui

    2016-01-01

    Diabetes is a potent risk factor for heart failure with preserved ejection fraction (HFpEF). Autophagy can be activated under pathological conditions, including diabetic cardiomyopathy. The therapeutic effects of chloroquine (CQ), an autophagy inhibitor, on left ventricle function in streptozotocin (STZ)-induced diabetic mice were investigated. The cardiac function, light chain 3 (LC3)-II/LC3-I ratio, p62, beclin 1, reactive oxygen species, apoptosis, and fibrosis were measured 14 days after CQ (ip 60 mg/kg/d) administration. In STZ-induced mice, cardiac diastolic function was decreased significantly with normal ejection fraction. CQ significantly ameliorated cardiac diastolic function in diabetic mice with HFpEF. In addition, CQ decreased the autophagolysosomes, cardiomyocyte apoptosis, and cardiac fibrosis but increased LC3-II and p62 expressions. These results suggested that CQ improved the cardiac diastolic function by inhibiting autophagy in STZ-induced HFpEF mice. Autophagic inhibitor CQ might be a potential therapeutic agent for HFpEF. PMID:27621594

  16. The dipeptidyl peptidase-4 inhibitor sitagliptin suppresses mouse colon tumorigenesis in type 2 diabetic mice.

    PubMed

    Yorifuji, Naoki; Inoue, Takuya; Iguchi, Munetaka; Fujiwara, Kaori; Kakimoto, Kazuki; Nouda, Sadaharu; Okada, Toshihiko; Kawakami, Ken; Abe, Yosuke; Takeuchi, Toshihisa; Higuchi, Kazuhide

    2016-02-01

    Patients with type 2 diabetes mellitus are known to have an increased risk of colorectal neoplasia. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been used as a new therapeutic tool for type 2 diabetes. Since the substrates for DPP-4 include intestinotrophic hormones and chemokines such as GLP-2 and stromal cell-derived factor-1 (SDF-1), which are associated with tumor progression, DPP-4 inhibitors may increase the risk of colorectal tumors. However, the influence of DPP-4 inhibitors on colorectal neoplasia in patients with type 2 diabetes remains unknown. In the present study, we show that long-term administration of a DPP-4 inhibitor, sitagliptin (STG), suppressed colon carcinogenesis in leptin-deficient (ob/ob) C57BL/6J mice. Colonic mucosal concentrations of glucagon‑like peptide-1 (GLP-1) and GLP-2 were significantly elevated in the ob/ob mice. However, mucosal GLP concentrations and the plasma level of SDF-1 were not affected by the administration of STG. Real‑time PCR analysis revealed that colonic mucosal IL-6 mRNA expression, which was significantly upregulated in the ob/ob mice, was significantly suppressed by the long-term administration of STG. These results suggest that a DPP-4 inhibitor may suppress colon carcinogenesis in mice with type 2 diabetes in a GLP-independent manner. Since DPP-4 has multiple biological functions, further studies analyzing other factors related to colon carcinogenesis are needed.

  17. Chloroquine improves left ventricle diastolic function in streptozotocin-induced diabetic mice.

    PubMed

    Yuan, Xun; Xiao, Yi-Chuan; Zhang, Gui-Ping; Hou, Ning; Wu, Xiao-Qian; Chen, Wen-Liang; Luo, Jian-Dong; Zhang, Gen-Shui

    2016-01-01

    Diabetes is a potent risk factor for heart failure with preserved ejection fraction (HFpEF). Autophagy can be activated under pathological conditions, including diabetic cardiomyopathy. The therapeutic effects of chloroquine (CQ), an autophagy inhibitor, on left ventricle function in streptozotocin (STZ)-induced diabetic mice were investigated. The cardiac function, light chain 3 (LC3)-II/LC3-I ratio, p62, beclin 1, reactive oxygen species, apoptosis, and fibrosis were measured 14 days after CQ (ip 60 mg/kg/d) administration. In STZ-induced mice, cardiac diastolic function was decreased significantly with normal ejection fraction. CQ significantly ameliorated cardiac diastolic function in diabetic mice with HFpEF. In addition, CQ decreased the autophagolysosomes, cardiomyocyte apoptosis, and cardiac fibrosis but increased LC3-II and p62 expressions. These results suggested that CQ improved the cardiac diastolic function by inhibiting autophagy in STZ-induced HFpEF mice. Autophagic inhibitor CQ might be a potential therapeutic agent for HFpEF. PMID:27621594

  18. Chloroquine improves left ventricle diastolic function in streptozotocin-induced diabetic mice

    PubMed Central

    Yuan, Xun; Xiao, Yi-Chuan; Zhang, Gui-Ping; Hou, Ning; Wu, Xiao-Qian; Chen, Wen-Liang; Luo, Jian-Dong; Zhang, Gen-Shui

    2016-01-01

    Diabetes is a potent risk factor for heart failure with preserved ejection fraction (HFpEF). Autophagy can be activated under pathological conditions, including diabetic cardiomyopathy. The therapeutic effects of chloroquine (CQ), an autophagy inhibitor, on left ventricle function in streptozotocin (STZ)-induced diabetic mice were investigated. The cardiac function, light chain 3 (LC3)-II/LC3-I ratio, p62, beclin 1, reactive oxygen species, apoptosis, and fibrosis were measured 14 days after CQ (ip 60 mg/kg/d) administration. In STZ-induced mice, cardiac diastolic function was decreased significantly with normal ejection fraction. CQ significantly ameliorated cardiac diastolic function in diabetic mice with HFpEF. In addition, CQ decreased the autophagolysosomes, cardiomyocyte apoptosis, and cardiac fibrosis but increased LC3-II and p62 expressions. These results suggested that CQ improved the cardiac diastolic function by inhibiting autophagy in STZ-induced HFpEF mice. Autophagic inhibitor CQ might be a potential therapeutic agent for HFpEF.

  19. Long term effect of gut microbiota transfer on diabetes development.

    PubMed

    Peng, Jian; Narasimhan, Sukanya; Marchesi, Julian R; Benson, Andrew; Wong, F Susan; Wen, Li

    2014-09-01

    The composition of the gut microbiome represents a very important environmental factor that influences the development of type 1 diabetes (T1D). We have previously shown that MyD88-deficient non-obese diabetic (MyD88-/-NOD) mice, that were protected from T1D development, had a different composition of gut microbiota compared to wild type NOD mice. The aim of our study was to investigate whether this protection could be transferred. We demonstrate that transfer of gut microbiota from diabetes-protected MyD88-deficient NOD mice, reduced insulitis and significantly delayed the onset of diabetes. Gut bacteria from MyD88-deficient mice, administered over a 3-week period, starting at 4 weeks of age, stably altered the family composition of the gut microbiome, with principally Lachnospiraceae and Clostridiaceae increased and Lactobacillaceae decreased. The transferred mice had a higher concentration of IgA and TGFβ in the lumen that was accompanied by an increase in CD8(+)CD103(+) and CD8αβ T cells in the lamina propria of the large intestine. These data indicate not only that gut bacterial composition can be altered after the neonatal/weaning period, but that the composition of the microbiome affects the mucosal immune system and can delay the development of autoimmune diabetes. This result has important implications for the development of probiotic treatment for T1D.

  20. The anti-diabetic activity of oat β-d-glucan in streptozotocin-nicotinamide induced diabetic mice.

    PubMed

    Liu, Mei; Zhang, Yu; Zhang, Hui; Hu, Bo; Wang, Li; Qian, Haifeng; Qi, Xiguang

    2016-10-01

    This study was initiated to investigate the mechanism by which oat β-d-glucan (OBG) can control blood sugar levels and improve hepatogenic glycometabolism in streptozotocin-nicotinamide induced mice. After administration of different concentrations and molecular weights of β-d-glucan by oral gavage for 28 days, the body weight, fasting blood glucose, serum insulin, hepatic glycogen, glucose kinase and glucose-6-phosphatase activity of the diabetic mice were measured. In comparison with a negative control group (saline), β-d-glucan, especially medium or high doses of high-molecular-weight β-d-glucan, had a strong hypoglycaemic effect in streptozotocin-nicotinamide-induced mice. The mechanism of this effect may be associated with the high viscosity of the solution, an increase in insulin secretion, a decline in insulin resistance, and especially an improvement in hepatogenic glycometabolism. Moreover, β-d-glucan also markedly repaired and improved the integrity of pancreatic islet β-cell and tissue structures.

  1. Hyperactivity of ON-type retinal ganglion cells in streptozotocin-induced diabetic mice.

    PubMed

    Yu, Jun; Wang, Lu; Weng, Shi-Jun; Yang, Xiong-Li; Zhang, Dao-Qi; Zhong, Yong-Mei

    2013-01-01

    Impairment of visual function has been detected in the early stage of diabetes but the underlying neural mechanisms involved are largely unknown. Morphological and functional alterations of retinal ganglion cells, the final output neurons of the vertebrate retina, are thought to be the major cause of visual defects in diabetes but direct evidence to support this notion is limited. In this study we investigated functional changes of retinal ganglion cells in a type 1-like diabetic mouse model. Our results demonstrated that the spontaneous spiking activity of ON-type retinal ganglion cells was increased in streptozotocin-diabetic mice after 3 to 4 months of diabetes. At this stage of diabetes, no apoptotic signals or cell loss were detected in the ganglion cell layer of the retina, suggesting that the functional alterations in ganglion cells occur prior to massive ganglion cell apoptosis. Furthermore, we found that the increased activity of ON-type ganglion cells was mainly a result of reduced inhibitory signaling to the cells in diabetes. This novel mechanism provides insight into how visual function is impaired in diabetic retinopathy. PMID:24069457

  2. Shengmai San Ameliorates Myocardial Dysfunction and Fibrosis in Diabetic db/db Mice

    PubMed Central

    Cao, Tong-Tong; Tian, Jing; Chen, Hui-hua; Lu, Rong

    2016-01-01

    In this study, we mainly investigated the effects of Shengmai San (SMS) on diabetic cardiomyopathy (DCM) in db/db mice. The db/db mice were randomly divided into model group and SMS group, while C57BLKS/J inbred mice were used as controls. After 24-week treatment, blood glucose, body weight, and heart weight were determined. Hemodynamic changes in the left ventricle were measured using catheterization. The myocardial structure and subcellular structural changes were observed by HE staining and electron microscopy; the myocardium collagen content was quantified by Masson staining. To further explore the protective mechanism of SMS, we analyzed the expression profiles of fibrotic related proteins. Compared to nondiabetic mice, db/db mice exhibited enhanced diastolic myocardial dysfunction and adverse structural remodeling. Higher expression of profibrotic proteins and lower levels of extracellular matrix degradation were also observed. After SMS oral administration for 24 weeks, cardiac dysfunction, hypertrophy, and fibrosis in diabetic mice were greatly improved. Moreover, increased profibrotic protein expression was strongly reversed by SMS treatment in db/db mice. The results demonstrate that SMS exerts a cardioprotective effect against DCM by attenuating myocardial hypertrophy and fibrosis via a TGF-β dependent pathway. PMID:27200101

  3. Shengmai San Ameliorates Myocardial Dysfunction and Fibrosis in Diabetic db/db Mice.

    PubMed

    Zhao, Juan; Cao, Tong-Tong; Tian, Jing; Chen, Hui-Hua; Zhang, Chen; Wei, Hong-Chang; Guo, Wei; Lu, Rong

    2016-01-01

    In this study, we mainly investigated the effects of Shengmai San (SMS) on diabetic cardiomyopathy (DCM) in db/db mice. The db/db mice were randomly divided into model group and SMS group, while C57BLKS/J inbred mice were used as controls. After 24-week treatment, blood glucose, body weight, and heart weight were determined. Hemodynamic changes in the left ventricle were measured using catheterization. The myocardial structure and subcellular structural changes were observed by HE staining and electron microscopy; the myocardium collagen content was quantified by Masson staining. To further explore the protective mechanism of SMS, we analyzed the expression profiles of fibrotic related proteins. Compared to nondiabetic mice, db/db mice exhibited enhanced diastolic myocardial dysfunction and adverse structural remodeling. Higher expression of profibrotic proteins and lower levels of extracellular matrix degradation were also observed. After SMS oral administration for 24 weeks, cardiac dysfunction, hypertrophy, and fibrosis in diabetic mice were greatly improved. Moreover, increased profibrotic protein expression was strongly reversed by SMS treatment in db/db mice. The results demonstrate that SMS exerts a cardioprotective effect against DCM by attenuating myocardial hypertrophy and fibrosis via a TGF-β dependent pathway. PMID:27200101

  4. Proteome wide reduction in AGE modification in streptozotocin induced diabetic mice by hydralazine mediated transglycation

    PubMed Central

    Kesavan, Suresh K.; Bhat, Shweta; Golegaonkar, Sandeep B.; Jagadeeshaprasad, Mashanipalya G.; Deshmukh, Arati B.; Patil, Harshal S.; Bhosale, Santosh D.; Shaikh, Mahemud L.; Thulasiram, Hirekodathakallu V.; Boppana, Ramanamurthy; Kulkarni, Mahesh J.

    2013-01-01

    The non-enzymatic reaction between glucose and protein can be chemically reversed by transglycation. Here we report the transglycation activity of hydralazine using a newly developed MALDI-TOF-MS based assay. Hydralazine mediated transglycation of HbA1c, plasma proteins and kidney proteins was demonstrated in streptozotocin (STZ) induced diabetic mice, as evidenced by decrease in protein glycation, as well as presence of hydralazine-glucose conjugate in urine of diabetic mice treated with hydralazine. Hydralazine down regulated the expression of Receptor for Advanced Glycation End products (RAGE), NADPH oxidase (NOX), and super oxide dismutase (SOD). These findings will provide a new dimension for developing intervention strategies for the treatment of glycation associated diseases such as diabetes complications, atherosclerosis, and aging. PMID:24126953

  5. High Fructose Diet inducing diabetes rapidly impacts olfactory epithelium and behavior in mice

    PubMed Central

    Rivière, Sébastien; Soubeyre, Vanessa; Jarriault, David; Molinas, Adrien; Léger-Charnay, Elise; Desmoulins, Lucie; Grebert, Denise; Meunier, Nicolas; Grosmaitre, Xavier

    2016-01-01

    Type 2 Diabetes (T2D), a major public health issue reaching worldwide epidemic, has been correlated with lower olfactory abilities in humans. As olfaction represents a major component of feeding behavior, its alteration may have drastic consequences on feeding behaviors that may in turn aggravates T2D. In order to decipher the impact of T2D on the olfactory epithelium, we fed mice with a high fructose diet (HFruD) inducing early diabetic state in 4 to 8 weeks. After only 4 weeks of this diet, mice exhibited a dramatic decrease in olfactory behavioral capacities. Consistently, this decline in olfactory behavior was correlated to decreased electrophysiological responses of olfactory neurons recorded as a population and individually. Our results demonstrate that, in rodents, olfaction is modified by HFruD-induced diabetes. Functional, anatomical and behavioral changes occurred in the olfactory system at a very early stage of the disease. PMID:27659313

  6. Proteome wide reduction in AGE modification in streptozotocin induced diabetic mice by hydralazine mediated transglycation.

    PubMed

    Kesavan, Suresh K; Bhat, Shweta; Golegaonkar, Sandeep B; Jagadeeshaprasad, Mashanipalya G; Deshmukh, Arati B; Patil, Harshal S; Bhosale, Santosh D; Shaikh, Mahemud L; Thulasiram, Hirekodathakallu V; Boppana, Ramanamurthy; Kulkarni, Mahesh J

    2013-10-15

    The non-enzymatic reaction between glucose and protein can be chemically reversed by transglycation. Here we report the transglycation activity of hydralazine using a newly developed MALDI-TOF-MS based assay. Hydralazine mediated transglycation of HbA1c, plasma proteins and kidney proteins was demonstrated in streptozotocin (STZ) induced diabetic mice, as evidenced by decrease in protein glycation, as well as presence of hydralazine-glucose conjugate in urine of diabetic mice treated with hydralazine. Hydralazine down regulated the expression of Receptor for Advanced Glycation End products (RAGE), NADPH oxidase (NOX), and super oxide dismutase (SOD). These findings will provide a new dimension for developing intervention strategies for the treatment of glycation associated diseases such as diabetes complications, atherosclerosis, and aging.

  7. Dammarenediol-II Prevents VEGF-Mediated Microvascular Permeability in Diabetic Mice.

    PubMed

    Kim, Su-Hyeon; Jung, Se-Hui; Lee, Yeon-Ju; Han, Jung Yeon; Choi, Yong-Eui; Hong, Hae-Deun; Jeon, Hye-Yoon; Hwang, JongYun; Na, SungHun; Kim, Young-Myeong; Ha, Kwon-Soo

    2015-12-01

    Diabetic retinopathy is a major diabetic complication predominantly caused by vascular endothelial growth factor (VEGF)-induced vascular permeability in the retina; however, treatments targeting glycemic control have not been successful. Here, we investigated the protective effect of dammarenediol-II, a precursor of triterpenoid saponin biosynthesis, on VEGF-induced vascular leakage using human umbilical vein endothelial cells (HUVECs) and diabetic mice. We overproduced the compound in transgenic tobacco expressing Panax ginseng dammarenediol-II synthase gene and purified using column chromatography. Analysis of the purified compound using a gas chromatography-mass spectrometry system revealed identical retention time and fragmentation pattern to those of authentic standard dammarenediol-II. Dammarenediol-II inhibited VEGF-induced intracellular reactive oxygen species generation, but it had no effect on the levels of intracellular Ca(2+) in HUVECs. We also found that dammarenediol-II inhibited VEGF-induced stress fiber formation and vascular endothelial-cadherin disruption, both of which play critical roles in modulating endothelial permeability. Notably, microvascular leakage in the retina of diabetic mice was successfully inhibited by intravitreal dammarenediol-II injection. Our results suggest that the natural drug dammarenediol-II may have the ability to prevent diabetic microvascular complications, including diabetic retinopathy. PMID:26400610

  8. Anti-oxidant effect of gold nanoparticles restrains hyperglycemic conditions in diabetic mice

    PubMed Central

    2010-01-01

    Background Oxidative stress is imperative for its morbidity towards diabetic complications, where abnormal metabolic milieu as a result of hyperglycemia, leads to the onset of several complications. A biological antioxidant capable of inhibiting oxidative stress mediated diabetic progressions; during hyperglycemia is still the need of the era. The current study was performed to study the effect of biologically synthesized gold nanoparticles (AuNPs) to control the hyperglycemic conditions in streptozotocin induced diabetic mice. Results The profound control of AuNPs over the anti oxidant enzymes such as GSH, SOD, Catalase and GPx in diabetic mice to normal, by inhibition of lipid peroxidation and ROS generation during hyperglycemia evidence their anti-oxidant effect during hyperglycemia. The AuNPs exhibited an insistent control over the blood glucose level, lipids and serum biochemical profiles in diabetic mice near to the control mice provokes their effective role in controlling and increasing the organ functions for better utilization of blood glucose. Histopathological and hematological studies revealed the non-toxic and protective effect of the gold nanoparticles over the vital organs when administered at dosage of 2.5 mg/kilogram.body.weight/day. ICP-MS analysis revealed the biodistribution of gold nanoparticles in the vital organs showing accumulation of AuNPs in the spleen comparatively greater than other organs. Conclusion The results obtained disclose the effectual role of AuNPs as an anti-oxidative agent, by inhibiting the formation of ROS, scavenging free radicals; thus increasing the anti-oxidant defense enzymes and creating a sustained control over hyperglycemic conditions which consequently evoke the potential of AuNPs as an economic therapeutic remedy in diabetic treatments and its complications. PMID:20630072

  9. Growth Hormone (GH) Hypersecretion and GH Receptor Resistance in Streptozotocin Diabetic Mice in Response to a GH Secretagogue

    PubMed Central

    Segev, Yael; Landau, Daniel; Phillip, Moshe; Flyvbjerg, Allan

    2003-01-01

    The growth hormone (GH) and insulin-like growth factor I (IGF-I) axis were studied in streptozotocin (STZ) diabetic and nondiabetic female mice following intravenous (IV) injection of the GH secretagogue (GHS) ipamorelin or saline. On day 14, blood samples were obtained before and 10 minutes after the injection. Livers were removed and frozen for determination of the mRNA expressions of the GH receptor, GH-binding protein, and IGF-I, and hepatic IGF-I peptide. Serum samples were analyzed for GH and IGF-I. Following ipamorelin injection, the GH levels were found to be 150 ± 35 μg/L and 62 ± 11 μg/L in the diabetic compared to the nondiabetic mice (P < .05). Serum IGF-I levels were lower in diabetic than in nondiabetic animals, and rose after stimulation only in the nondiabetic animals. Furthermore, hepatic GH resistance and IGF-I mRNA levels and IGF-I peptide were increased in nondiabetic animals in response to GH stimulation, whereas the low levels per se of all these parameters in diabetic mice were unaffected. The study shows that STZ diabetic mice demonstrate a substantial part of the clinical features of type 1 diabetes in humans, including GH hypersecretion and GH resistance. Accordingly, it is proposed that STZ diabetic mice may be a better model of the perturbations of the GH/IGF-I axis in diabetes than STZ diabetic rats. PMID:14630569

  10. Multi-tissue computational modeling analyzes pathophysiology of type 2 diabetes in MKR mice.

    PubMed

    Kumar, Amit; Harrelson, Thomas; Lewis, Nathan E; Gallagher, Emily J; LeRoith, Derek; Shiloach, Joseph; Betenbaugh, Michael J

    2014-01-01

    Computational models using metabolic reconstructions for in silico simulation of metabolic disorders such as type 2 diabetes mellitus (T2DM) can provide a better understanding of disease pathophysiology and avoid high experimentation costs. There is a limited amount of computational work, using metabolic reconstructions, performed in this field for the better understanding of T2DM. In this study, a new algorithm for generating tissue-specific metabolic models is presented, along with the resulting multi-confidence level (MCL) multi-tissue model. The effect of T2DM on liver, muscle, and fat in MKR mice was first studied by microarray analysis and subsequently the changes in gene expression of frank T2DM MKR mice versus healthy mice were applied to the multi-tissue model to test the effect. Using the first multi-tissue genome-scale model of all metabolic pathways in T2DM, we found out that branched-chain amino acids' degradation and fatty acids oxidation pathway is downregulated in T2DM MKR mice. Microarray data showed low expression of genes in MKR mice versus healthy mice in the degradation of branched-chain amino acids and fatty-acid oxidation pathways. In addition, the flux balance analysis using the MCL multi-tissue model showed that the degradation pathways of branched-chain amino acid and fatty acid oxidation were significantly downregulated in MKR mice versus healthy mice. Validation of the model was performed using data derived from the literature regarding T2DM. Microarray data was used in conjunction with the model to predict fluxes of various other metabolic pathways in the T2DM mouse model and alterations in a number of pathways were detected. The Type 2 Diabetes MCL multi-tissue model may explain the high level of branched-chain amino acids and free fatty acids in plasma of Type 2 Diabetic subjects from a metabolic fluxes perspective.

  11. Multi-Tissue Computational Modeling Analyzes Pathophysiology of Type 2 Diabetes in MKR Mice

    PubMed Central

    Kumar, Amit; Harrelson, Thomas; Lewis, Nathan E.; Gallagher, Emily J.; LeRoith, Derek; Shiloach, Joseph; Betenbaugh, Michael J.

    2014-01-01

    Computational models using metabolic reconstructions for in silico simulation of metabolic disorders such as type 2 diabetes mellitus (T2DM) can provide a better understanding of disease pathophysiology and avoid high experimentation costs. There is a limited amount of computational work, using metabolic reconstructions, performed in this field for the better understanding of T2DM. In this study, a new algorithm for generating tissue-specific metabolic models is presented, along with the resulting multi-confidence level (MCL) multi-tissue model. The effect of T2DM on liver, muscle, and fat in MKR mice was first studied by microarray analysis and subsequently the changes in gene expression of frank T2DM MKR mice versus healthy mice were applied to the multi-tissue model to test the effect. Using the first multi-tissue genome-scale model of all metabolic pathways in T2DM, we found out that branched-chain amino acids' degradation and fatty acids oxidation pathway is downregulated in T2DM MKR mice. Microarray data showed low expression of genes in MKR mice versus healthy mice in the degradation of branched-chain amino acids and fatty-acid oxidation pathways. In addition, the flux balance analysis using the MCL multi-tissue model showed that the degradation pathways of branched-chain amino acid and fatty acid oxidation were significantly downregulated in MKR mice versus healthy mice. Validation of the model was performed using data derived from the literature regarding T2DM. Microarray data was used in conjunction with the model to predict fluxes of various other metabolic pathways in the T2DM mouse model and alterations in a number of pathways were detected. The Type 2 Diabetes MCL multi-tissue model may explain the high level of branched-chain amino acids and free fatty acids in plasma of Type 2 Diabetic subjects from a metabolic fluxes perspective. PMID:25029527

  12. Gastric carcinogenesis by N-Methyl-N-nitrosourea is enhanced in db/db diabetic mice.

    PubMed

    Yoshizawa, Nao; Yamaguchi, Hirokazu; Yamamoto, Masami; Shimizu, Nobuyuki; Furihata, Chie; Tatematsu, Masae; Seto, Yasuyuki; Kaminishi, Michio

    2009-07-01

    In 2005, a Japanese epidemiological study showed that increase in plasma glucose levels is a risk factor for gastric cancer. However, no animal model has hitherto shown any association between diabetes mellitus and neoplasia in the stomach. Diabetic (db/db) mice have obese and diabetic phenotypes, including hyperglycemia, because of disruption of the leptin receptor. In the present study, effects of hyperglycemia and/or hyperinsulinemia on the development of proliferative lesions were therefore examined in db/db mice given N-methyl-N-nitrosourea (MNU). A total of 120 mice were assigned to four groups: Group A, 40 db/db mice with MNU; Group B, 40 + /db mice with MNU; Group C, 30 misty (wild-type) mice with MNU; Group D, 10 db/db mice without MNU. MNU was given at 60 ppm in drinking water for 20 weeks. Subgroups of animals were sacrificed at weeks 21 and 30 and blood samples were collected to measure glucose, insulin, leptin, and adiponectin concentrations. The removed stomachs were fixed in formalin, and embedded in paraffin for histological examination and immunohistochemistry. At week 30 in Groups A, B, C and D, hyperplasia was observed in 100, 79, 57, and 0%, and dysplasia in 91, 43, 71, and 0%, respectively. Adenocarcinomas and pepsinogen-altered pyloric glands (PAPG), putative preneoplastic lesions, were observed only in Group A, at an incidence of 45%. The serum levels of insulin and leptin were also elevated in Group A. Gastric carcinogenesis by MNU was enhanced in db/db mice, possibly in association with hyperinsulinemia and hyperleptinemia. PMID:19432903

  13. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice.

    PubMed

    Zhang, Yanqiao; Lee, Florence Ying; Barrera, Gabriel; Lee, Hans; Vales, Charisse; Gonzalez, Frank J; Willson, Timothy M; Edwards, Peter A

    2006-01-24

    Farnesoid X receptor (FXR) plays an important role in maintaining bile acid and cholesterol homeostasis. Here we demonstrate that FXR also regulates glucose metabolism. Activation of FXR by the synthetic agonist GW4064 or hepatic overexpression of constitutively active FXR by adenovirus-mediated gene transfer significantly lowered blood glucose levels in both diabetic db/db and wild-type mice. Consistent with these data, FXR null mice exhibited glucose intolerance and insulin insensitivity. We further demonstrate that activation of FXR in db/db mice repressed hepatic gluconeogenic genes and increased hepatic glycogen synthesis and glycogen content by a mechanism that involves enhanced insulin sensitivity. In view of its central roles in coordinating regulation of both glucose and lipid metabolism, we propose that FXR agonists are promising therapeutic agents for treatment of diabetes mellitus.

  14. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice

    NASA Astrophysics Data System (ADS)

    Zhang, Yanqiao; Lee, Florence Ying; Barrera, Gabriel; Lee, Hans; Vales, Charisse; Gonzalez, Frank J.; Willson, Timothy M.; Edwards, Peter A.

    2006-01-01

    Farnesoid X receptor (FXR) plays an important role in maintaining bile acid and cholesterol homeostasis. Here we demonstrate that FXR also regulates glucose metabolism. Activation of FXR by the synthetic agonist GW4064 or hepatic overexpression of constitutively active FXR by adenovirus-mediated gene transfer significantly lowered blood glucose levels in both diabetic db/db and wild-type mice. Consistent with these data, FXR null mice exhibited glucose intolerance and insulin insensitivity. We further demonstrate that activation of FXR in db/db mice repressed hepatic gluconeogenic genes and increased hepatic glycogen synthesis and glycogen content by a mechanism that involves enhanced insulin sensitivity. In view of its central roles in coordinating regulation of both glucose and lipid metabolism, we propose that FXR agonists are promising therapeutic agents for treatment of diabetes mellitus. glucose | GW4064 | farnesoid X receptor-VP16 | triglyceride | cholesterol

  15. Effects of metformin on inflammation and short-term memory in streptozotocin-induced diabetic mice.

    PubMed

    Oliveira, Wilma Helena; Nunes, Ana Karolina; França, Maria Eduarda Rocha; Santos, Laise Aline; Lós, Deniele Bezerra; Rocha, Sura Wanessa; Barbosa, Karla Patrícia; Rodrigues, Gabriel Barros; Peixoto, Christina Alves

    2016-08-01

    The aim of the present study was to analyze the action of metformin on short-term memory, glial cell activation and neuroinflammation caused by experimental diabetic encephalopathy in C57BL/6 mice. Diabetes was induced by the intraperitoneal injection of a dose of 90mg/kg of streptozotocin on two successive days. Mice with blood glucose levels ≥200dl/ml were considered diabetic and were given metformin hydrochloride at doses of 100mg/kg and 200mg/kg (by gavage, twice daily) for 21 days. On the final day of treatment, the mice underwent a T-maze test. On the 22nd day of treatment all the animals were anesthetized and euthanized. Diabetic animals treated with metformin had a higher spatial memory score. The hippocampus of the diabetic animals presented reactive gliosis, neuronal loss, NF-kB signaling activation, and high levels of IL-1 and VEGF. In addition, the T-maze test scores of these animals were low. Treatment with metformin reduced the expression of GFAP, Iba-1 (astrocyte and microglial markers) and the inflammation markers (p-IKB, IL-1 and VEGF), while enhancing p-AMPK and eNOS levels and increasing neuronal survival (Fox-1 and NeuN). Treatment with metformin also improved the spatial memory scores of diabetic animals. In conclusion, the present study showed that metformin can significantly reduce neuroinflammation and can decrease the loss of neurons in the hippocampus of diabetic animals, which can subsequently promote improvements in spatial memory. PMID:27174003

  16. The Induction of Heme Oxygenase 1 Decreases Painful Diabetic Neuropathy and Enhances the Antinociceptive Effects of Morphine in Diabetic Mice

    PubMed Central

    Castany, Sílvia; Carcolé, Mireia; Leánez, Sergi; Pol, Olga

    2016-01-01

    Painful diabetic neuropathy is a common complication of diabetes mellitus which is poorly controlled by conventional analgesics. This study investigates if treatment with an heme oxygenase 1 (HO-1) inducer, cobalt protoporphyrin IX (CoPP), could modulate the allodynia and hyperalgesia induced by diabetes and enhanced the antinociceptive effects of morphine. In a diabetic mice model induced by the injection of streptozotocin (STZ), we evaluated the antiallodynic and antihyperalgesic effects produced by the intraperitoneal administration of 5 and 10 mg/kg of CoPP at several days after its administration. The antinociceptive actions produced by the systemic administration of morphine alone or combined with CoPP were also evaluated. In addition, the effects of CoPP treatment on the expression of HO-1, the microglial activation marker (CD11b/c), the inducible nitric oxide synthase (NOS2) and μ-opioid receptors (MOR), were also assessed. Our results showed that the administration of 10 mg/kg of CoPP during 5 consecutive days completely blocked the mechanical and thermal hypersensitivity induced by diabetes. These effects are accompanied by the increased spinal cord, dorsal root ganglia and sciatic nerve protein levels of HO-1. In addition, the STZ-induced activation of microglia and overexpression of NOS2 in the spinal cord were inhibited by CoPP treatment. Furthermore, the antinociceptive effects of morphine were enhanced by CoPP treatment and reversed by the administration of an HO-1 inhibitor, tin protoporphyrin IX (SnPP). The spinal cord expression of MOR was also increased by CoPP treatment in diabetic mice. In conclusion, our data provide the first evidence that the induction of HO-1 attenuated STZ-induced painful diabetic neuropathy and enhanced the antinociceptive effects of morphine via inhibition of microglia activation and NOS2 overexpression as well as by increasing the spinal cord levels of MOR. This study proposes the administration of CoPP alone or

  17. The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension.

    PubMed

    Gembardt, Florian; Bartaun, Christoph; Jarzebska, Natalia; Mayoux, Eric; Todorov, Vladimir T; Hohenstein, Bernd; Hugo, Christian

    2014-08-01

    Diabetic nephropathy is the leading cause of end-stage renal disease in humans in the Western world. The recent development of Na+-glucose cotransporter 2 (SGLT2) inhibitors offers a new antidiabetic therapy via enhanced glucose excretion. Whether this strategy exerts beneficial effects on the development of type 2 diabetic nephropathy is still largely unclear. We investigated the effects of the specific SGLT2 inhibitor empagliflozin in BTBR.Cg-Lep/WiscJ (BTBR ob/ob) mice, which spontaneously develop type 2 diabetic nephropathy. In the first experiment, BTBR ob/ob mice received either a diet containing 300 ppm empagliflozin or equicaloric placebo chow for 12 wk. In the second experiment, BTBR ob/ob mice received 1 μg·kg body wt(-1)·day(-1) ANG II to induce arterial hypertension and were separated into the same two diet groups for 6 wk. In both experiments, empagliflozin treatment enhanced glucosuria, thereby lowering blood glucose. Independently of hypertension, empagliflozin reduced albuminuria in diabetic mice. However, empagliflozin treatment affected diabetes-related glomerular hypertrophy, markers of renal inflammation, and mesangial matrix expansion only in BTBR ob/ob mice without hypertension. In summary, empagliflozin demonstrated significant antihyperglycemic effects, differentially ameliorating early features of diabetic nephropathy in BTBR ob/ob mice with and without hypertension.

  18. Differentially expressed proteins in the pancreas of diet-induced diabetic mice.

    PubMed

    Qiu, Linghua; List, Edward O; Kopchick, John J

    2005-09-01

    The pancreas is a heterogeneous organ mixed with both exocrine and endocrine cells. The pancreas is involved in metabolic activities with the endocrine cells participating in the regulation of blood glucose, while the exocrine portion provides a compatible environment for the pancreatic islets and is responsible for secretion of digestive enzymes. The purpose of this study was to identify pancreatic proteins that are differentially expressed in normal mice and those with diet-induced type 2 diabetes (T2DM). In this study, C57BL/6J male mice fed a high fat diet became obese and developed T2DM. The pancreatic protein profiles were compared between control and diabetic mice using two-dimensional gel electrophoresis. Differentially expressed protein "spots" were identified by mass spectrometry. REG1 and REG2 proteins, which may be involved in the proliferation of pancreatic beta cells, were up-regulated very early in the progression of obese mice to T2DM. Glutathione peroxidase, which functions in the clearance of reactive oxidative species, was found to be down-regulated in the diabetic mice at later stages. The RNA levels encoding REG2 and glutathione peroxidase were compared by Northern blot analysis and were consistent to the changes in protein levels between diabetic and control mice. The up-regulation of REG1 and REG2 suggests the effort of the pancreas in trying to ameliorate the hyperglycemic condition by stimulating the proliferation of pancreatic beta cells and enhancing the subsequent insulin secretion. The down-regulation of glutathione peroxidase in pancreas could contribute to the progressive deterioration of beta cell function due to the hyperglycemia-induced oxidative stress. PMID:15961380

  19. Role of endothelial nitric oxide synthase in diabetic nephropathy: lessons from diabetic eNOS knockout mice.

    PubMed

    Takahashi, Takamune; Harris, Raymond C

    2014-01-01

    Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in many countries. The animal models that recapitulate human DN undoubtedly facilitate our understanding of this disease and promote the development of new diagnostic markers and therapeutic interventions. Based on the clinical evidence showing the association of eNOS dysfunction with advanced DN, we and others have created diabetic mice that lack eNOS expression and shown that eNOS-deficient diabetic mice exhibit advanced nephropathic changes with distinct features of progressive DN, including pronounced albuminuria, nodular glomerulosclerosis, mesangiolysis, and arteriolar hyalinosis. These studies clearly defined a critical role of eNOS in DN and developed a robust animal model of this disease, which enables us to study the pathogenic mechanisms of progressive DN. Further, recent studies with this animal model have explored the novel mechanisms by which eNOS deficiency causes advanced DN and provided many new insights into the pathogenesis of DN. Therefore, here we summarize the findings obtained with this animal model and discuss the roles of eNOS in DN, unresolved issues, and future investigations of this animal model study. PMID:25371905

  20. Metabolic stress–induced activation of FoxO1 triggers diabetic cardiomyopathy in mice

    PubMed Central

    Battiprolu, Pavan K.; Hojayev, Berdymammet; Jiang, Nan; Wang, Zhao V.; Luo, Xiang; Iglewski, Myriam; Shelton, John M.; Gerard, Robert D.; Rothermel, Beverly A.; Gillette, Thomas G.; Lavandero, Sergio; Hill, Joseph A.

    2012-01-01

    The leading cause of death in diabetic patients is cardiovascular disease; diabetic cardiomyopathy is typified by alterations in cardiac morphology and function, independent of hypertension or coronary disease. However, the molecular mechanism that links diabetes to cardiomyopathy is incompletely understood. Insulin resistance is a hallmark feature of diabetes, and the FoxO family of transcription factors, which regulate cell size, viability, and metabolism, are established targets of insulin and growth factor signaling. Here, we set out to evaluate a possible role of FoxO proteins in diabetic cardiomyopathy. We found that FoxO proteins were persistently activated in cardiac tissue in mice with diabetes induced either genetically or by high-fat diet (HFD). FoxO activity was critically linked with development of cardiomyopathy: cardiomyocyte-specific deletion of FoxO1 rescued HFD-induced declines in cardiac function and preserved cardiomyocyte insulin responsiveness. FoxO1-depleted cells displayed a shift in their metabolic substrate usage, from free fatty acids to glucose, associated with decreased accumulation of lipids in the heart. Furthermore, we found that FoxO1-dependent downregulation of IRS1 resulted in blunted Akt signaling and insulin resistance. Together, these data suggest that activation of FoxO1 is an important mediator of diabetic cardiomyopathy and is a promising therapeutic target for the disease. PMID:22326951

  1. Knockout Mice Challenge our Concepts of Glucose Homeostasis and the Pathogenesis of Diabetes

    PubMed Central

    2003-01-01

    A central component of type 2 diabetes and the metabolic syndrome is insulin resistance. Insulin exerts a multifaceted and highly integrated series of actions via its intracellular signaling systems. Generation of mice carrying null mutations of the genes encoding proteins in the insulin signaling pathway provides a unique approach to determining the role of individual proteins in the molecular mechanism of insulin action and the pathogenesis of insulin resistance and diabetes. The role of the four major insulin receptor substrates (IRS1-4) in insulin and IGF-1 signaling have been examined by creating mice with targeted gene knockouts. Each produces a unique phenotype, indicating the complementary role of these signaling components. Combined heterozygous defects often produce synergistic or epistatic effects, although the final severity of the phenotype depends on the genetic background of the mice. Conditional knockouts of the insulin receptor have also been created using the Cre-lox system. These tissue specific knockouts have provide unique insights into the control of glucose homeostasis and the pathogenesis of type 2 diabetes, and have led to development of new hypotheses about the nature of the insulin action and development of diabetes. PMID:15061645

  2. Protease-activated receptor-1 deficiency protects against streptozotocin-induced diabetic nephropathy in mice.

    PubMed

    Waasdorp, Maaike; Duitman, JanWillem; Florquin, Sandrine; Spek, C Arnold

    2016-01-01

    Endogenously administered activated protein C ameliorates diabetic nephropathy (DN) in a protease-activated receptor-1 (PAR-1)-dependent manner, suggesting that PAR-1 activation limits the progression of DN. Activation of PAR-1 in fibroblast-like cells, however, induces proliferation and extracellular matrix production, thereby driving fibrotic disease. Considering the key role of mesangial proliferation and extracellular matrix production during DN, PAR-1 may in fact potentiate diabetes-induced kidney injury. To determine the net effect of PAR-1 in DN, streptozotocin-induced DN was studied in wild type and PAR-1 deficient mice. Subsequent mechanistic insight was obtained by assessing profibrotic responses of mesangial and tubular epithelial cells in vitro, following PAR-1 stimulation and inhibition. Despite having similar glucose levels, PAR-1 deficient mice developed less kidney damage after induction of diabetes, as evidenced by diminished proteinuria, plasma cystatin C levels, expansion of the mesangial area, and tubular atrophy. In vitro, PAR-1 signaling in mesangial cells led to increased proliferation and expression of matrix proteins fibronectin and collagen IV. Conversely, a reduction in both proliferation and fibronectin deposition was observed in diabetic PAR-1 deficient mice. Overall, we show that PAR-1 plays an important role in the development of DN and PAR-1 might therefore be an attractive therapeutic target to pursue in DN. PMID:27618774

  3. Protease-activated receptor-1 deficiency protects against streptozotocin-induced diabetic nephropathy in mice

    PubMed Central

    Waasdorp, Maaike; Duitman, JanWillem; Florquin, Sandrine; Spek, C. Arnold

    2016-01-01

    Endogenously administered activated protein C ameliorates diabetic nephropathy (DN) in a protease-activated receptor-1 (PAR-1)-dependent manner, suggesting that PAR-1 activation limits the progression of DN. Activation of PAR-1 in fibroblast-like cells, however, induces proliferation and extracellular matrix production, thereby driving fibrotic disease. Considering the key role of mesangial proliferation and extracellular matrix production during DN, PAR-1 may in fact potentiate diabetes-induced kidney injury. To determine the net effect of PAR-1 in DN, streptozotocin-induced DN was studied in wild type and PAR-1 deficient mice. Subsequent mechanistic insight was obtained by assessing profibrotic responses of mesangial and tubular epithelial cells in vitro, following PAR-1 stimulation and inhibition. Despite having similar glucose levels, PAR-1 deficient mice developed less kidney damage after induction of diabetes, as evidenced by diminished proteinuria, plasma cystatin C levels, expansion of the mesangial area, and tubular atrophy. In vitro, PAR-1 signaling in mesangial cells led to increased proliferation and expression of matrix proteins fibronectin and collagen IV. Conversely, a reduction in both proliferation and fibronectin deposition was observed in diabetic PAR-1 deficient mice. Overall, we show that PAR-1 plays an important role in the development of DN and PAR-1 might therefore be an attractive therapeutic target to pursue in DN. PMID:27618774

  4. Abnormal essential fatty acid composition of tissue lipids in genetically diabetic mice is partially corrected by dietary linoleic and gamma-linolenic acids.

    PubMed

    Cunnane, S C; Manku, M S; Horrobin, D F

    1985-05-01

    Genetically diabetic mice (db/db) and their non-diabetic litter-mates were maintained for 15 weeks on diets supplemented with safflower oil or evening primrose (Oenothera bienis) oil, both essential fatty acid (EFA)-rich sources, or hydrogenated coconut oil (devoid of EFA). Plasma glucose was higher in the diabetic mice supplemented with the oils than in the unsupplemented diabetic mice. In the oil-supplemented non-diabetic mice, plasma glucose did not differ compared with the unsupplemented non-diabetic mice. The proportional content of arachidonic acid in the phospholipids of the pancreas was significantly decreased in diabetic mice, an effect which was completely prevented by supplementation with safflower or evening primrose oil but not hydrogenated coconut oil. In the liver phospholipids of the diabetic mice, dihomo-gamma-linolenic acid was proportionally increased, an effect reduced by supplementation with safflower oil but not evening primrose or hydrogenated coconut oils. In the liver triglycerides of the diabetic mice, gamma-linolenic acid, dihomo-gamma-linolenic acid and arachidonic acid were all proportionally decreased, effects which were also prevented by safflower or evening primrose oil but not hydrogenated coconut oil. Alopecia and dry scaly skin were prominent in the diabetic mice but less extensive in the diabetic mice supplemented with EFA.

  5. Hypoglycemic activities of lyophilized powder of Gynura divaricata by improving antioxidant potential and insulin signaling in type 2 diabetic mice

    PubMed Central

    Xu, Bing-Qing; Yang, Ping; Zhang, Yu-Qing

    2015-01-01

    Background Diabetes mellitus is a serious disease affecting about 5% of people worldwide. Although several studies have indicated hypoglycemic activities of Gynura divaricata (GD), the mechanisms by which GD improves the symptoms of diabetes remain unclear. Objective The aim of this study was to investigate the potential hypoglycemic effects of GD. Design The leaves and stems of GD were prepared and lyophilized into a powder, which was added to the diet of mice with type 2 diabetes induced by a high-fat diet in combination with streptozotocin for 4 weeks. During this period, fasting blood glucose (FBG) levels and body weight of mice were measured. In addition, at the end of the experiment, a series of assays was performed. Results GD administration effectively alleviates insulin resistance and induces a decrease in FBG by 59.54% in 1.2% (L) GD-treated diabetic group and 56.13% in 4.8% (H) GD-treated diabetic group after 4 weeks, respectively, relative to diabetic model mice. The antioxidant capacity was improved by increasing the activities of glutathione peroxidase (GSH-Px) and total superoxide dismutase (T-SOD) by 64.87% and 53.42% in treatment group H, compared to diabetic model mice, while GD treatment induced a significant decrease in malondialdehyde (MDA) level by 50% in treatment group L, compared to the level in diabetic model mice. Furthermore, glucose metabolism was ameliorated by the increased glycogen synthesis in the livers of diabetic mice. In addition, we also demonstrated that the messenger RNA (mRNA) and protein expression levels of AKT, PI3K and PDK-1, which are involved in insulin signaling, were significantly increased. Conclusions Oral administration of the GD-lyophilized powder has been effectively hypoglycemic, which is done by activating insulin signaling and improving antioxidant capacity in mice with type 2 diabetes. PMID:26715102

  6. Phycocyanin ameliorates alloxan-induced diabetes mellitus in mice: Involved in insulin signaling pathway and GK expression.

    PubMed

    Ou, Yu; Ren, Zhiheng; Wang, Jianhui; Yang, Xuegan

    2016-03-01

    The therapeutic potential and molecular mechanism of phycocyanin from Spirulina on alloxan-induced diabetes mice was investigated. In the experiment, 4-week treatment of phycocyanin at the dose of 100 and 200 mg/kg body weight in alloxan-induced diabetes mice resulted in improved metrics in comparison with alloxan-induced diabetes group. These metrics include blood glucose levels, glycosylated serum protein (GSP), glycosylated hemoglobin (GHb) and fasting serum insulin (FINS) levels. As its molecular mode of action, phycocyanin leads to the increase of IRS-1 tyrosine phosphorylation and the decrease of IRS-1 serine phosphorylation, also accompany with increased level of Akt phosphorylation on Ser473 in the liver and pancreas in diabetic mice. In addition, phycocyanin treatment enhanced the glucokinase (GK) level in the liver and pancreas, and the glucokinase regulatory protein (GKRP) level in the liver in diabetic mice. The results suggest that phycocyanin ameliorates alloxan-induced diabetes mellitus in mice by activating insulin signaling pathway and GK expression in pancreas and liver in diabetic mice. PMID:26827782

  7. Assessment of DNA damage and lipid peroxidation in diabetic mice: effects of propolis and epigallocatechin gallate (EGCG).

    PubMed

    Oršolić, Nada; Sirovina, Damir; Gajski, Goran; Garaj-Vrhovac, Vera; Jazvinšćak Jembrek, Maja; Kosalec, Ivan

    2013-09-18

    There is growing recognition that polyphenolic compounds present in many plants and natural products may have beneficial effects on human health. Propolis - a substance produced by honeybees - and catechins in tea, in particular (-)-epigallocatechin gallate (EGCG), are strong antioxidants that appear to have anti-obesity and anti-diabetic effects. The present study was designed to elucidate the anti-diabetic effect of the water-soluble derivative of propolis (WSDP), which contains phenolic acids as the main compounds, and EGCG in alloxan-induced (75mg/kg, iv) diabetes in mice. Intraperitoneal administration of EGCG or propolis at doses of 50mg/kg body weight (bw) to diabetic mice for a period of 7 days resulted in a significant increase in body weight and in haematological/immunological blood parameters, as well as in 100% survival of the mice. A significant decrease in lipid peroxidation in liver, kidney and brain tissue was also observed in diabetic mice treated with these two agents. Additionally, EGCG and propolis clearly reduced DNA damage in peripheral lymphocytes of diabetic mice. Our studies demonstrate the anti-oxidative and anti-inflammatory potential of WSDP and EGCG, which could exert beneficial effects against diabetes and the associated consequences of free-radical formation in kidney, liver, spleen and brain tissue. The results suggest that dietary supplementation with WSDP or EGCG could potentially contribute to nutritional strategies for the prevention and treatment of diabetes mellitus. PMID:23859956

  8. Altered parasympathetic nervous system regulation of the sinoatrial node in Akita diabetic mice.

    PubMed

    Krishnaswamy, Pooja S; Egom, Emmanuel E; Moghtadaei, Motahareh; Jansen, Hailey J; Azer, John; Bogachev, Oleg; Mackasey, Martin; Robbins, Courtney; Rose, Robert A

    2015-05-01

    Cardiovascular autonomic neuropathy (CAN) is a serious complication of diabetes mellitus that impairs autonomic regulation of heart rate (HR). This has been attributed to damage to the nerves that modulate spontaneous pacemaker activity in the sinoatrial node (SAN). Our objective was to test the hypothesis that impaired parasympathetic regulation of HR in diabetes is due to reduced responsiveness of the SAN to parasympathetic agonists. We used the Akita mouse model of type 1 diabetes to study the effects of the parasympathetic agonist carbachol (CCh) on SAN function using intracardiac programmed stimulation, high resolution optical mapping and patch-clamping of SAN myocytes. CCh decreased HR by 30% and increased corrected SAN recovery time (cSNRT) by 123% in wildtype mice. In contrast, CCh only decreased HR by 12%, and only increased cSNRT by 37% in Akita mice. These alterations were due to smaller effects of CCh on SAN electrical conduction and spontaneous action potential firing in isolated SAN myocytes. Voltage clamp experiments demonstrate that the acetylcholine-activated K(+) current (IKACh) is reduced in Akita SAN myocytes due to enhanced desensitization and faster deactivation kinetics. These IKACh alterations were normalized by treating Akita SAN myocytes with PI(3,4,5)P3 or an inhibitor of regulator of G-protein signaling 4 (RGS4). There was no difference in the effects of CCh on the hyperpolarization-activated current (If) between wildtype and Akita mice. Our study demonstrates that Akita diabetic mice demonstrate impaired parasympathetic regulation of HR and SAN function due to reduced responses of the SAN to parasympathetic agonists. Our experiments demonstrate a key role for insulin-dependent phosphoinositide 3-kinase (PI3K) signaling in the parasympathetic dysfunction seen in the SAN in diabetes. PMID:25754673

  9. Methadone ameliorates multiple-low-dose streptozotocin-induced type 1 diabetes in mice

    SciTech Connect

    Amirshahrokhi, K.; Dehpour, A.R.; Hadjati, J.; Sotoudeh, M.; Ghazi-Khansari, M.

    2008-10-01

    Type 1 diabetes is an autoimmune disease characterized by inflammation of pancreatic islets and destruction of {beta} cells by the immune system. Opioids have been shown to modulate a number of immune functions, including T helper 1 (Th1) and T helper 2 (Th2) cytokines. The immunosuppressive effect of long-term administration of opioids has been demonstrated both in animal models and humans. The aim of this study was to determine the effect of methadone, a {mu}-opioid receptor agonist, on type 1 diabetes. Administration of multiple low doses of streptozotocin (STZ) (MLDS) (40mg/kg intraperitoneally for 5 consecutive days) to mice resulted in autoimmune diabetes. Mice were treated with methadone (10mg/kg/day subcutaneously) for 24days. Blood glucose, insulin and pancreatic cytokine levels were measured. Chronic methadone treatment significantly reduced hyperglycemia and incidence of diabetes, and restored pancreatic insulin secretion in the MLDS model. The protective effect of methadone can be overcome by pretreatment with naltrexone, an opioid receptor antagonist. Also, methadone treatment decreased the proinflammatory Th1 cytokines [interleukin (IL)-1{beta}, tumor necrosis factor-{alpha} and interferon-{gamma}] and increased anti-inflammatory Th2 cytokines (IL-4 and IL-10). Histopathological observations indicated that STZ-mediated destruction of {beta} cells was attenuated by methadone treatment. It seems that methadone as an opioid agonist may have a protective effect against destruction of {beta} cells and insulitis in the MLDS model of type 1 diabetes.

  10. Additional deleterious effects of alcohol consumption on sperm parameters and DNA integrity in diabetic mice.

    PubMed

    Pourentezari, M; Talebi, A R; Mangoli, E; Anvari, M; Rahimipour, M

    2016-06-01

    The aim of this study was to survey the impact of alcohol consumption on sperm parameters and DNA integrity in experimentally induced diabetic mice. A total of 32 adult male mice were divided into four groups: mice of group 1 served as control fed on basal diet, group 2 received streptozotocin (STZ) (200 mg kg(-1) , single dose, intraperitoneal) and basal diet, group 3 received alcohol (10 mg kg(-1) , water soluble) and basal diet, and group 4 received STZ and alcohol for 35 days. The cauda epididymidis of each mouse was dissected and placed in 1 ml of pre-warm Ham's F10 culture medium for 30 min. The swim-out spermatozoa were analysed for count, motility, morphology and viability. Sperm chromatin quality was evaluated with aniline blue, toluidine blue, acridine orange and chromomycin A3 staining. The results showed that all sperm parameters had significant differences (P < 0.05), also when sperm chromatin was assessed with cytochemical tests. There were significant differences (P < 0.001) between the groups. According to our results, alcohol and diabetes can cause abnormalities in sperm parameters and chromatin quality. In addition, alcohol consumption in diabetic mice can intensify sperm chromatin/DNA damage. PMID:26358836

  11. Antihyperglycemic effects of Platycodon grandiflorum (Jacq.) A. DC. extract on streptozotocin-induced diabetic mice.

    PubMed

    Zheng, Jie; He, Jiguo; Ji, Baoping; Li, Ye; Zhang, Xiaofeng

    2007-03-01

    The root of Platycodon grandiflorum (Jacq.) A. DC has been reported to have a wide range of health benefits in oriental food. This study examined the hypoglycemic effects of Platycodon grandiflorum (Jacq.) A. DC aqueous-ethanol extract (PGE) in streptozotocin (STZ) -induced diabetic ICR mice (STZ diabetic mice) for the first time. The effects of PGE on blood glucose, plasma insulin levels and body weight were investigated. A significant decrease in blood glucose levels was observed after single administration of PGE. Furthermore, Glibenclamide and PGE significantly suppressed the rise in blood glucose after 30 min in the acute glucose tolerance test. Treatment with glibenclamide and PGE resulted in a reduction in blood glucose levels from the 2nd week, and this reduction was maintained until the 4th week of treatment. The body weight changed slightly in glibenclamide and PGE treated mice in comparison with the STZ control group. Plasma insulin levels were increased with glibenclamide treatment in STZ diabetic mice, whereas such effect was not observed with PGE. These results indicated that PGE could induce hypoglycemic effects without stimulating insulin secretion. PMID:17226070

  12. Impaired musculoskeletal response to age and exercise in PPARβ(-/-) diabetic mice.

    PubMed

    Fu, He; Desvergne, Beatrice; Ferrari, Serge; Bonnet, Nicolas

    2014-12-01

    Fragility fractures are recognized complication of diabetes, but yet the underlying mechanisms remain poorly understood. This is particularly pronounced in type 2 diabetes in which the propensity to fall is increased but bone mass is not necessarily low. Thus, whether factors implicated in the development of insulin resistance and diabetes directly impact on the musculoskeletal system remains to be investigated. PPARβ(-/-) mice have reduced metabolic activity and are glucose intolerant. We examined changes in bone and muscle in PPARβ(-/-) mice and investigated both the mechanism behind those changes with age as well as their response to exercise. Compared with their wild type, PPARβ(-/-) mice had an accelerated and parallel decline in both muscle and bone strength with age. These changes were accompanied by increased myostatin expression, low bone formation, and increased resorption. In addition, mesenchymal cells from PPARβ(-/-) had a reduced proliferation capacity and appeared to differentiate into more of an adipogenic phenotype. Concomitantly we observed an increased expression of PPARγ, characteristic of adipocytes. The anabolic responses of muscle and bone to exercise were also diminished in PPARβ(-/-) mice. The periosteal bone formation response to direct bone compression was, however, maintained, indicating that PPARβ controls periosteal bone formation through muscle contraction and/or metabolism. Taken together, these data indicate that PPARβ deficiency leads to glucose intolerance, decreased muscle function, and reduced bone strength. On a molecular level, PPARβ appears to regulate myostatin and PPARγ expression in muscle and bone, thereby providing potential new targets to reverse bone fragility in patients with metabolic disturbances.

  13. The PKD Inhibitor CID755673 Enhances Cardiac Function in Diabetic db/db Mice

    PubMed Central

    Venardos, Kylie; De Jong, Kirstie A.; Elkamie, Mansour; Connor, Timothy; McGee, Sean L.

    2015-01-01

    The development of diabetic cardiomyopathy is a key contributor to heart failure and mortality in obesity and type 2 diabetes (T2D). Current therapeutic interventions for T2D have limited impact on the development of diabetic cardiomyopathy. Clearly, new therapies are urgently needed. A potential therapeutic target is protein kinase D (PKD), which is activated by metabolic insults and implicated in the regulation of cardiac metabolism, contractility and hypertrophy. We therefore hypothesised that PKD inhibition would enhance cardiac function in T2D mice. We first validated the obese and T2D db/db mouse as a model of early stage diabetic cardiomyopathy, which was characterised by both diastolic and systolic dysfunction, without overt alterations in left ventricular morphology. These functional characteristics were also associated with increased PKD2 phosphorylation in the fed state and a gene expression signature characteristic of PKD activation. Acute administration of the PKD inhibitor CID755673 to normal mice reduced both PKD1 and 2 phosphorylation in a time and dose-dependent manner. Chronic CID755673 administration to T2D db/db mice for two weeks reduced expression of the gene expression signature of PKD activation, enhanced indices of both diastolic and systolic left ventricular function and was associated with reduced heart weight. These alterations in cardiac function were independent of changes in glucose homeostasis, insulin action and body composition. These findings suggest that PKD inhibition could be an effective strategy to enhance heart function in obese and diabetic patients and provide an impetus for further mechanistic investigations into the role of PKD in diabetic cardiomyopathy. PMID:25798941

  14. Exenatide suppresses 1,2-dimethylhydrazine-induced colon cancer in diabetic mice: Effect on tumor angiogenesis and cell proliferation.

    PubMed

    Tawfik, Mona K; Mohamed, Magda I

    2016-08-01

    Colon cancer is the third leading cause of cancer mortality worldwide, which results from interactions of different factors. It is frequently a pathological consequence of persistent inflammation. Diabetes affects several cancers and is positively correlated with the incidence of colon cancer. This study aimed to study the effect of exenatide in ameliorating inflammation, angiogenesis and cell proliferation in 1,2-dimethyl hydrazine (DMH) induced colorectal carcinoma in diabetic mice. Mice were randomly allocated into six groups, 8 mice each. Group 1: vehicle control group. Group 2: diabetic control group. Group 3: DMH control group: diabetic mice treated with DMH (20mg/kg/week,s.c.) for 15 week. Group 4: DMH-cisplatin group: mice received cisplatin (4mg/kg/week, i.p.). Groups 5 & 6: DMH-exenatide (10 and 20μg/kg) group: mice received exenatide (10 or 20μg/kg/day,s.c.), respectively. The present results highlighted an increase in angiogenic markers and cell proliferation in the DMH-diabetic group in comparison with the control group with greater expression of endothelial marker (CD34) and Ki-67 in colon tissue. Monotherapy with cisplatin or exenatide (10 and 20μg/kg) downregulated these markers to different extents. The current results provided evidence that exenatide represents a promising chemopreventive effect against DMH-induced colon carcinogenesis in diabetic mice, at least in part, attributed to its anti-angiogenic and anti-proliferative mechanisms.

  15. Glomerular volume and renal histology in obese and non-obese living kidney donors.

    PubMed

    Rea, D J; Heimbach, J K; Grande, J P; Textor, S C; Taler, S J; Prieto, M; Larson, T S; Cosio, F G; Stegall, M D

    2006-11-01

    The link between obesity and renal disease is unclear, and there is no consensus as to whether obese individuals are at increased risk for kidney disease after living kidney donation if they otherwise meet acceptance criteria. We retrospectively studied time-zero (implantation) biopsies in 49 obese (body mass index (BMI) > or = 30 kg/m2) and 41 non-obese (BMI < 30 kg/m2) renal donors that met acceptance criteria. We found that our obese donor population had higher systolic blood pressure (P < 0.001 vs non-obese) and higher absolute iothalamate clearance (P = 0.001 vs non-obese) before donation. The obese donors had larger glomerular planar surface area compared to non-obese controls (P = 0.017), and this parameter correlated with patient weight and urinary microalbumin excretion. Detailed examination of the biopsies revealed that although most histologic findings were similar between groups, the obese donors had more tubular dilation (P = 0.01), but less tubular vacuolization (P = 0.02) than the non-obese controls. There was also a trend toward more arterial hyalinosis in the obese patients than controls (P = 0.08). From these data, our studies detected subtle differences in donor organs obtained from obese compared to non-obese individuals. Further studies should be carried out to quantify the long-term impact of these findings.

  16. [Effects of sex hormone on the dilatation of urinary tubule and acidophil body in NON mice].

    PubMed

    Sahata, H; Suzuki, S; Ago, A; Mifune, H; Sakamoto, H

    1994-10-01

    The influences of sex hormones on the dilatation of the urinary tubules and acidophil bodies were histologically investigated in NON (Non-Obese Non-diabetic) mice. Although the dilatation of the proximal tubules and acidophil bodies in NON mice were observed only in female but not in male, a slight dilatation and a few bodies were also observed in castrated male NON mice. Moreover, in ovariectomized female NON mice the dilatation and bodies were less compared with intact female NON mice. Estradiol administration induced prominent dilatation and numerous acidophil bodies, while the administration of testosterone showed a complete preventive effect. Therefore, it is suggested that the dilatation of the tubules and the acidophil bodies can be profoundly influenced by sex hormones. PMID:7805803

  17. Maintenance of Normoglycemia in Diabetic Mice by Subcutaneous Xenografts of Encapsulated Islets

    NASA Astrophysics Data System (ADS)

    Lacy, Paul E.; Hegre, Orion D.; Gerasimidi-Vazeou, Andriani; Gentile, Frank T.; Dionne, Keith E.

    1991-12-01

    The goal of islet transplantation in human diabetes is to maintain the islet grafts in the recipients without the use of immunosuppression. One approach is to encapsulate the donor islets in permselective membranes. Hollow fibers fabricated from an acrylic copolymer were used to encapsulate small numbers of rat islets that were immobilized in an alginate hydrogel for transplantation in diabetic mice. The fibers were biocompatible, prevented rejection, and maintained normoglycemia when transplanted intraperitoneally; hyperglycemia returned when the fibers were removed at 60 days. Normoglycemia was also maintained by subcutaneous implants that had an appropriately constructed outer surface on the fibers.

  18. Improvement of diabetes, obesity and hypertension in type 2 diabetic KKA{sup y} mice by bis(allixinato)oxovanadium(IV) complex

    SciTech Connect

    Adachi, Yusuke; Yoshikawa, Yutaka; Yoshida, Jiro; Kodera, Yukihiro . E-mail: kodera_y@wakunaga.co.jp; Katoh, Akira . E-mail: katoh@st.seikei.ac.jp; Takada, Jitsuya . E-mail: takada@hl.rri.kyoto-u.ac.jp; Sakurai, Hiromu . E-mail: sakurai@mb.kyoto-phu.ac.jp

    2006-07-07

    Previously, we found that bis(allixinato)oxovanadium(IV) (VO(alx){sub 2}) exhibits a potent hypoglycemic activity in type 1-like diabetic mice. Since the enhancement of insulin sensitivity is involved in one of the mechanisms by which vanadium exerts its anti-diabetic effects, VO(alx){sub 2} was further tested in type 2 diabetes with low insulin sensitivity. The effect of oral administration of VO(alx){sub 2} was examined in obesity-linked type 2 diabetic KKA{sup y} mice. Treatment of VO(alx){sub 2} for 4 weeks normalized hyperglycemia, glucose intolerance, hyperinsulinemia, hypercholesterolemia and hypertension in KKA{sup y} mice; however, it had no effect on hypoadiponectinemia. VO(alx){sub 2} also improved hyperleptinemia, following attenuation of obesity in KKA{sup y} mice. This is the first example in which a vanadium compound improved leptin resistance in type 2 diabetes by oral administration. On the basis of these results, VO(alx){sub 2} is proposed to enhance not only insulin sensitivity but also leptin sensitivity, which in turn improves diabetes, obesity and hypertension in an obesity-linked type 2 diabetic animal.

  19. Proregenerative Microenvironment Triggered by Donor Mesenchymal Stem Cells Preserves Renal Function and Structure in Mice with Severe Diabetes Mellitus

    PubMed Central

    Ezquer, Fernando; Giraud-Billoud, Maximiliano; Carpio, Daniel; Cabezas, Fabián; Conget, Paulette; Ezquer, Marcelo

    2015-01-01

    The aim of our work was to evaluate, in an animal model of severe diabetes mellitus, the effect of mesenchymal stem cells (MSCs) administration on diabetic nephropathy (DN) progression. After diabetes induction, one group of mice received the vehicle (DM) and other group received a single dose of MSCs (DM + MSCs). DM + MSCs mice showed a significant improvement in functional parameters of the kidney compared with untreated mice. While DM mice presented marked histopathological changes characteristics of advanced stages of DN (fibrosis, glomerulosclerosis, glomerular basement membrane thickening, capillary occlusion, decreased podocyte density, and effacement of foot processes), DM + MSCs mice showed only slight tubular dilatation. The renoprotection was not associated with an improvement in diabetic condition and very low number of donor cells was found in the kidney of DM + MSCs mice, suggesting that renoprotection could be mediated by paracrine effects. Indeed, DM + MSC mice presented increased renal proliferation index, decreased renal apoptotic index and the restoration of proregenerative factors, and anti-inflammatory cytokines levels. Moreover, macrophage infiltration and oxidative stress damage were also reduced in DM + MSCs mice. Our data demonstrate that MSC administration triggers a proregenerative microenvironment in DN kidney, which allows the preservation of the renal function even if diabetes was uncorrected. PMID:26167475

  20. Proregenerative Microenvironment Triggered by Donor Mesenchymal Stem Cells Preserves Renal Function and Structure in Mice with Severe Diabetes Mellitus.

    PubMed

    Ezquer, Fernando; Giraud-Billoud, Maximiliano; Carpio, Daniel; Cabezas, Fabián; Conget, Paulette; Ezquer, Marcelo

    2015-01-01

    The aim of our work was to evaluate, in an animal model of severe diabetes mellitus, the effect of mesenchymal stem cells (MSCs) administration on diabetic nephropathy (DN) progression. After diabetes induction, one group of mice received the vehicle (DM) and other group received a single dose of MSCs (DM + MSCs). DM + MSCs mice showed a significant improvement in functional parameters of the kidney compared with untreated mice. While DM mice presented marked histopathological changes characteristics of advanced stages of DN (fibrosis, glomerulosclerosis, glomerular basement membrane thickening, capillary occlusion, decreased podocyte density, and effacement of foot processes), DM + MSCs mice showed only slight tubular dilatation. The renoprotection was not associated with an improvement in diabetic condition and very low number of donor cells was found in the kidney of DM + MSCs mice, suggesting that renoprotection could be mediated by paracrine effects. Indeed, DM + MSC mice presented increased renal proliferation index, decreased renal apoptotic index and the restoration of proregenerative factors, and anti-inflammatory cytokines levels. Moreover, macrophage infiltration and oxidative stress damage were also reduced in DM + MSCs mice. Our data demonstrate that MSC administration triggers a proregenerative microenvironment in DN kidney, which allows the preservation of the renal function even if diabetes was uncorrected.

  1. Neurotensin-loaded collagen dressings reduce inflammation and improve wound healing in diabetic mice.

    PubMed

    Moura, Liane I F; Dias, Ana M A; Suesca, Edward; Casadiegos, Sergio; Leal, Ermelindo C; Fontanilla, Marta R; Carvalho, Lina; de Sousa, Hermínio C; Carvalho, Eugénia

    2014-01-01

    Impaired wound healing is an important clinical problem in diabetes mellitus and results in failure to completely heal diabetic foot ulcers (DFUs), which may lead to lower extremity amputations. In the present study, collagen based dressings were prepared to be applied as support for the delivery of neurotensin (NT), a neuropeptide that acts as an inflammatory modulator in wound healing. The performance of NT alone and NT-loaded collagen matrices to treat wounds in streptozotocin (STZ) diabetic induced mice was evaluated. Results showed that the prepared dressings were not-cytotoxic up to 72h after contact with macrophages (Raw 264.7) and human keratinocyte (HaCaT) cell lines. Moreover, those cells were shown to adhere to the collagen matrices without noticeable change in their morphology. NT-loaded collagen dressings induced faster healing (17% wound area reduction) in the early phases of wound healing in diabetic wounded mice. In addition, they also significantly reduced inflammatory cytokine expression namely, TNF-α (p<0.01) and IL-1β (p<0.01) and decreased the inflammatory infiltrate at day 3 post-wounding (inflammatory phase). After complete healing, metalloproteinase 9 (MMP-9) is reduced in diabetic skin (p<0.05) which significantly increased fibroblast migration and collagen (collagen type I, alpha 2 (COL1A2) and collagen type III, alpha 1 (COL3A1)) expression and deposition. These results suggest that collagen-based dressings can be an effective support for NT release into diabetic wound enhancing the healing process. Nevertheless, a more prominent scar is observed in diabetic wounds treated with collagen when compared to the treatment with NT alone. PMID:24161538

  2. Association of Bactericidal Dysfunction of Paneth Cells in Streptozocin-Induced Diabetic Mice with Insulin Deficiency.

    PubMed

    Yu, Tao; Yang, Hong-Sheng; Lu, Xi-Ji; Xia, Zhong-Sheng; Ouyang, Hui; Shan, Ti-Dong; Huang, Can-Ze; Chen, Qi-Kui

    2016-01-01

    BACKGROUND Type 1 diabetes mellitus (T1DM) is associated with increased risks of enteric infection. Paneth cells constitute the first line of the gut defense. Little is known about the impact of T1DM on the bactericidal function of intestinal Paneth cells. MATERIAL AND METHODS A T1DM mouse model was induced by intraperitoneal injection of streptozocin. The analysis of intestinal microbiota and the mucosal bactericidal assay were conducted to evaluate intestinal innate defense. Numbers of Paneth cells and their expression of related antimicrobial peptides were analyzed. Expression of total insulin receptor (IR) mRNA and relative levels of IR-A/IR-B were analyzed. The primary mouse small intestinal crypt culture was used to analyze the effect of insulin and glucose on the expression of related antimicrobial peptides of Paneth cells. RESULTS In T1DM mice, bacterial loads were increased and there was an alteration in the composition of the intestinal microflora. Exogenous bacteria had better survival in the small bowel of the T1DM mice. The expression of Paneth cell-derived antimicrobial peptides was significantly decreased in the T1DM mice, although the number of Paneth cells was increased. Relative levels of IR-A/IR-B in Paneth cells of diabetic mice were elevated, but the total IR mRNA did not change. Insulin treatment restored the expression of antimicrobial peptides and normalized the microbiota in the gut of T1DM mice. Subsequently, in vitro culture assay demonstrated that insulin rather than glucose was essential for the optimal expression of Paneth cell-derived antimicrobial peptides. CONCLUSIONS The bactericidal function of intestinal Paneth cells was impaired in STZ-induced diabetic mice, resulting in the altered intestinal flora, and insulin was essential for the optimal expression of Paneth cell-derived antimicrobial peptides. PMID:27572949

  3. Association of Bactericidal Dysfunction of Paneth Cells in Streptozocin-Induced Diabetic Mice with Insulin Deficiency

    PubMed Central

    Yu, Tao; Yang, Hong-Sheng; Lu, Xi-Ji; Xia, Zhong-Sheng; Ouyang, Hui; Shan, Ti-Dong; Huang, Can-Ze; Chen, Qi-Kui

    2016-01-01

    Background Type 1 diabetes mellitus (T1DM) is associated with increased risks of enteric infection. Paneth cells constitute the first line of the gut defense. Little is known about the impact of T1DM on the bactericidal function of intestinal Paneth cells. Material/Methods A T1DM mouse model was induced by intraperitoneal injection of streptozocin. The analysis of intestinal microbiota and the mucosal bactericidal assay were conducted to evaluate intestinal innate defense. Numbers of Paneth cells and their expression of related antimicrobial peptides were analyzed. Expression of total insulin receptor (IR) mRNA and relative levels of IR-A/IR-B were analyzed. The primary mouse small intestinal crypt culture was used to analyze the effect of insulin and glucose on the expression of related antimicrobial peptides of Paneth cells. Results In T1DM mice, bacterial loads were increased and there was an alteration in the composition of the intestinal microflora. Exogenous bacteria had better survival in the small bowel of the T1DM mice. The expression of Paneth cell-derived antimicrobial peptides was significantly decreased in the T1DM mice, although the number of Paneth cells was increased. Relative levels of IR-A/IR-B in Paneth cells of diabetic mice were elevated, but the total IR mRNA did not change. Insulin treatment restored the expression of antimicrobial peptides and normalized the microbiota in the gut of T1DM mice. Subsequently, in vitro culture assay demonstrated that insulin rather than glucose was essential for the optimal expression of Paneth cell-derived antimicrobial peptides. Conclusions The bactericidal function of intestinal Paneth cells was impaired in STZ-induced diabetic mice, resulting in the altered intestinal flora, and insulin was essential for the optimal expression of Paneth cell-derived antimicrobial peptides. PMID:27572949

  4. Long-term low carbohydrate diet leads to deleterious metabolic manifestations in diabetic mice.

    PubMed

    Handa, Keiko; Inukai, Kouichi; Onuma, Hirohisa; Kudo, Akihiko; Nakagawa, Fumiyuki; Tsugawa, Kazue; Kitahara, Atsuko; Moriya, Rie; Takahashi, Kazuto; Sumitani, Yoshikazu; Hosaka, Toshio; Kawakami, Hayato; Oyadomari, Seiichi; Ishida, Hitoshi

    2014-01-01

    We investigated long-term effects of low carbohydrate diets on wild type mice, streptozotocin-injected and KKAy obese diabetic mice. These mice were pair-fed three different types of diets, standard chow (SC, C∶P∶F = 63∶15∶22), a low carbohydrate (LC, C∶P∶F = 38∶25∶37) diet and a severely carbohydrate restricted (SR, C∶P∶F = 18∶45∶37) diet for 16 weeks. Despite comparable body weights and serum lipid profiles, wild type and diabetic mice fed the low carbohydrate diets exhibited lower insulin sensitivity and this reduction was dependent on the amount of carbohydrate in the diet. When serum fatty acid compositions were investigated, monounsaturation capacity, i.e. C16:1/C16:0 and C18:1/C18:0, was impaired in all murine models fed the low carbohydrate diets, consistent with the decreased expression of hepatic stearoyl-CoA desaturase-1 (SCD1). Interestingly, both the hepatic expressions and serum levels of fibroblast growth factor 21 (FGF21), which might be related to longevity, were markedly decreased in both wild type and KKAy mice fed the SR diet. Taking into consideration that fat compositions did not differ between the LC and SR diets, we conclude that low carbohydrate diets have deleterious metabolic effects in both wild type and diabetic mice, which may explain the association between diets relatively low in carbohydrate and the elevated risk of cardiovascular events observed in clinical studies.

  5. Diabetes

    MedlinePlus

    ... version of this page please turn Javascript on. Diabetes What is Diabetes? Too Much Glucose in the Blood Diabetes means ... high, causing pre-diabetes or diabetes. Types of Diabetes There are three main kinds of diabetes: type ...

  6. Antidiabetic effects of ajoene in genetically diabetic KK-A(y) mice.

    PubMed

    Hattori, Atsuhiko; Yamada, Norihiko; Nishikawa, Tomoaki; Fukuda, Hiroyuki; Fujino, Tsuchiyoshi

    2005-10-01

    Antidiabetic effects of ajoene, derived from garlic, were investigated in genetically diabetic KK-A(y) mice. Four-week-old male KK-A(y) mice were kept on a laboratory diet containing 0.02 or 0.05% of ajoene for 8 wk. The elevation of water intake was suppressed depending on ajoene intake. The levels of plasma glucose in the 0.05% ajoene-containing diet group was significantly suppressed to 73.8% compared with the control group at the 8th wk. Similarly, the plasma triglyceride level was significantly suppressed. It is suggested that hyperglycemia and hypertriglyceridemia are suppressed by ajoene treatment.

  7. Differential anti-diabetic effects and mechanism of action of charantin-rich extract of Taiwanese Momordica charantia between type 1 and type 2 diabetic mice.

    PubMed

    Wang, Hsien-Yi; Kan, Wei-Chih; Cheng, Tain-Junn; Yu, Sung-Hsun; Chang, Liang-Hao; Chuu, Jiunn-Jye

    2014-07-01

    Momordica charantia Linn. (Cucurbitaceae), also called bitter melon, has traditionally been used as a natural anti-diabetic agent for anti-hyperglycemic activity in several animal models and clinical trials. We investigated the differences in the anti-diabetic properties and mechanism of action of Taiwanese M. charantia (MC) between type 1 diabetic (T1D) and type 2 diabetic (T2D) mice. To clarify the beneficial effects of MC, we measured non-fasting glucose, oral glucose tolerance, and plasma insulin levels in KK/HIJ mice with high-fat diet-induced diabetes (200 mg/kg/day of charantin-rich extract of MC [CEMC]) and in ICR mice with STZ-induced diabetes. After 8 weeks, all the mice were exsanguinated, and the expression of the insulin-signaling-associated proteins in their tissue was evaluated, in coordination with the protective effects of CEMC against pancreatic β-cell toxicity (in vitro). Eight weeks of data indicated that CEMC caused a significant decline in non-fasting blood glucose, plasma glucose intolerance, and insulin resistance in the KK/HIJ mice, but not in the ICR mice. Furthermore, CEMC decreased plasma insulin and promoted the sensitivity of insulin by increasing the expression of GLUT4 in the skeletal muscle and of IRS-1 in the liver of KK/HIJ mice; however, CEMC extract had no effect on the insulin sensitivity of ICR mice. In vitro study showed that CEMC prevented pancreatic β cells from high-glucose-induced cytotoxicity after 24 h of incubation, but the protective effect was not detectable after 72 h. Collectively, the hypoglycemic effects of CEMC suggest that it has potential for increasing insulin sensitivity in patients with T2D rather than for protecting patients with T1D against β-cell dysfunction.

  8. Heparanase and Autoimmune Diabetes

    PubMed Central

    Simeonovic, Charmaine J.; Ziolkowski, Andrew F.; Wu, Zuopeng; Choong, Fui Jiun; Freeman, Craig; Parish, Christopher R.

    2013-01-01

    Heparanase (Hpse) is the only known mammalian endo-β-d-glucuronidase that degrades the glycosaminoglycan heparan sulfate (HS), found attached to the core proteins of heparan sulfate proteoglycans (HSPGs). Hpse plays a homeostatic role in regulating the turnover of cell-associated HS and also degrades extracellular HS in basement membranes (BMs) and the extracellular matrix (ECM), where HSPGs function as a barrier to cell migration. Secreted Hpse is harnessed by leukocytes to facilitate their migration from the blood to sites of inflammation. In the non-obese diabetic (NOD) model of autoimmune Type 1 diabetes (T1D), Hpse is also used by insulitis leukocytes to solubilize the islet BM to enable intra-islet entry of leukocytes and to degrade intracellular HS, an essential component for the survival of insulin-producing islet beta cells. Treatment of pre-diabetic adult NOD mice with the Hpse inhibitor PI-88 significantly reduced the incidence of T1D by ~50% and preserved islet HS. Hpse therefore acts as a novel immune effector mechanism in T1D. Our studies have identified T1D as a Hpse-dependent disease and Hpse inhibitors as novel therapeutics for preventing T1D progression and possibly the development of T1D vascular complications. PMID:24421779

  9. Immunomodulatory and Antidiabetic Effects of a New Herbal Preparation (HemoHIM) on Streptozotocin-Induced Diabetic Mice

    PubMed Central

    Kim, Jong-Jin; Choi, Jina; Lee, Mi-Kyung; Kang, Kyung-Yun; Paik, Man-Jeong; Jo, Sung-Kee; Jung, Uhee; Park, Hae-Ran; Yee, Sung-Tae

    2014-01-01

    HemoHIM (a new herbal preparation of three edible herbs: Angelica gigas Nakai, Cnidium officinale Makino, and Paeonia japonica Miyabe) was developed to protect immune, hematopoietic, and self-renewal tissues against radiation. This study determined whether or not HemoHIM could alter hyperglycemia and the immune response in diabetic mice. Both nondiabetic and diabetic mice were orally administered HemoHIM (100 mg/kg) once a day for 4 weeks. Diabetes was induced by single injection of streptozotocin (STZ, 200 mg/kg, i.p.). In diabetic mice, HemoHIM effectively improved hyperglycemia and glucose tolerance compared to the diabetic control group as well as elevated plasma insulin levels with preservation of insulin staining in pancreatic β-cells. HemoHIM treatment restored thymus weight, white blood cells, lymphocyte numbers, and splenic lymphocyte populations (CD4+ T and CD8+ T), which were reduced in diabetic mice, as well as IFN-γ production in response to Con A stimulation. These results indicate that HemoHIM may have potential as a glucose-lowering and immunomodulatory agent by enhancing the immune function of pancreatic β-cells in STZ-induced diabetic mice. PMID:25045390

  10. Evaluation of the Hypoglycemic Effect of Composite Rice Flour in Diabetic Mice.

    PubMed

    Ding, Zhigang; Gao, Hongmei; Du, Chuanlai; Zheng, Yimei; Guo, Yuanxin; Pan, Dongmei

    2016-03-01

    To study the hypoglycemic effect of composite rice flour, the diabetic mouse model was established through the intraperitoneal injection of alloxan saline (twice, 200 mg/kg bw). The mice were randomly divided into 4 groups: negative control, positive control, metformin medication group, and composite rice flour feed group. After 21 days, the fasting blood glucose levels were determined by glucose oxidase method and followed with a glucose tolerance test. The results show that the body weight growth rate of mice in the rice flour group was significantly higher than that of the medication group (P < 0.01). Comparing with the positive control group, the fasting blood glucose levels of medication group and rice flour group were significantly lower, and the glucose tolerance was significantly increased in rice flour group (P < 0.01). In conclusion, the composite rice flour has obvious hypoglycemic and protective effect for diabetic mouse model. PMID:26972304

  11. Caprine pancreatic islet xenotransplantation into diabetic immunosuppressed BALB/c mice

    PubMed Central

    Hani, Homayoun; Allaudin, Zeenathul N; Mohd-Lila, Mohd-Azmi; Ibrahim, Tengku A Tengku; Othman, Abas M

    2014-01-01

    Background Type 1 diabetes mellitus is a devastating disease for which there is currently no cure, but only lifetime management. Islet xenotransplantation is a promising technique for the restoration of blood glucose control in patients with diabetes mellitus. The purpose of this study was to explore the potential use of caprine (goat) islet cells as xenogeneic grafts in the treatment for diabetes in a mouse model. Methods Caprine pancreases were harvested and transported to the laboratory under conditions optimized to prevent ischemia. Islets were isolated, purified, and tested for functionality. Caprine islets (2000 islet equivalent) were transplanted beneath the kidney capsules of diabetic BALB/c mice under thalidomide-induced immunosuppression. Blood glucose and insulin levels of grafted mice were evaluated by glucometer and enzyme-linked immunosorbent assay kit, respectively. The functionality and quality of caprine pancreatic islet grafts were assessed by intraperitoneal glucose tolerance tests. Results The viability of purified islet cells exceeded 90%. Recipient mice exhibited normoglycemia (<11 mm glucose) for 30 days. In addition, weight gain negatively correlated with blood glucose level. The findings verified diabetes reversal in caprine islet recipient mice. A significant drop in non-fasting blood glucose level (from 23.3 ± 5.4 to 8.04 ± 0.44 mm) and simultaneous increase in serum insulin level (from 0.01 ± 0.001 to 0.56 ± 0.17 μg/l) and body weights (from 23.64 ± 0.31 to 25.85 ± 0.34 g) were observed (P < 0.05). Immunohistochemical analysis verified insulin production in the transplanted islets. Conclusions Purified caprine islets were demonstrated to successfully sustain viability and functionality for controlling blood glucose levels in an immunosuppressed mouse model of diabetes. These results suggest the use of caprine islets as an addition to the supply of xenogeneic islets for diabetes research. PMID:24645790

  12. Rapamycin Increases Mortality in db/db Mice, a Mouse Model of Type 2 Diabetes.

    PubMed

    Sataranatarajan, Kavithalakshmi; Ikeno, Yuji; Bokov, Alex; Feliers, Denis; Yalamanchili, Himabindu; Lee, Hak Joo; Mariappan, Meenalakshmi M; Tabatabai-Mir, Hooman; Diaz, Vivian; Prasad, Sanjay; Javors, Martin A; Ghosh Choudhury, Goutam; Hubbard, Gene B; Barnes, Jeffrey L; Richardson, Arlan; Kasinath, Balakuntalam S

    2016-07-01

    We examined the effect of rapamycin on the life span of a mouse model of type 2 diabetes, db/db mice. At 4 months of age, male and female C57BLKSJ-lepr (db/db) mice (db/db) were placed on either a control diet, lacking rapamycin or a diet containing rapamycin and maintained on these diets over their life span. Rapamycin was found to reduce the life span of the db/db mice. The median survival of male db/db mice fed the control and rapamycin diets was 349 and 302 days, respectively, and the median survival of female db/db mice fed the control and rapamycin diets was 487 and 411 days, respectively. Adjusting for gender differences, rapamycin increased the mortality risk 1.7-fold in both male and female db/db mice. End-of-life pathological data showed that suppurative inflammation was the main cause of death in the db/db mice, which is enhanced slightly by rapamycin treatment.

  13. Anti-hyperglycemic effect of fangchinoline isolated from Stephania tetrandra Radix in streptozotocin-diabetic mice.

    PubMed

    Tsutsumi, Taiki; Kobayashi, Shinjiro; Liu, Yuan Ying; Kontani, Hitoshi

    2003-03-01

    Kampo medicine, Stephania tetrandra Radix (Stephania) in Boi-ogi-to increases the blood insulin level and falls the blood glucose level in streptozotocin (STZ)-diabetic ddY mice. These actions of Stephania are potentiated by Astragalus membranaceus Bunge Radix (Astragali) in Boi-ogi-to (Liu et al., J. Traditional Med., 17, 253-260, 2000). In the present study, actions of bis-benzylisoquinoline alkaloids isolated from Stephania were investigated in the hyperglycemia of STZ-diabetic mice. A main bis-benzylisoquinoline alkaloid, fangchinoline (0.3-3 mg/kg) significantly fell the blood glucose level of the diabetic mice in a dose-dependent manner. The effect of fangchinoline was 3.9-fold greater than that of water extract of Stephania. However, another main compound, tetrandrine (1-100 mg/kg) did not have any effect. The water extract of Astragali did not affect singly but potentiated the anti-hyperglycemic action of fangchinoline (0.3 mg/kg). Out of used compounds (1 mg/kg) isolated from Stephania, fangchinoline, fangchinoline 2'-N-alpha-oxide and 2'-N-norfangchinoline, which are substituted with 7-hydroxy side chain for 7-O-methyl side chain, decreased to near 50% of high blood glucose level. In addition, tetrandrine 2'-N-beta-oxide, tetrandrine 2'-N-alpha-oxide, tetrandrine 2-N-beta-oxide, fangchinoline 2'-N-alpha-oxide, which are added to 2- or 2'-N-oxide side chain, also decreased to near 50% of the high blood glucose level. In conclusion, fangchinoline but not tetrandrine from Stephania shows the anti-hyperglycemic action in the STZ-diabetic mice. The demethylation of 7-O-position and/or addition of 2- or 2'-N-oxide side chain in bis-benzylisoquinoline compounds in Stephania have a role for the induction of the anti-hyperglycemic actions. PMID:12612439

  14. Hypoglycemic Effect of Jicama (Pachyrhizus erosus) Extract on Streptozotocin-Induced Diabetic Mice.

    PubMed

    Park, Chan Joo; Han, Ji-Sook

    2015-06-01

    The purpose of this research was to investigate the inhibitory effect of jicama extract on α-glucosidase activity, α-amylase activity, and postprandial hyperglycemia in streptozotocin (STZ)-induced diabetic mice. Jicama extract showed prominent inhibitory effects against α-glucosidase and α-amylase. The IC50 values of jicama extract against α-glucosidase and α-amylase were 0.083±0.004 and 0.091±0.017 mg/mL, respectively. The increase in postprandial blood glucose levels was more significantly suppressed in the jicama extract-administered group than in the control group of both STZ-induced diabetic and normal mice. Blood glucose levels of the control group increased to 383.75±11.54 and 402.50±15.32 mg/dL at 30 and 60 min after a meal and decreased to 349.67±11.62 mg/dL at 120 min. However, postprandial blood glucose levels were significantly decreased, when diabetic mice were fed with jicama extract (342.00±15.73, 367.00±13.00, and 329.67±12.43 mg/dL at 30, 60, and 120 min, respectively). Furthermore, the area under the curve was significantly decreased with jicama extract administration in diabetic mice (P<0.05). Therefore, these results indicate that jicama extract may help decrease postprandial blood glucose level by inhibiting α-glucosidase. PMID:26175995

  15. Hypoglycemic Effect of Jicama (Pachyrhizus erosus) Extract on Streptozotocin-Induced Diabetic Mice

    PubMed Central

    Park, Chan Joo; Han, Ji-Sook

    2015-01-01

    The purpose of this research was to investigate the inhibitory effect of jicama extract on α-glucosidase activity, α-amylase activity, and postprandial hyperglycemia in streptozotocin (STZ)-induced diabetic mice. Jicama extract showed prominent inhibitory effects against α-glucosidase and α-amylase. The IC50 values of jicama extract against α-glucosidase and α-amylase were 0.083±0.004 and 0.091±0.017 mg/mL, respectively. The increase in postprandial blood glucose levels was more significantly suppressed in the jicama extract-administered group than in the control group of both STZ-induced diabetic and normal mice. Blood glucose levels of the control group increased to 383.75±11.54 and 402.50±15.32 mg/dL at 30 and 60 min after a meal and decreased to 349.67±11.62 mg/dL at 120 min. However, postprandial blood glucose levels were significantly decreased, when diabetic mice were fed with jicama extract (342.00±15.73, 367.00±13.00, and 329.67±12.43 mg/dL at 30, 60, and 120 min, respectively). Furthermore, the area under the curve was significantly decreased with jicama extract administration in diabetic mice (P<0.05). Therefore, these results indicate that jicama extract may help decrease postprandial blood glucose level by inhibiting α-glucosidase. PMID:26175995

  16. Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice.

    PubMed

    Foti, Daniela; Chiefari, Eusebio; Fedele, Monica; Iuliano, Rodolfo; Brunetti, Leonardo; Paonessa, Francesco; Manfioletti, Guidalberto; Barbetti, Fabrizio; Brunetti, Arturo; Croce, Carlo M; Fusco, Alfredo; Brunetti, Antonio

    2005-07-01

    Type 2 diabetes mellitus is a widespread disease, affecting millions of people globally. Although genetics and environmental factors seem to have a role, the cause of this metabolic disorder is largely unknown. Here we report a genetic flaw that markedly reduced the intracellular expression of the high mobility group A1 (HMGA1) protein, and adversely affected insulin receptor expression in cells and tissues from four subjects with insulin resistance and type 2 diabetes. Restoration of HMGA1 protein expression in subjects' cells enhanced INSR gene transcription, and restored cell-surface insulin receptor protein expression and insulin-binding capacity. Loss of Hmga1 expression, induced in mice by disrupting the Hmga1 gene, considerably decreased insulin receptor expression in the major targets of insulin action, largely impaired insulin signaling and severely reduced insulin secretion, causing a phenotype characteristic of human type 2 diabetes. PMID:15924147

  17. Hepatocyte TRAF3 promotes insulin resistance and type 2 diabetes in mice with obesity

    PubMed Central

    Chen, Zheng; Canet, Mark J.; Sheng, Liang; Jiang, Lin; Xiong, Yi; Yin, Lei; Rui, Liangyou

    2015-01-01

    Objective Metabolic inflammation is believed to promote insulin resistance and type 2 diabetes progression in obesity. TRAF3, a cytoplasmic signaling protein, has been known to mediate/modulate cytokine signaling in immune cells. The goal is to define the metabolic function of hepatic TRAF3 in the setting of obesity. Methods Hepatocyte-specific TRAF3 knockout mice were generated using the loxp/albumin-cre system. Liver TRAF3 was deleted in adult obese mice via Cre adenoviral infection. Both high fat diet-induced and genetic obesity were examined. TRAF3 levels and insulin signaling were measured by immunoblotting. Insulin sensitivity, hepatic glucose production, and glucose metabolism were examined by glucose, insulin, and pyruvate tolerance tests. Hepatic steatosis was examined by Oil red O staining of liver sections and measuring liver triacylglycerol levels. Results Liver TRAF3 levels were lower in the fasted states in normal mice, and were aberrantly higher in obese mice and in mice with streptozotocin-induced hyperglycemia. Glucose directly increased TRAF3 levels in primary hepatocytes. Hepatocyte-specific deletion of TRAF3 decreased hyperinsulinemia, insulin resistance, glucose intolerance, and hepatic steatosis in mice with either high fat diet-induced obesity or genetic obesity (ob/ob); conversely, in lean mice, adenovirus-mediated overexpression of TRAF3 in the liver induced hyperinsulinemia, insulin resistance, and glucose intolerance. Deletion of TRAF3 enhanced the ability of insulin to stimulate phosphorylation of Akt in hepatocytes, whereas overexpression of TRAF3 suppressed insulin signaling. Conclusions Glucose increases the levels of hepatic TRAF3. TRAF3 in turn promotes hyperglycemia through increasing hepatic glucose production, thus forming a glucose-TRAF3 reinforcement loop in the liver. This positive feedback loop may drive the progression of type 2 diabetes and nonalcoholic fatty liver disease in obesity. PMID:26909311

  18. Selenium-enriched exopolysaccharides improve skeletal muscle glucose uptake of diabetic KKAy mice via AMPK pathway.

    PubMed

    Zhou, Xihong; Chen, Jingqing; Wang, Fengqin; Yang, Hangxian; Yang, Ren; Wang, Xinxia; Wang, Yizhen

    2014-06-01

    Selenium-enriched exopolysaccharides (EPS) produced by Enterobacter cloacae Z0206 have been proven to possess effect on reducing blood glucose level in diabetic mice. To investigate the specific mechanism, we studied the effects of oral supply with EPS on skeletal muscle glucose transportation and consumption in high-fat-diet-induced diabetic KKAy mice. We found that EPS supplementation increased expressions of glucose transporter 4 (Glut4), hexokinase 2 (hk2), phosphorylation of AMP-activated kinase subunit α2 (pAMPKα2), and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), and increased expression of characteristic protein of oxidative fibers such as troponin I and cytochrome c (Cytc). Furthermore, we found that EPS increased glucose uptake and expressions of pAMPKα2 and PGC-1α in palmitic acid (PA)-induced C2C12 cells. However, while EPS inhibited AMPKα2 with interference RNA (iRNA), effects of EPS on the improvement of glucose uptake diminished. These results indicated that EPS may improve skeletal muscle glucose uptake of diabetic KKAy mice through AMPKα2-PGC-1α pathway. PMID:24729044

  19. Skeletal muscle PGC-1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice

    PubMed Central

    Svensson, Kristoffer; Albert, Verena; Cardel, Bettina; Salatino, Silvia; Handschin, Christoph

    2016-01-01

    Ketone bodies are crucial energy substrates during states of low carbohydrate availability. However, an aberrant regulation of ketone body homeostasis can lead to complications such as diabetic ketoacidosis. Exercise and diabetes affect systemic ketone body homeostasis, but the regulation of ketone body metabolism is still enigmatic. Using mice with either a knockout or overexpression of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in skeletal muscle, we show that PGC-1α regulates ketolytic gene transcription in muscle. Furthermore, ketone body homeostasis of these mice was investigated during fasting, exercise, ketogenic diet feeding and after streptozotocin injection. In response to these ketogenic stimuli, we show that modulation of PGC-1α levels in muscle affects systemic ketone body homeostasis. Moreover, our data demonstrate that skeletal muscle PGC-1α is necessary for the enhanced ketolytic capacity in response to exercise training and overexpression of PGC-1α in muscle enhances systemic ketolytic capacity and is sufficient to ameliorate diabetic hyperketonemia in mice. Using cultured myotubes, we also show that the transcription factor estrogen related receptor α (ERRα) is a partner of PGC-1α in the regulation of ketolytic gene transcription. Collectively, these results demonstrate a central role of skeletal muscle PGC-1α in the transcriptional regulation of systemic ketolytic capacity. PMID:26849960

  20. Effects of Bauhinia forficata Tea on Oxidative Stress and Liver Damage in Diabetic Mice.

    PubMed

    Salgueiro, Andréia Caroline Fernandes; Folmer, Vanderlei; da Silva, Marianne Pires; Mendez, Andreas Sebastian Loureiro; Zemolin, Ana Paula Pegoraro; Posser, Thaís; Franco, Jeferson Luis; Puntel, Robson Luiz; Puntel, Gustavo Orione

    2016-01-01

    This study was designed to evaluate the effects of Bauhinia forficata Link subsp. pruinosa (BF) tea on oxidative stress and liver damage in streptozotocin (STZ)-induced diabetic mice. Diabetic male mice have remained 30 days without any treatment. BF treatment started on day 31 and continued for 21 days as a drinking-water substitute. We evaluated (1) BF chemical composition; (2) glucose levels; (3) liver/body weight ratio and liver transaminases; (4) reactive oxygen species (ROS), lipid peroxidation, and protein carbonylation in liver; (5) superoxide dismutase (SOD) and catalase (CAT) activities in liver; (6) δ-aminolevulinate dehydratase (δ-ALA-D) and nonprotein thiols (NPSH) in liver; (7) Nrf2, NQO-1, and HSP70 levels in liver and pancreas. Phytochemical analyses identified four phenols compounds. Diabetic mice present high levels of NQO-1 in pancreas, increased levels of ROS and lipid peroxidation in liver, and decrease in CAT activity. BF treatment normalized all these parameters. BF did not normalize hyperglycemia, liver/body weight ratio, aspartate aminotransferase, protein carbonyl, NPSH levels, and δ-ALA-D activity. The raised oxidative stress seems to be a potential mechanism involved in liver damage in hyperglycemic conditions. Our results indicated that BF protective effect could be attributed to its antioxidant capacity, more than a hypoglycemic potential. PMID:26839634

  1. BIM Deficiency Protects NOD Mice From Diabetes by Diverting Thymocytes to Regulatory T Cells.

    PubMed

    Krishnamurthy, Balasubramanian; Chee, Jonathan; Jhala, Gaurang; Trivedi, Prerak; Catterall, Tara; Selck, Claudia; Gurzov, Esteban N; Brodnicki, Thomas C; Graham, Kate L; Wali, Jibran A; Zhan, Yifan; Gray, Daniel; Strasser, Andreas; Allison, Janette; Thomas, Helen E; Kay, Thomas W H

    2015-09-01

    Because regulatory T-cell (Treg) development can be induced by the same agonist self-antigens that induce negative selection, perturbation of apoptosis will affect both negative selection and Treg development. But how the processes of thymocyte deletion versus Treg differentiation bifurcate and their relative importance for tolerance have not been studied in spontaneous organ-specific autoimmune disease. We addressed these questions by removing a critical mediator of thymocyte deletion, BIM, in the NOD mouse model of autoimmune diabetes. Despite substantial defects in the deletion of autoreactive thymocytes, BIM-deficient NOD (NODBim(-/-)) mice developed less insulitis and were protected from diabetes. BIM deficiency did not impair effector T-cell function; however, NODBim(-/-) mice had increased numbers of Tregs, including those specific for proinsulin, in the thymus and peripheral lymphoid tissues. Increased levels of Nur77, CD5, GITR, and phosphorylated IκB-α in thymocytes from NODBim(-/-) mice suggest that autoreactive cells receiving strong T-cell receptor signals that would normally delete them escape apoptosis and are diverted into the Treg pathway. Paradoxically, in the NOD model, reduced thymic deletion ameliorates autoimmune diabetes by increasing Tregs. Thus, modulating apoptosis may be one of the ways to increase antigen-specific Tregs and prevent autoimmune disease.

  2. BIM Deficiency Protects NOD Mice From Diabetes by Diverting Thymocytes to Regulatory T Cells.

    PubMed

    Krishnamurthy, Balasubramanian; Chee, Jonathan; Jhala, Gaurang; Trivedi, Prerak; Catterall, Tara; Selck, Claudia; Gurzov, Esteban N; Brodnicki, Thomas C; Graham, Kate L; Wali, Jibran A; Zhan, Yifan; Gray, Daniel; Strasser, Andreas; Allison, Janette; Thomas, Helen E; Kay, Thomas W H

    2015-09-01

    Because regulatory T-cell (Treg) development can be induced by the same agonist self-antigens that induce negative selection, perturbation of apoptosis will affect both negative selection and Treg development. But how the processes of thymocyte deletion versus Treg differentiation bifurcate and their relative importance for tolerance have not been studied in spontaneous organ-specific autoimmune disease. We addressed these questions by removing a critical mediator of thymocyte deletion, BIM, in the NOD mouse model of autoimmune diabetes. Despite substantial defects in the deletion of autoreactive thymocytes, BIM-deficient NOD (NODBim(-/-)) mice developed less insulitis and were protected from diabetes. BIM deficiency did not impair effector T-cell function; however, NODBim(-/-) mice had increased numbers of Tregs, including those specific for proinsulin, in the thymus and peripheral lymphoid tissues. Increased levels of Nur77, CD5, GITR, and phosphorylated IκB-α in thymocytes from NODBim(-/-) mice suggest that autoreactive cells receiving strong T-cell receptor signals that would normally delete them escape apoptosis and are diverted into the Treg pathway. Paradoxically, in the NOD model, reduced thymic deletion ameliorates autoimmune diabetes by increasing Tregs. Thus, modulating apoptosis may be one of the ways to increase antigen-specific Tregs and prevent autoimmune disease. PMID:25948683

  3. Effects of Bauhinia forficata Tea on Oxidative Stress and Liver Damage in Diabetic Mice

    PubMed Central

    Salgueiro, Andréia Caroline Fernandes; da Silva, Marianne Pires; Mendez, Andreas Sebastian Loureiro; Zemolin, Ana Paula Pegoraro; Posser, Thaís; Puntel, Robson Luiz; Puntel, Gustavo Orione

    2016-01-01

    This study was designed to evaluate the effects of Bauhinia forficata Link subsp. pruinosa (BF) tea on oxidative stress and liver damage in streptozotocin (STZ)-induced diabetic mice. Diabetic male mice have remained 30 days without any treatment. BF treatment started on day 31 and continued for 21 days as a drinking-water substitute. We evaluated (1) BF chemical composition; (2) glucose levels; (3) liver/body weight ratio and liver transaminases; (4) reactive oxygen species (ROS), lipid peroxidation, and protein carbonylation in liver; (5) superoxide dismutase (SOD) and catalase (CAT) activities in liver; (6) δ-aminolevulinate dehydratase (δ-ALA-D) and nonprotein thiols (NPSH) in liver; (7) Nrf2, NQO-1, and HSP70 levels in liver and pancreas. Phytochemical analyses identified four phenols compounds. Diabetic mice present high levels of NQO-1 in pancreas, increased levels of ROS and lipid peroxidation in liver, and decrease in CAT activity. BF treatment normalized all these parameters. BF did not normalize hyperglycemia, liver/body weight ratio, aspartate aminotransferase, protein carbonyl, NPSH levels, and δ-ALA-D activity. The raised oxidative stress seems to be a potential mechanism involved in liver damage in hyperglycemic conditions. Our results indicated that BF protective effect could be attributed to its antioxidant capacity, more than a hypoglycemic potential. PMID:26839634

  4. Berberine enhances antidiabetic effects and attenuates untoward effects of canagliflozin in streptozotocin-induced diabetic mice.

    PubMed

    Tian, Cai-Ming; Jiang, Xin; Ouyang, Xiao-Xi; Zhang, Ya-Ou; Xie, Wei-Dong

    2016-07-01

    The present study aimed at determining whether berberine can enhance the antidiabetic effects and alleviate the adverse effects of canagliflozin in diabetes mellitus. Streptozotocin-induced diabetic mice were introduced, and the combined effects of berberine and canagliflozin on glucose metabolism and kidney functions were investigated. Our results showed that berberine combined with canagliflozin (BC) increased reduction of fasting and postprandial blood glucose, diet, and water intake compared with berberine or canagliflozin alone. Interestingly, BC showed greater decrease in blood urea nitrogen and creatinine levels and lower total urine glucose excretion than canagliflozin alone. In addition, BC showed increased phosphorylated 5' AMP-activated protein kinase (pAMPK) expression and decreased tumor necrosis factor alpha (TNFα) levels in kidneys, compared with berberine or canagliflozin alone. These results indicated that BC was a stronger antidiabetic than berberine or canagliflozin alone with less negative side effects on the kidneys in the diabetic mice. The antidiabetic effect was likely to be mediated by synergically promoting the expression of pAMPK and reducing the expression of TNFα in kidneys. The present study represented the first report that canagliflozin combined with berberine was a promising treatment for diabetes mellitus. The exact underlying mechanisms of action should be investigated in future studies. PMID:27507202

  5. Clostridium butyricum attenuates cerebral ischemia/reperfusion injury in diabetic mice via modulation of gut microbiota.

    PubMed

    Sun, Jing; Wang, Fangyan; Ling, Zongxin; Yu, Xichong; Chen, Wenqian; Li, Haixiao; Jin, Jiangtao; Pang, Mengqi; Zhang, Huiqing; Yu, Junjie; Liu, Jiaming

    2016-07-01

    Diabetes is known to exacerbate cerebral ischemia/reperfusion (I/R) injury. Here, we investigated the effects of Clostridium butyricum on cerebral I/R injury in the diabetic mice subjected to 30min of bilateral common carotid arteries occlusion (BCCAO). The cognitive impairment, the blood glucose level, neuronal injury, apoptosis, and expressions of Akt, phospho-Akt (p-Akt), and caspase-3 level were assessed. Meanwhile, the changes of gut microbiota in composition and diversity in the colonic feces were evaluated. Our results showed that diabetic mice subjected to BCCAO exhibited worsened cognitive impairment, cell damage and apoptosis. These were all attenuated by C. butyricum. Moreover, C. butyricum reversed cerebral I/R induced decreases in p-Akt expression and increases in caspase-3 expression, leading to inhibiting neuronal apoptosis. C. butyricum partly restored cerebral I/R induced decreases of fecal microbiota diversity, changes of fecal microbiota composition. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain probiotics might prove to be useful therapeutic adjuncts in cerebral I/R injury with diabetes. PMID:27037183

  6. Transplantation of insulin-secreting multicellular spheroids for the treatment of type 1 diabetes in mice.

    PubMed

    Kusamori, Kosuke; Nishikawa, Makiya; Mizuno, Narumi; Nishikawa, Tomoko; Masuzawa, Akira; Shimizu, Kazunori; Konishi, Satoshi; Takahashi, Yuki; Takakura, Yoshinobu

    2014-01-10

    The efficacy of cell-based therapy depends on the function and survival of transplanted cells, which have been suggested to be enhanced by spheroid formation. However, few attempts at spheroid generation from insulin-secreting cells, which may be used to treat type 1 diabetes, have been reported. We therefore developed spheroids from the mouse insulinoma cell line NIT-1 by using polydimethylsiloxane (PDMS)-based microwells with a coating of poly(N-isopropylacrylamide) (PNIPAAm). The prepared NIT-1 spheroids or dissociated NIT-1 cells were transplanted into the subrenal capsule in streptozotocin-induced diabetic mice. NIT-1 spheroids prepared using the PNIPAAm-coated PDMS-based microwells had a uniformly sized spherical structure with a diameter of 200-300μm. The PNIPAAm coating increased cell survival in the spheroids and the recovery of the spheroids from the microwells. In diabetic mice, the transplanted NIT-1 spheroids reduced blood glucose levels to normal values faster than dissociated NIT-1 cells did. Additionally, survival was higher among NIT-1 cells in spheroids than among dissociated NIT-1 cells 24h after transplantation. These results indicate that insulin-secreting NIT-1 spheroids prepared using PNIPAAm-coated PDMS-based microwells are more effective for the treatment of type 1 diabetes than dissociated cells in suspension. PMID:24184345

  7. FSP-1 Impairs the Function of Endothelium Leading to Failure of Arteriovenous Grafts in Diabetic Mice

    PubMed Central

    Luo, Jinlong; Liang, Ming; Mitch, William E.; Danesh, Farhad R.; Yu, Michael

    2015-01-01

    To understand how endothelial cell (EC) dysfunction contributes to the failure of arteriovenous graft (AVG), we investigated the role of fibroblast-specific protein 1 (FSP-1) in cultured ECs and a mouse AVG model. In vitro, we uncovered a new FSP-1-dependent pathway that activates rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) in ECs, leading to phosphorylation of myosin light chain 2 resulting in EC dysfunction. In cultured ECs, high glucose stimulated FSP-1 expression and increased permeability of an EC monolayer. The increase in permeability by the high glucose concentration was mediated by FSP-1 expression. Treatment of cultured ECs with FSP-1 caused leakage of the endothelial barrier plus increased expression of adhesion molecules and decreased expression of junction molecules. These responses were initiated by binding of FSP-1 to receptor for advanced glycation end products, which resulted in ROCK1 activation. In vivo, diabetes increased infiltration of inflammatory cells into AVGs and stimulated neointima formation. Increased FSP-1 expression and ROCK1 activation were found in AVGs of diabetic mice. Blocking FSP-1 suppressed diabetes-induced ROCK1 activation in AVGs. In mice with FSP-1 knockout or with ROCK1 knockout, accumulation of inflammatory cells and neointima formation in AVG were attenuated despite diabetes. Thus, mechanisms of inhibiting FSP-1 in ECs could improve AVG function. PMID:25774552

  8. Naringenin ameliorates pathological changes in liver and kidney of diabetic mice: a preliminary study.

    PubMed

    Sirovina, Damir; Oršolić, Nada; Gregorović, Gordana; Končić, Marijana Zovko

    2016-03-01

    The effect of naringenin, a flavonoid found in grapefruit, orange, and tomato, on lipid peroxidation and histopathological changes in the liver and kidneys of alloxan-induced diabetic mice were investigated. Two days after alloxan injection (75 mg kg-1, i.v.), naringenin ethanolic solution (0.5 % v/v) was given to mice intraperitoneally (50 mg kg-1 per day) for seven days. Naringenin's impact on lipid peroxidation was measured by the 2-thiobarbituric acid test and histopathological changes were examined under a light microscope. Naringenin administration resulted in a significant decrease of lipid peroxidation level in liver and kidney tissue, as well as in a decreased number of vacuolated liver cells and degree of vacuolisation. Indications of tissue repair in kidney suggested that amelioration of diabetes-induced renal damage could be achieved over a longer period of time. Findings suggest that naringenin could be considered a dietary supplement in the prevention or treatment of diabetic complications and other diseases connected with oxidative stress, and gives a hope that it could show similar effects in the treatment of diabetes in humans.

  9. The thromboxane receptor antagonist S18886 attenuates renal oxidant stress and proteinuria in diabetic apolipoprotein E-deficient mice.

    PubMed

    Xu, Shanqin; Jiang, Bingbing; Maitland, Karlene A; Bayat, Hossein; Gu, Jiali; Nadler, Jerry L; Corda, Stefano; Lavielle, Gilbert; Verbeuren, Tony J; Zuccollo, Adriana; Cohen, Richard A

    2006-01-01

    Arachidonic acid metabolites, some of which may activate thromboxane A(2) receptors (TPr) and contribute to the development of diabetes complications, including nephropathy, are elevated in diabetes. This study determined the effect of blocking TPr with S18886 or inhibiting cyclooxygenase with aspirin on oxidative stress and the early stages of nephropathy in streptozotocin-induced diabetic apolipoprotein E(-/-) mice. Diabetic mice were treated with S18886 (5 mg . kg(-1) . day(-1)) or aspirin (30 mg . kg(-1) . day(-1)) for 6 weeks. Neither S18886 nor aspirin affected hyperglycemia or hypercholesterolemia. There was intense immunohistochemical staining for nitrotyrosine in diabetic mouse kidney. In addition, a decrease in manganese superoxide dismutase (MnSOD) activity was associated with an increase in MnSOD tyrosine-34 nitration. Tyrosine nitration was significantly reduced by S18886 but not by aspirin. Staining for the NADPH oxidase subunit p47(phox), inducible nitric oxide synthase, and 12-lipoxygenase was increased in diabetic mouse kidney, as were urine levels of 12-hydroxyeicosatetraenoic acid and 8-iso-prostaglandin F(2alpha). S18886 attenuated all of these markers of oxidant stress and inflammation. Furthermore, S18886 significantly attenuated microalbuminuria in diabetic mice and ameliorated histological evidence of diabetic nephropathy, including transforming growth factor-beta and extracellular matrix expression. Thus, in contrast to inhibiting cyclooxygenase, blockade of TPr may have therapeutic potential in diabetic nephropathy, in part by attenuating oxidative stress. PMID:16380483

  10. Early Treatment of NOD Mice With B7-H4 Reduces the Incidence of Autoimmune Diabetes

    PubMed Central

    Wang, Xiaojie; Hao, Jianqiang; Metzger, Daniel L.; Mui, Alice; Ao, Ziliang; Akhoundsadegh, Noushin; Langermann, Solomon; Liu, Linda; Chen, Lieping; Ou, Dawei; Verchere, C. Bruce

    2011-01-01

    OBJECTIVE Autoimmune diabetes is a T cell–mediated disease in which insulin-producing β-cells are destroyed. Autoreactive T cells play a central role in mediating β-cell destruction. B7-H4 is a negative cosignaling molecule that downregulates T-cell responses. In this study, we aim to determine the role of B7-H4 on regulation of β-cell–specific autoimmune responses. RESEARCH DESIGN AND METHODS Prediabetic (aged 3 weeks) female NOD mice (group 1, n = 21) were treated with intraperitoneal injections of B7-H4.Ig at 7.5 mg/kg, with the same amount of mouse IgG (group 2, n = 24), or with no protein injections (group 3, n = 24), every 3 days for 12 weeks. RESULTS B7-H4.Ig reduced the incidence of autoimmune diabetes, compared with the control groups (diabetic mice 28.6% of group 1, 66.7% of group 2 [P = 0.0081], and 70.8% of group 3 [group 1 vs. 3, P = 0.0035]). Histological analysis revealed that B7-H4 treatment did not block islet infiltration but rather suppressed further infiltrates after 9 weeks of treatment (group 1 vs. 2, P = 0.0003). B7-H4 treatment also reduced T-cell proliferation in response to GAD65 stimulation ex vivo. The reduction of diabetes is not due to inhibition of activated T cells in the periphery but rather to a transient increase of Foxp3+ CD4+ T-cell population at one week posttreatment (12.88 ± 1.29 vs. 11.58 ± 1.46%; n = 8; P = 0.03). CONCLUSIONS Our data demonstrate the protective role of B7-H4 in the development of autoimmune diabetes, suggesting a potential means of preventing type 1 diabetes by targeting the B7-H4 pathway. PMID:21984581

  11. Role of metformin in suppressing 1,2-dimethylhydrazine-induced colon cancer in diabetic and non-diabetic mice: effect on tumor angiogenesis and cell proliferation.

    PubMed

    Zaafar, Dalia K; Zaitone, Sawsan A; Moustafa, Yasser M

    2014-01-01

    Several studies indicated that type 2 diabetes mellitus and insulin resistance are associated with increased colon cancer risk. Recently, studies suggest that metformin can reduce cancer risk in diabetic or non-diabetic patients with unclear mechanisms. This work aimed to determine the effect of metformin on chemically-induced colon cancer in mice. Colon cancer was induced using 1,2-dimethylhydrazine (DMH, 20 mg/kg/week, s.c.) for fifteen weeks. Experiment I: healthy mice were fed with basal diet for four weeks and then allocated into seven groups, (i) saline, (ii) DMH, (iii) oxaliplatin, (iv-v): metformin (100 or 200 mg/kg) and (vi-vii): oxaliplatin+metformin (100 or 200 mg/kg), respectively. Experiment II: type 2 diabetes mellitus was induced by injection of STZ (30 mg/kg) after four weeks of high-fat feeding and then mice were allocated into seven groups similar to those reported in experiment I. Examination of the colonic tissue at the end of the experiment highlighted an increase in angiogenic markers and cell proliferation and showed a greater immunostaining for insulin growth factor I receptors and CD34 in the colon of diabetic mice compared to non-diabetics. In general, metformin downregulated tumor angiogenesis and augmented the antitumor effect of oxaliplatin. Overall, the current results showed that metformin protected against DMH-induced colon cancer in non-diabetic and diabetic mice. This therapeutic effect was, at least in part, attributed to its anti-angiogenic and anti-proliferative mechanisms.

  12. Improved insulin sensitivity and islet function after PPARdelta activation in diabetic db/db mice.

    PubMed

    Winzell, Maria Sörhede; Wulff, Erik Max; Olsen, Grith Skytte; Sauerberg, Per; Gotfredsen, Carsten F; Ahrén, Bo

    2010-01-25

    The peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. Several reports have shown that PPARdelta is involved in lipid metabolism, increasing fat oxidation and depleting lipid accumulation. Whether PPARdelta is involved in the regulation of glucose metabolism is not completely understood. In this study, we examined effects of long-term PPARdelta activation on glycemic control, islet function and insulin sensitivity in diabetic db/db mice. Male db/db mice were administered orally once daily with a selective and partial PPARdelta agonist (NNC 61-5920, 30 mg/kg) for eight weeks; control mice received vehicle. Fasting and non-fasting plasma glucose were reduced, reflected in reduced hemoglobinA(1c) (3.6+/-1.6% vs. 5.4+/-1.8 in db/db controls, P<0.05) and furthermore, the AUC(glucose) after oral glucose (3g/kg) was reduced by 67% (P<0.05) after long-term PPARdelta activation. Following intravenous glucose (1g/kg), glucose tolerance was improved after PPARdelta activation (K(G) 1.3+/-0.6 vs. -0.05+/-0.7 %/min, P=0.048). Insulin sensitivity, measured as the glucose clearance after intravenous injection of glucose (1g/kg) and insulin (0.75 or 1.0 U/kg), during inhibition of endogenous insulin secretion by diazoxide (25mg/kg), was improved (K(G) 2.9+/-0.6 vs. 1.3+/-0.3 %/min in controls, P<0.05) despite lower insulin levels. Furthermore, islets isolated from PPARdelta agonist treated mice demonstrated improved glucose responsiveness as well as improved cellular topography. In conclusion, PPARdelta agonism alleviates insulin resistance and improves islet function and topography, resulting in improved glycemia in diabetic db/db mice. This suggests that activation of PPARdelta improves glucose metabolism and may therefore potentially be target for treatment of type 2 diabetes.

  13. Physical Activity and Sedentary Behavior in Metabolically Healthy versus Unhealthy Obese and Non-Obese Individuals – The Maastricht Study

    PubMed Central

    van der Berg, Julianne D.; van der Kallen, Carla J. H.; Schram, Miranda T.; Savelberg, Hans H. C. M.; Schaper, Nicolaas C.; Dagnelie, Pieter C.; Henry, Ronald M. A.; Kroon, Abraham A.; Stehouwer, Coen D. A.; Koster, Annemarie

    2016-01-01

    Background Both obesity and the metabolic syndrome are associated with increased risk of cardiovascular diseases and type 2 diabetes. Although both frequently occur together in the same individual, obesity and the metabolic syndrome can also develop independently from each other. The (patho)physiology of “metabolically healthy obese” (i.e. obese without metabolic syndrome) and “metabolically unhealthy non-obese” phenotypes (i.e. non-obese with metabolic syndrome) is not fully understood, but physical activity and sedentary behavior may play a role. Objective To examine objectively measured physical activity and sedentary behavior across four groups: I) “metabolically healthy obese” (MHO); II) “metabolically unhealthy obese” (MUO); III)”metabolically healthy non-obese” (MHNO); and IV) “metabolically unhealthy non-obese” (MUNO). Methods Data were available from 2,449 men and women aged 40–75 years who participated in The Maastricht Study from 2010 to 2013. Participants were classified into the four groups according to obesity (BMI≥30kg/m2) and metabolic syndrome (ATPIII definition). Daily activity was measured for 7 days with the activPAL physical activity monitor and classified as time spent sitting, standing, and stepping. Results In our study population, 562 individuals were obese. 19.4% of the obese individuals and 72.7% of the non-obese individuals was metabolically healthy. After adjustments for age, sex, educational level, smoking, alcohol use, waking time, T2DM, history of CVD and mobility limitation, MHO (n = 107) spent, per day, more time stepping (118.2 versus 105.2 min; p<0.01) and less time sedentary (563.5 versus 593.0 min., p = 0.02) than MUO (n = 440). In parallel, MHNO (n = 1384) spent more time stepping (125.0 versus 115.4 min; p<0.01) and less time sedentary (553.3 versus 576.6 min., p<0.01) than MUNO (n = 518). Conclusion Overall, the metabolically healthy groups were less sedentary and more physically active than the

  14. Study of the pathogenesis and treatment of diabetes mellitus through animal models.

    PubMed

    Brito-Casillas, Yeray; Melián, Carlos; Wägner, Ana María

    2016-01-01

    Most research in diabetes mellitus (DM) has been conducted in animals, and their replacement is currently a chimera. As compared to when they started to be used by modern science in the 17th century, a very high number of animal models of diabetes is now available, and they provide new insights into almost every aspect of diabetes. Approaches combining human, in vitro, and animal studies are probably the best strategy to improve our understanding of the underlying mechanisms of diabetes, and the choice of the best model to achieve such objective is crucial. Traditionally classified based on pathogenesis as spontaneous or induced models, each has its own advantages and disadvantages. The most common animal models of diabetes are described, and in addition to non-obese diabetic mice, biobreeding diabetes-prone (BB-DP) rats, streptozotocin-induced models, or high-fat diet-induced diabetic C57Bl/6J mice, new valuable models, such as dogs and cats with spontaneous diabetes, are described.

  15. Study of the pathogenesis and treatment of diabetes mellitus through animal models.

    PubMed

    Brito-Casillas, Yeray; Melián, Carlos; Wägner, Ana María

    2016-01-01

    Most research in diabetes mellitus (DM) has been conducted in animals, and their replacement is currently a chimera. As compared to when they started to be used by modern science in the 17th century, a very high number of animal models of diabetes is now available, and they provide new insights into almost every aspect of diabetes. Approaches combining human, in vitro, and animal studies are probably the best strategy to improve our understanding of the underlying mechanisms of diabetes, and the choice of the best model to achieve such objective is crucial. Traditionally classified based on pathogenesis as spontaneous or induced models, each has its own advantages and disadvantages. The most common animal models of diabetes are described, and in addition to non-obese diabetic mice, biobreeding diabetes-prone (BB-DP) rats, streptozotocin-induced models, or high-fat diet-induced diabetic C57Bl/6J mice, new valuable models, such as dogs and cats with spontaneous diabetes, are described. PMID:27246633

  16. Oxidative stress contributes to the impaired sonic hedgehog pathway in type 1 diabetic mice with myocardial infarction

    PubMed Central

    XIAO, QING; YANG, YA; ZHAO, XIAO-YA; HE, LI-SHAN; QIN, YUAN; HE, YAN-HUA; ZHANG, GUI-PING; LUO, JIAN-DONG

    2015-01-01

    Our previous study demonstrated that an impaired sonic hedgehog (Shh) pathway contributed to cardiac dysfunction in type 1 diabetic mice with myocardial infarction (MI). The present study aimed to test the hypothesis that oxidative stress may contribute to the impaired Shh pathway and cardiac dysfunction in type 1 diabetic mice with MI. Streptozotocin-induced type 1 diabetic mice (C57/Bl6, male) and rat neonatal cardiomyocytes were used in the present study. Mice were randomly assigned to undergo ligation of the coronary artery or pseudosurgery. A potent antioxidant Tempol was administered in vivo and in vitro. Cardiac function was assessed by echocardiography, capillary density by immunohistochemisty, percentage of myocardial infarct using Massons trichrome staining, reactive oxygen species detection using dihydroethidium dye or 2,7-dichlorofluorescein diacetate probe and protein expression levels of the Shh pathway by western blot analysis. The antioxidant Tempol was shown to significantly increase myocardial protein expression levels of Shh and patched-1 (Ptc1) at 7–18 weeks and improved cardiac function at 18 weeks in type 1 diabetic mice, as compared with mice receiving no drug treatment. Furthermore, myocardial protein expression levels of Shh and Ptc1 were significantly upregulated on day 7 after MI, and capillary density was enhanced. In addition, the percentage area of myocardial infarct was reduced, and the cardiac dysfunction and survival rate were improved on day 21 in diabetic mice treated with Tempol. In vitro, treatment of rat neonatal cardiomyocytes with a mixture of xanthine oxidase and xanthine decreased protein expression levels of Shh and Ptc1 in a concentration-dependent manner, and Tempol attenuated this effect. These results indicate that oxidative stress may contribute to an impaired Shh pathway in type 1 diabetic mice, leading to diminished myocardial healing and cardiac dysfunction. Antioxidative strategies aimed at restoring the

  17. Irisin Increased the Number and Improved the Function of Endothelial Progenitor Cells in Diabetes Mellitus Mice

    PubMed Central

    Wang, Jinxiang; Song, Mingbao; Zhou, Fang; Fu, Dagan; Ruan, Guangping; Zhu, Xiangqing; Bai, Yinyin; Huang, Lan; Pang, Rongqing; Kang, Huali

    2016-01-01

    Abstract: The dysfunction of endothelial progenitor cells (EPCs) was found to be associated with vascular complications in diabetes mellitus (DM) patients. Previous studies found that regular exercise could improve the function of EPCs in DM patients, but the underling mechanism was unclear. Irisin, a newly identified myokine, was induced by exercise and has been demonstrated to mediate some of the positive effects of exercise. In this study, we hypothesize that irisin may have direct effects on EPC function in DM mice. These data showed for the first time that irisin increased the number of EPCs in peripheral blood of DM mice and improved the function of EPCs derived from DM mice bone marrow. The mechanism for the effect of irisin is related to the PI3K/Akt/eNOS pathway. Furthermore, irisin was demonstrated to improve endothelial repair in DM mice that received EPC transplants after carotid artery injury. The results of this study indicate a novel effect of irisin in regulating the number and function of EPCs via the PI3K/Akt/eNOS pathway, suggesting a potential for the administration of exogenous irisin as a succedaneum to improve EPC function in diabetic patients who fail to achieve such improvements through regular exercise. PMID:27002278

  18. Epigallocatechin-3-gallate Attenuates Renal Damage by Suppressing Oxidative Stress in Diabetic db/db Mice

    PubMed Central

    Yang, Xiu Hong; Pan, Yu; Zhan, Xiao Li; Zhang, Bao Long

    2016-01-01

    Epigallocatechin-3-gallate (EGCG), extracted from green tea, has been shown to have antioxidative activity. In the present study, we evaluated the effect of EGCG on the kidney function in db/db mice and also tried to investigate the underlying mechanism of the renoprotective effects of EGCG in both animals and cells. EGCG treatment could decrease the level of urinary protein, 8-iso-PGF2a, and Ang II. Moreover, EGCG could also change the level of several parameters associated with oxidative stress. In addition, the protein expression levels of AT-1R, p22-phox, p47-phox, p-ERK1/2, p-p38 MAPK, TGF-β1, and α-SMA in diabetic db/db mice were upregulated, and all of these symptoms were downregulated with the treatment of EGCG at 50 and 100 mg/kg/d. Furthermore, the pathological changes were ameliorated in db/db mice after EGCG treatment. HK-2 cell-based experiments indicated that EGCG could inhibit the expression of MAPK pathways, which is the downstream effector of Ang II mediated oxidative stress. All these results indicated that EGCG treatment could ameliorate changes of renal pathology and delay the progression of DKD by suppressing hyperglycemia-induced oxidative stress in diabetic db/db mice. PMID:27698952

  19. Epigallocatechin-3-gallate Attenuates Renal Damage by Suppressing Oxidative Stress in Diabetic db/db Mice

    PubMed Central

    Yang, Xiu Hong; Pan, Yu; Zhan, Xiao Li; Zhang, Bao Long

    2016-01-01

    Epigallocatechin-3-gallate (EGCG), extracted from green tea, has been shown to have antioxidative activity. In the present study, we evaluated the effect of EGCG on the kidney function in db/db mice and also tried to investigate the underlying mechanism of the renoprotective effects of EGCG in both animals and cells. EGCG treatment could decrease the level of urinary protein, 8-iso-PGF2a, and Ang II. Moreover, EGCG could also change the level of several parameters associated with oxidative stress. In addition, the protein expression levels of AT-1R, p22-phox, p47-phox, p-ERK1/2, p-p38 MAPK, TGF-β1, and α-SMA in diabetic db/db mice were upregulated, and all of these symptoms were downregulated with the treatment of EGCG at 50 and 100 mg/kg/d. Furthermore, the pathological changes were ameliorated in db/db mice after EGCG treatment. HK-2 cell-based experiments indicated that EGCG could inhibit the expression of MAPK pathways, which is the downstream effector of Ang II mediated oxidative stress. All these results indicated that EGCG treatment could ameliorate changes of renal pathology and delay the progression of DKD by suppressing hyperglycemia-induced oxidative stress in diabetic db/db mice.

  20. TCR transgenic mice reveal the impact of type 1 diabetes loci on early and late disease checkpoints.

    PubMed

    Hillhouse, Erin E; Liston, Adrian; Collin, Roxanne; Desautels, Eric; Goodnow, Christopher C; Lesage, Sylvie

    2016-08-01

    Linkage analysis studies for autoimmune diabetes have revealed multiple non-major histocompatibility complex (MHC) chromosomal regions linked to disease susceptibility. To date, more than 20 insulin-dependent diabetes (Idd) loci linked to diabetes susceptibility have been identified in NOD mice and validated via congenic breeding. Importantly, evidence suggests that Idd loci may regulate at least two pathological steps during autoimmune diabetes development, namely the onset of insulitis and the transition from insulitis to overt diabetes. Here we assess the role of various non-MHC Idd diabetes-resistance loci, which have been validated in the non-transgenic setting, on autoimmune diabetes progression in the transgenic setting. Specifically, we generated multiple Idd congenic strains in the 3A9-TCR:insHEL NOD.H2(k) transgenic model and monitored their diabetes incidence. We show that 3A9-TCR:insHEL NOD.H2(k) mice congenic for Idd3 or Idd5 display a reduction in diabetes development, whereas mice congenic for Idd9 or Idd13 exhibit an increase, in comparison with 3A9-TCR:insHEL NOD.H2(k) mice. These results suggest that the presence of the 3A9-TCR and hen egg lysosyme transgenes can offset the regulatory function of certain diabetes-resistance genetic variants contained within the Idd loci, including Idd9 and Idd13. We propose the antigen-specific 3A9-TCR:insHEL transgenic model as a useful tool for the study of the genetics of autoimmune diabetes development. PMID:27046082

  1. [Effect and mechanism of polydatin on diabetic myocardial hypertrophy in mice].

    PubMed

    Huang, Bo; Xue, Lai; Wu, Yang; Jiang, Qing-song

    2015-11-01

    To observe the preventive effect of polydatin on diabetic myocardial hypertrophy in mice and discuss its and mechanism. The diabetic model was induced with low dose STZ (40 mg x kg(-1) x d(-1) x 5 d, ip) for five days in mice. The myocardial hypertrophy was determined by hypertrophy indexes (LVHI, left ventricular/right ventricle and septum), left ventricular/body weight (LV/BW), the histological examination and the mRNA expression of atrial natriuretic factor(ANF). The fast blood glucose(FBG), serum insulin and plasma hemoglobin A1c ( HbA1c) levels were detected, and then HOMA insulin resistance index ( HOMA. IR) was calculated. The mRNA and protein expressions were measured by qRT-PCR and western blotting, respectively. According to the results, the FBG of the model group exceeded 11.1 mmol x L(-1), with notable decrease in BW and significant increase in insulin, HbA1c and HOME. IR, suggesting the successful establishment and stability of the diabetic model. The increases in LVHI, LV/BW, cell surface and ANF mRNA indicated a myocardial hypertrophy in diabetic mice. Meanwhile, the model group showed decrease in mRNA and protein expressions of PPARβ and significant increase in NF-κB p65, COX-2 and iNOS expressions. After the preventation with PD (50, 100 mg x kg(-1) x d(-1)), diabetic mice showed increase in BW, reduction in the levels of FBG, insulin and HbA1 c, relief in insulin resistance and significant recovery in hypertrophy indexes, indicating PD has the protective effect in diabetic myocardial hypertrophy. Meanwhile, PD up-regulated the expression of PPARβ, inhibited the expressions of NF-κB p65, COX-2 and iNOS, demonstrating that PD's protective effect may be related to the activation of PPARβ and the inhibition of NF-κB, COX-2 and iNOS signaling pathways. PMID:27071267

  2. Knockout of the TauT Gene Predisposes C57BL/6 Mice to Streptozotocin-Induced Diabetic Nephropathy

    PubMed Central

    Han, Xiaobin; Patters, Andrea B.; Ito, Takashi; Schaffer, Stephen W.; Chesney, Russell W.

    2015-01-01

    Diabetic nephropathy is the leading cause of end stage renal disease in the world. Although tremendous efforts have been made, scientists have yet to identify an ideal animal model that can reproduce the characteristics of human diabetic nephropathy. In this study, we hypothesize that taurine insufficiency is a critical risk factor for development of diabetic nephropathy associated with diabetes mellitus. This hypothesis was tested in vivo in TauT heterozygous (TauT+/-) and homozygous (TauT-/-) knockout in C57BL/6 background mice. We have shown that alteration of the TauT gene (also known as SLC6A6) has a substantial effect on the susceptibility to development of extensive diabetic kidney disease in both TauT+/- and TauT-/-mouse models of diabetes. These animals developed histological changes characteristic of human diabetic nephropathy that included glomerulosclerosis, nodular lesions, arteriosclerosis, arteriolar dilation, and tubulointerstitial fibrosis. Immunohistochemical staining of molecular markers of smooth muscle actin, CD34, Ki67 and collagen IV further confirmed these observations. Our results demonstrated that both homozygous and heterozygous TauT gene deletion predispose C57BL/6 mice to develop end-stage diabetic kidney disease, which closely replicates the pathological features of diabetic nephropathy in human diabetic patients. PMID:25629817

  3. Human fibrocyte-derived exosomes accelerate wound healing in genetically diabetic mice.

    PubMed

    Geiger, Adolf; Walker, Audrey; Nissen, Erwin

    2015-11-13

    Diabetic ulcers represent a substantial societal and healthcare burden worldwide and scarcely respond to current treatment strategies. This study was addressed to evaluate the therapeutic potential of exosomes secreted by human circulating fibrocytes, a population of mesenchymal progenitors involved in normal wound healing via paracrine signaling. The exosomes released from cells sequentially stimulated with platelet-derived growth factor-BB and transforming growth factor-β1, in the presence of fibroblast growth factor 2, did not show potential immunogenicity. These exosomes exhibited in-vitro proangiogenic properties, activated diabetic dermal fibroblasts, induced the migration and proliferation of diabetic keratinocytes, and accelerated wound closure in diabetic mice in vivo. Important components of the exosomal cargo were heat shock protein-90α, total and activated signal transducer and activator of transcription 3, proangiogenic (miR-126, miR-130a, miR-132) and anti-inflammatory (miR124a, miR-125b) microRNAs, and a microRNA regulating collagen deposition (miR-21). This proof-of-concept study demonstrates the feasibility of the use of fibrocytes-derived exosomes for the treatment of diabetic ulcers.

  4. Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice.

    PubMed

    Yokota, Takashi; Kinugawa, Shintaro; Hirabayashi, Kagami; Matsushima, Shouji; Inoue, Naoki; Ohta, Yukihiro; Hamaguchi, Sanae; Sobirin, Mochamad A; Ono, Taisuke; Suga, Tadashi; Kuroda, Satoshi; Tanaka, Shinya; Terasaki, Fumio; Okita, Koichi; Tsutsui, Hiroyuki

    2009-09-01

    Insulin resistance or diabetes is associated with limited exercise capacity, which can be caused by the abnormal energy metabolism in skeletal muscle. Oxidative stress is involved in mitochondrial dysfunction in diabetes. We hypothesized that increased oxidative stress could cause mitochondrial dysfunction in skeletal muscle and make contribution to exercise intolerance in diabetes. C57/BL6J mice were fed on normal diet or high fat diet (HFD) for 8 wk to induce obesity with insulin resistance and diabetes. Treadmill tests with expired gas analysis were performed to determine the exercise capacity and whole body oxygen uptake (Vo(2)). The work (vertical distance x body weight) to exhaustion was reduced in the HFD mice by 36%, accompanied by a 16% decrease of peak Vo(2). Mitochondrial ADP-stimulated respiration, electron transport chain complex I and III activities, and mitochondrial content in skeletal muscle were decreased in the HFD mice. Furthermore, superoxide production and NAD(P)H oxidase activity in skeletal muscle were significantly increased in the HFD mice. Intriguingly, the treatment of HFD-fed mice with apocynin [10 mmol/l; an inhibitor of NAD(P)H oxidase activation] improved exercise intolerance and mitochondrial dysfunction in skeletal muscle without affecting glucose metabolism itself. The exercise capacity and mitochondrial function in skeletal muscle were impaired in type 2 diabetes, which might be due to enhanced oxidative stress. Therapies designed to regulate oxidative stress and maintain mitochondrial function could be beneficial to improve the exercise capacity in type 2 diabetes.

  5. Experimental induction of type 2 diabetes in aging-accelerated mice triggered Alzheimer-like pathology and memory deficits.

    PubMed

    Mehla, Jogender; Chauhan, Balwantsinh C; Chauhan, Neelima B

    2014-01-01

    Alzheimer's disease (AD) is an age-dependent neurodegenerative disease constituting ~95% of late-onset non-familial/sporadic AD, and only ~5% accounting for early-onset familial AD. Availability of a pertinent model representing sporadic AD is essential for testing candidate therapies. Emerging evidence indicates a causal link between diabetes and AD. People with diabetes are >1.5-fold more likely to develop AD. Senescence-accelerated mouse model (SAMP8) of accelerated aging displays many features occurring early in AD. Given the role played by diabetes in the pre-disposition of AD, and the utility of SAMP8 non-transgenic mouse model of accelerated aging, we examined if high fat diet-induced experimental type 2 diabetes in SAMP8 mice will trigger pathological aging of the brain. Results showed that compared to non-diabetic SAMP8 mice, diabetic SAMP8 mice exhibited increased cerebral amyloid-β, dysregulated tau-phosphorylating glycogen synthase kinase 3β, reduced synaptophysin immunoreactivity, and displayed memory deficits, indicating Alzheimer-like changes. High fat diet-induced type 2 diabetic SAMP8 mice may represent the metabolic model of AD.

  6. Experimental Induction of Type 2 Diabetes in Aging-Accelerated Mice Triggered Alzheimer-Like Pathology and Memory Deficits

    PubMed Central

    Mehla, Jogender; Chauhan, Balwantsinh C.; Chauhan, Neelima B.

    2014-01-01

    Alzheimer’s disease (AD) is an age-dependent neurodegenerative disease constituting ~95% of late-onset non-familial/sporadic AD, and only ~5% accounting for early-onset familial AD. Availability of a pertinent model representing sporadic AD is essential for testing candidate therapies. Emerging evidence indicates a causal link between diabetes and AD. People with diabetes are >1.5-fold more likely to develop AD. Senescence-accelerated mouse model (SAMP8) of accelerated aging displays many features occurring early in AD. Given the role played by diabetes in the pre-disposition of AD, and the utility of SAMP8 non-transgenic mouse model of accelerated aging, we examined if high fat diet-induced experimental type 2 diabetes in SAMP8 mice will trigger pathological aging of the brain. Results showed that compared to non-diabetic SAMP8 mice, diabetic SAMP8 mice exhibited increased cerebral amyloid-β, dysregulated tau-phosphorylating glycogen synthase kinase 3β, reduced synaptophysin immunoreactivity, and displayed memory deficits, indicating Alzheimer-like changes. High fat diet-induced type 2 diabetic SAMP8 mice may represent the metabolic model of AD. PMID:24121970

  7. Selenium supplementation restores the decreased albumin level of peripheral blood mononuclear cells in streptozotocin-induced diabetic mice

    PubMed Central

    AHN, Taeho; BAE, Chun-Sik; YUN, Chul-Ho

    2016-01-01

    Previously, it has been suggested that the phenotypic level of albumin in peripheral blood mononuclear cells (PBMC) decreased in streptozotocin (STZ)-induced diabetic rats. Concomitantly, the production of oxidative stresses was also elevated in the diabetic PBMC compared to that of normal control. These results suggest the close relationship between PBMC-albumin and its antioxidant roles. Here, we expanded the previous studies and investigated the effect of selenium supplementation as inorganic (sodium selenate) forms on the levels of albumin expression and oxidative stress in PBMC of STZ-induced diabetic mice. Selenium intake recovered the decreased albumin levels to those of normal mice and reduced the production of reactive oxygen species (ROS). These results support that selenium intake may alleviate the etiology and pathology of PBMC in type 1 diabetic mice by restoring the decrease in albumin contents and the production of ROS. PMID:26726102

  8. Expression of gluconeogenic enzymes and 11β-hydroxysteroid dehydrogenase type 1 in liver of diabetic mice after acute exercise

    PubMed Central

    Brust, Korie B; Corbell, Kathryn A; Al-Nakkash, Layla; Babu, Jeganathan Ramesh; Broderick, Tom L

    2014-01-01

    During acute exercise, normoglycemia is maintained by a precise match between hepatic glucose production and its peripheral utilization. This is met by a complex interplay of hepatic responses and glucose uptake by muscle. However, the effect of a single bout of exercise on hepatic gluconeogenesis, corticosterone (CORT) secretion, and glucose homeostasis in the db/db mouse model of type 2 diabetes is poorly understood. Diabetic db/db and lean control littermates were subjected to a 30 minute session of treadmill running and sacrificed either immediately after exercise or 8 hours later. Plasma glucose levels were markedly increased in db/db mice after exercise, whereas no change in glucose was observed in lean mice. Post-exercise measurements revealed that plasma CORT levels were also significantly increased in db/db mice compared to lean mice. Plasma hypothalamic corticotropin releasing hormone and pituitary adrenocorticotropic hormone levels were reciprocally decreased in both db/db and lean mice after exercise, indicating intact feedback mechanisms. Protein expression, determined by Western blot analysis, of the glucocorticoid receptor in liver was significantly increased in db/db mice subjected to prior exercise. In liver of db/db mice, a significant increase in the expression of phosphoenolpyruvate carboxykinase was noted compared to lean mice after exercise. However, no change in the expression of glucose-6-phosphatase (G6Pase) α or β was observed in db/db mice. Expression of 11β-hydroxysteroid dehydrogenase type 1 was increased significantly in db/db mice compared to lean mice after exercise. Our results show differences in plasma glucose and protein expression of gluconeogenic enzymes after acute exercise between lean and diabetic db/db mice. The db/db diabetic mouse is hyperglycemic after acute exercise. This hyperglycemic state may be explained, in part, by enhanced endogenous CORT secretion and regulated hepatic phosphoenolpyruvate carboxykinase and 11

  9. Senescence-associated phenotypes in Akita diabetic mice are enhanced by absence of bradykinin B2 receptors

    PubMed Central

    Kakoki, Masao; Kizer, Catherine M.; Yi, Xianwen; Takahashi, Nobuyuki; Kim, Hyung-Suk; Bagnell, C. Robert; Edgell, Cora-Jean S.; Maeda, Nobuyo; Jennette, J. Charles; Smithies, Oliver

    2006-01-01

    We have previously reported that genetically increased angiotensin-converting enzyme levels, or absence of the bradykinin B2 receptor, increase kidney damage in diabetic mice. We demonstrate here that this is part of a more general phenomenon — diabetes and, to a lesser degree, absence of the B2 receptor, independently but also largely additively when combined, enhance senescence-associated phenotypes in multiple tissues. Thus, at 12 months of age, indicators of senescence (alopecia, skin atrophy, kyphosis, osteoporosis, testicular atrophy, lipofuscin accumulation in renal proximal tubule and testicular Leydig cells, and apoptosis in the testis and intestine) are virtually absent in WT mice, detectable in B2 receptor–null mice, clearly apparent in mice diabetic because of a dominant mutation (Akita) in the Ins2 gene, and most obvious in Akita diabetic plus B2 receptor–null mice. Renal expression of several genes that encode proteins associated with senescence and/or apoptosis (TGF-β1, connective tissue growth factor, p53, α-synuclein, and forkhead box O1) increases in the same progression. Concomitant increases occur in 8-hydroxy-2′-deoxyguanosine, point mutations and deletions in kidney mitochondrial DNA, and thiobarbituric acid–reactive substances in plasma, together with decreases in the reduced form of glutathione in erythrocytes. Thus, absence of the bradykinin B2 receptor increases the oxidative stress, mitochondrial DNA damage, and many senescence-associated phenotypes already present in untreated Akita diabetic mice. PMID:16604193

  10. Neuronatin: A New Inflammation Gene Expressed on the Aortic Endothelium of Diabetic Mice

    PubMed Central

    Mzhavia, Nino; Yu, Shuiqing; Ikeda, Shota; Chu, Tehua T.; Goldberg, Ira; Dansky, Hayes M.

    2008-01-01

    OBJECTIVE—Identification of arterial genes and pathways altered in obesity and diabetes. RESEARCH DESIGN AND METHODS—Aortic gene expression profiles of obese and diabetic db/db, high-fat diet–fed C57BL/6J, and control mice were obtained using mouse Affymetrix arrays. Neuronatin (Nnat) was selected for further analysis. To determine the function of Nnat, a recombinant adenovirus (Ad-Nnat) was used to overexpress the Nnat gene in primary endothelial cells and in the mouse aorta in vivo. RESULTS—Nnat, a gene of unknown vascular function, was upregulated in the aortas of db/db and high-fat diet–fed mice. Nnat gene expression was increased in db/db mouse aorta endothelial cells. Nnat protein was localized to aortic endothelium and was selectively increased in the endothelium of db/db mice. Infection of primary human aortic endothelial cells (HAECs) with Ad-Nnat increased expression of a panel of nuclear factor-κB (NF-κB)-regulated genes, including inflammatory cytokines, chemokines, and cell adhesion molecules. Infection of mouse carotid arteries in vivo with the Ad-Nnat increased expression of vascular cell adhesion molecule 1 protein. Nnat activation of NF-κB and inflammatory gene expression in HAECs was mediated through pathways distinct from tumor necrosis factor-α. Nnat expression stimulated p38, Jun NH2-terminal kinase, extracellular signal–related kinase, and AKT kinase phosphorylation. Phosphatidylinositol 3-kinase and p38 inhibitors prevented Nnat-mediated activation of NF-κB–induced gene expression. CONCLUSIONS—Nnat expression is increased in endothelial cells of obese and diabetic mouse blood vessels. The effects of Nnat on inflammatory pathways in vitro and in vivo suggest a pathophysiological role of this new gene in diabetic vascular diseases. PMID:18591389

  11. Hyperglycemia and xerostomia are key determinants of tooth decay in type 1 diabetic mice

    PubMed Central

    Yeh, Chih-Ko; Harris, Stephen E; Mohan, Sumathy; Horn, Diane; Fajardo, Roberto; Chun, Yong-Hee Patricia; Jorgensen, James; MacDougall, Mary; Abboud-Werner, Sherry

    2012-01-01

    Insulin-dependent type 1 diabetes mellitus (DM) and oral diseases are closely interrelated. Poor metabolic control in diabetics is associated with a high risk of gingivitis, periodontitis and tooth loss. Salivary flow declines in diabetics and patients suffer from xerostomia. Reduced saliva predisposes to enamel hypomineralization and caries formation; however, the mechanisms that initiate and lead to progression of tooth decay and periodontitis in type 1 DM have not been explored. To address this issue, we analyzed tooth morphology in Akita −/− mice that harbor a point mutation in the Ins2 insulin gene, which leads to progressive hyperglycemia. Mandibles from Akita −/− and wild-type littermates were analyzed by microCT, scanning EM and histology; teeth were examined for amelogenin (Amel) and ameloblastin (Ambn) expression. Mice were injected with pilocarpine to assess saliva production. As hyperglycemia may alter pulp repair, the effect of high glucose levels on the proliferation/differentiation of cultured MD10-F2 pulp cells was also analyzed. Results showed that Akita −/− mice at 6 weeks of age showed chalky white incisors that correlated with marked hyperglycemia and impaired saliva production. MicroCT of Akita −/− teeth revealed excessive enamel wearing and hypomineralization; immunostaining for Amel and Ambn was decreased. A striking feature was invasion of dentinal tubules with Streptococcus mitis and microabcesses that originated in the coronal pulp and progressed to pulp necrosis and periapical periodontitis. High levels of glucose also inhibited MD10-F2 cell proliferation and differentiation. Our findings provide the first evidence that hyperglycemia in combination with reduced saliva in a model of type1 DM leads to decreased enamel mineralization/matrix proteins and predisposes to excessive wearing and decay. Importantly, hyperglycemia adversely affects enamel matrix proteins and pulp repair. Early detection and treatment of hyperglycemia

  12. Increased oxidative stress and apoptosis in the hypothalamus of diabetic male mice in the insulin receptor substrate-2 knockout model

    PubMed Central

    Canelles, Sandra; Argente, Jesús; Barrios, Vicente

    2016-01-01

    ABSTRACT Insulin receptor substrate-2-deficient (IRS2−/−) mice are considered a good model to study the development of diabetes because IRS proteins mediate the pleiotropic effects of insulin-like growth factor-I (IGF-I) and insulin on metabolism, mitogenesis and cell survival. The hypothalamus might play a key role in the early onset of diabetes, owing to its involvement in the control of glucose homeostasis and energy balance. Because some inflammatory markers are elevated in the hypothalamus of diabetic IRS2−/− mice, our aim was to analyze whether the diabetes associated with the absence of IRS2 results in hypothalamic injury and to analyze the intracellular mechanisms involved. Only diabetic IRS2−/− mice showed increased cell death and activation of caspase-8 and -3 in the hypothalamus. Regulators of apoptosis such as FADD, Bcl-2, Bcl-xL and p53 were also increased, whereas p-IκB and c-FLIPL were decreased. This was accompanied by increased levels of Nox-4 and catalase, enzymes involved in oxidative stress. In summary, the hypothalamus of diabetic IRS2−/− mice showed an increase in oxidative stress and inflammatory markers that finally resulted in cell death via substantial activation of the extrinsic apoptotic pathway. Conversely, non-diabetic IRS2−/− mice did not show cell death in the hypothalamus, possibly owing to an increase in the levels of circulating IGF-I and in the enhanced hypothalamic IGF-IR phosphorylation that would lead to the stimulation of survival pathways. In conclusion, diabetes in IRS2-deficient male mice is associated with increased oxidative stress and apoptosis in the hypothalamus. PMID:27013528

  13. Increased oxidative stress and apoptosis in the hypothalamus of diabetic male mice in the insulin receptor substrate-2 knockout model.

    PubMed

    Baquedano, Eva; Burgos-Ramos, Emma; Canelles, Sandra; González-Rodríguez, Agueda; Chowen, Julie A; Argente, Jesús; Barrios, Vicente; Valverde, Angela M; Frago, Laura M

    2016-05-01

    Insulin receptor substrate-2-deficient (IRS2(-/-)) mice are considered a good model to study the development of diabetes because IRS proteins mediate the pleiotropic effects of insulin-like growth factor-I (IGF-I) and insulin on metabolism, mitogenesis and cell survival. The hypothalamus might play a key role in the early onset of diabetes, owing to its involvement in the control of glucose homeostasis and energy balance. Because some inflammatory markers are elevated in the hypothalamus of diabetic IRS2(-/-) mice, our aim was to analyze whether the diabetes associated with the absence of IRS2 results in hypothalamic injury and to analyze the intracellular mechanisms involved. Only diabetic IRS2(-/-) mice showed increased cell death and activation of caspase-8 and -3 in the hypothalamus. Regulators of apoptosis such as FADD, Bcl-2, Bcl-xL and p53 were also increased, whereas p-IκB and c-FLIPL were decreased. This was accompanied by increased levels of Nox-4 and catalase, enzymes involved in oxidative stress. In summary, the hypothalamus of diabetic IRS2(-/-) mice showed an increase in oxidative stress and inflammatory markers that finally resulted in cell death via substantial activation of the extrinsic apoptotic pathway. Conversely, non-diabetic IRS2(-/-) mice did not show cell death in the hypothalamus, possibly owing to an increase in the levels of circulating IGF-I and in the enhanced hypothalamic IGF-IR phosphorylation that would lead to the stimulation of survival pathways. In conclusion, diabetes in IRS2-deficient male mice is associated with increased oxidative stress and apoptosis in the hypothalamus. PMID:27013528

  14. Increased oxidative stress and apoptosis in the hypothalamus of diabetic male mice in the insulin receptor substrate-2 knockout model.

    PubMed

    Baquedano, Eva; Burgos-Ramos, Emma; Canelles, Sandra; González-Rodríguez, Agueda; Chowen, Julie A; Argente, Jesús; Barrios, Vicente; Valverde, Angela M; Frago, Laura M

    2016-05-01

    Insulin receptor substrate-2-deficient (IRS2(-/-)) mice are considered a good model to study the development of diabetes because IRS proteins mediate the pleiotropic effects of insulin-like growth factor-I (IGF-I) and insulin on metabolism, mitogenesis and cell survival. The hypothalamus might play a key role in the early onset of diabetes, owing to its involvement in the control of glucose homeostasis and energy balance. Because some inflammatory markers are elevated in the hypothalamus of diabetic IRS2(-/-) mice, our aim was to analyze whether the diabetes associated with the absence of IRS2 results in hypothalamic injury and to analyze the intracellular mechanisms involved. Only diabetic IRS2(-/-) mice showed increased cell death and activation of caspase-8 and -3 in the hypothalamus. Regulators of apoptosis such as FADD, Bcl-2, Bcl-xL and p53 were also increased, whereas p-IκB and c-FLIPL were decreased. This was accompanied by increased levels of Nox-4 and catalase, enzymes involved in oxidative stress. In summary, the hypothalamus of diabetic IRS2(-/-) mice showed an increase in oxidative stress and inflammatory markers that finally resulted in cell death via substantial activation of the extrinsic apoptotic pathway. Conversely, non-diabetic IRS2(-/-) mice did not show cell death in the hypothalamus, possibly owing to an increase in the levels of circulating IGF-I and in the enhanced hypothalamic IGF-IR phosphorylation that would lead to the stimulation of survival pathways. In conclusion, diabetes in IRS2-deficient male mice is associated with increased oxidative stress and apoptosis in the hypothalamus.

  15. Gold nanorods in an oil-base formulation for transdermal treatment of type 1 diabetes in mice.

    PubMed

    Nose, Keisuke; Pissuwan, Dakrong; Goto, Masahiro; Katayama, Yoshiki; Niidome, Takuro

    2012-06-21

    Efficient transdermal insulin delivery to the systemic circulation would bring major benefit to diabetic patients. We investigated the possibility of using gold nanorods (GNRs) that formed a complex with an edible surfactant and insulin (INS) in an oil phase to form a solid-in-oil (SO) formulation (SO-INS-GNR) for transdermal treatment of diabetes. Diabetic mice comprised the model for our study. In vitro, there was high penetration of insulin through the stratum corneum (SC) and the dermis in mouse skin treated with an SO-INS-GNR complex plus near-infrared (NIR) light irradiation. Blood glucose levels in the diabetic mice were significantly decreased after treatment with SO-INS-GNR plus irradiation. To our knowledge, this is the first study to use gold nanorods for systemic insulin delivery through the skin. The use of an SO-INS-GNR complex combined with NIR irradiation may provide the possibility of transdermal insulin delivery to diabetic patients.

  16. Transplantation of insulin-secreting cells differentiated from human adipose tissue-derived stem cells into type 2 diabetes mice.

    PubMed

    Nam, Ji Sun; Kang, Hyun Mi; Kim, Jiyoung; Park, Seah; Kim, Haekwon; Ahn, Chul Woo; Park, Jin Oh; Kim, Kyung Rae

    2014-01-10

    Currently, there are limited ways to preserve or recover insulin secretory capacity in human pancreas. We evaluated the efficacy of cell therapy using insulin-secreting cells differentiated from human eyelid adipose tissue-derived stem cells (hEAs) into type 2 diabetes mice. After differentiating hEAs into insulin-secreting cells (hEA-ISCs) in vitro, cells were transplanted into a type 2 diabetes mouse model. Serum levels of glucose, insulin and c-peptide were measured, and changes of metabolism and inflammation were assessed in mice that received undifferentiated hEAs (UDC group), differentiated hEA-ISCs (DC group), or sham operation (sham group). Human gene expression and immunohistochemical analysis were done. DC group mice showed improved glucose level, and survival up to 60 days compared to those of UDC and sham group. Significantly increased levels of human insulin and c-peptide were detected in sera of DC mice. RT-PCR and immunohistochemical analysis showed human gene expression and the presence of human cells in kidneys of DC mice. When compared to sham mice, DC mice exhibited lower levels of IL-6, triglyceride and free fatty acids as the control mice. Transplantation of hEA-ISCs lowered blood glucose level in type 2 diabetes mice by increasing circulating insulin level, and ameliorating metabolic parameters including IL-6.

  17. Angiography reveals novel features of the retinal vasculature in healthy and diabetic mice.

    PubMed

    McLenachan, Samuel; Magno, Aaron Len; Ramos, David; Catita, Joana; McMenamin, Paul G; Chen, Fred Kuanfu; Rakoczy, Elizabeth Piroska; Ruberte, Jesus

    2015-09-01

    The mouse retina is a commonly used animal model for the study of pathogenesis and treatment of blinding retinal vascular diseases such as diabetic retinopathy. In this study, we aimed to characterize normal and pathological variations in vascular anatomy in the mouse retina using fluorescein angiography visualized with scanning laser ophthalmoscopy and optical coherence tomography (SLO-OCT). We examined eyes from C57BL/6J wild type mice as well as the Ins2(Akita) and Akimba mouse models of diabetic retinopathy using the Heidelberg Retinal Angiography (HRA) and OCT system. Angiography was performed on three focal planes to examine distinct vascular layers. For comparison with angiographic data, ex vivo analyses, including Indian ink angiography, histology and 3D confocal scanning laser microscopy were performed in parallel. All layers of the mouse retinal vasculature could be readily visualized during fluorescein angiography by SLO-OCT. Blood vessel density was increased in the deep vascular plexus (DVP) compared with the superficial vascular plexus (SVP). Arteriolar and venular typologies were established and structural differences were observed between venular types. Unexpectedly, the hyaloid artery was found to persist in 15% of C57BL/6 mice, forming anastomoses with peripheral retinal capillaries. Fluorescein leakage was easily detected in Akimba retinae by angiography, but was not observed in Ins2(Akita) mice. Blood vessel density was increased in the DVP of 6 month old Ins2(Akita) mice, while the SVP displayed reduced branching in precapillary arterioles. In summary, we present the first comprehensive characterization of the mouse retinal vasculature by SLO-OCT fluorescein angiography. Using this clinical imaging technique, we report previously unrecognized variations in C57BL/6J vascular anatomy and novel features of vascular retinopathy in the Ins2(Akita) mouse model of diabetes.

  18. Chlorogenic Acid Improves Late Diabetes through Adiponectin Receptor Signaling Pathways in db/db Mice

    PubMed Central

    Jin, Shasha; Chang, Cuiqing; Zhang, Lantao; Liu, Yang; Huang, Xianren; Chen, Zhimin

    2015-01-01

    The aim of this study was to examine the effects of chlorogenic acid (CGA) on glucose and lipid metabolism in late diabetic db/db mice, as well as on adiponectin receptors and their signaling molecules, to provide evidence for CGA in the prevention of type 2 diabetes. We randomly divided 16 female db/db mice into db/db-CGA and db/db-control (CON) groups equally; db/m mice were used as control mice. The mice in both the db/db-CGA and db/m-CGA groups were administered 80 mg/kg/d CGA by lavage for 12 weeks, whereas the mice in both CON groups were given equal volumes of phosphate-buffered saline (PBS) by lavage. At the end of the intervention, we assessed body fat and the parameters of glucose and lipid metabolism in the plasma, liver and skeletal muscle tissues as well as the levels of aldose reductase (AR) and transforming growth factor-β1 (TGF-β1) in the kidneys and measured adiponectin receptors and the protein expression of their signaling molecules in liver and muscle tissues. After 12 weeks of intervention, compared with the db/db-CON group, the percentage of body fat, fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) in the db/db-CGA group were all significantly decreased; TGF-β1 protein expression and AR activity in the kidney were both decreased; and the adiponectin level in visceral adipose was increased. The protein expression of adiponectin receptors (ADPNRs), the phosphorylation of AMP-activated protein kinase (AMPK) in the liver and muscle, and the mRNA and protein levels of peroxisome proliferator-activated receptor alpha (PPAR-α) in the liver were all significantly greater. CGA could lower the levels of fasting plasma glucose and HbA1c during late diabetes and improve kidney fibrosis to some extent through the modulation of adiponectin receptor signaling pathways in db/db mice. PMID:25849026

  19. Impaired vascular responses to parasympathetic nerve stimulation and muscarinic receptor activation in the submandibular gland in nonobese diabetic mice

    PubMed Central

    Berggreen, Ellen; Nyløkken, Krister; Delaleu, Nicolas; Hajdaragic-Ibricevic, Hamijeta; Jonsson, Malin V

    2009-01-01

    Introduction Decreased vascular responses to salivary gland stimulation are observed in Sjögren's syndrome patients. We investigate whether impaired vascular responses to parasympathetic stimulation and muscarinic receptor activation in salivary glands parallels hyposalivation in an experimental model for Sjögren's syndrome. Methods Blood flow responses in the salivary glands were measured by laser Doppler flowmeter. Muscarinic receptor activation was followed by saliva secretion measurements. Nitric oxide synthesis-mediated blood flow responses were studied after administration of a nitric oxide synthase inhibitor. Glandular autonomic nerves and muscarinic 3 receptor distributions were also investigated. Results Maximal blood flow responses to parasympathetic stimulation and muscarinic receptor activation were significantly lower in nonobese diabetic (NOD) mice compared with BALB/c mice, coinciding with impaired saliva secretion in nonobese diabetic mice (P < 0.005). Nitric oxide synthase inhibitor had less effect on blood flow responses after parasympathetic nerve stimulation in nonobese diabetic mice compared with BALB/c mice (P < 0.02). In nonobese diabetic mice, salivary gland parasympathetic nerve fibres were absent in areas of focal infiltrates. Muscarinic 3 receptor might be localized in the blood vessel walls of salivary glands. Conclusions Impaired vasodilatation in response to parasympathetic nerve stimulation and muscarinic receptor activation may contribute to hyposalivation observed in nonobese diabetic mice. Reduced nitric oxide signalling after parasympathetic nerve stimulation may contribute in part to the impaired blood flow responses. The possibility of muscarinic 3 receptor in the vasculature supports the notion that muscarinic 3 receptor autoantibodies present in nonobese diabetic mice might impair the fluid transport required for salivation. Parasympathetic nerves were absent in areas of focal infiltrates, whereas a normal distribution was

  20. Effects of a high-monounsaturated fat diet on glucose and lipid metabolisms in normal and diabetic mice.

    PubMed

    Kotake, Jiro; Tanaka, Yoshiaki; Umehara, Norimitsu; Miyashita, Akira; Tsuru, Tomomitsu; Hikida, Shigeki; Mizote, Hiroyoshi

    2004-04-01

    The beneficial effects of high-monounsaturated fat (high-MUFA) diets on diabetic patients have been reported, whereas studies concerning the effects on animals have been few. Although experiments on animals should be useful in elucidating underlying mechanisms, it is not clear even whether there are benefits of a high-MUFA diet in animals. This study examined the short-term effects of a high-MUFA diet on normal and genetically diabetic mice. The high-MUFA diet supplied 38% of the total calories as fat (26% from MUFA), while a regular diet was 13% fat (3% from MUFA). Normal C5 7BL/6J and diabetic C57BL/KsJ-db/db mice were fed either the regular or the high-MUFA diet for 1 wk. Serum glucose and lipid levels were then measured. In normal mice, hepatic triglyceride production was also compared between the two dietary groups using the Triton WR1339 method. An oral glucose tolerance test was conducted on the diabetic mice. After 1 wk of feeding to normal mice, the high-MUFA diet was seen to lower serum triglyceride levels and reduce hepatic triglyceride production in comparison with the regular diet; it is suggested that the lowering of triglyceride consists of mechanisms including reduced hepatic triglyceride production. When diabetic mice were fed the high-MUFA diet with a controlled caloric intake, the serum glucose levels lowered without an accompanying deterioration in lipid metabolism and the impaired glucose tolerance was ameliorated. This study demonstrates that a high-MUFA diet can lower serum triglyceride levels in normal mice and improve disorders of glucose metabolism in diabetic mice.

  1. Estrogen Therapy Delays Autoimmune Diabetes and Promotes the Protective Efficiency of Natural Killer T-Cell Activation in Female Nonobese Diabetic Mice.

    PubMed

    Gourdy, Pierre; Bourgeois, Elvire A; Levescot, Anaïs; Pham, Linh; Riant, Elodie; Ahui, Marie-Louise; Damotte, Diane; Gombert, Jean-Marc; Bayard, Francis; Ohlsson, Claes; Arnal, Jean-François; Herbelin, André

    2016-01-01

    Therapeutic strategies focused on restoring immune tolerance remain the main avenue to prevent type 1 diabetes (T1D). Because estrogens potentiate FoxP3+ regulatory T cells (Treg) and invariant natural killer T (iNKT) cells, two regulatory lymphocyte populations that are functionally deficient in nonobese diabetic (NOD) mice, we investigated whether estradiol (E2) therapy influences the course of T1D in this model. To this end, female NOD mice were sc implanted with E2- or placebo-delivering pellets to explore the course of spontaneous and cyclophosphamide-induced diabetes. Treg-depleted and iNKT-cell-deficient (Jα18(-/-)) NOD mice were used to assess the respective involvement of these lymphocyte populations in E2 effects. Early E2 administration (from 4 wk of age) was found to preserve NOD mice from both spontaneous and cyclophosphamide-induced diabetes, and a complete protection was also observed throughout treatment when E2 treatment was initiated after the onset of insulitis (from 12 wk of age). This delayed E2 treatment remained fully effective in Treg-depleted mice but failed to entirely protect Jα18(-/-) mice. Accordingly, E2 administration was shown to restore the cytokine production of iNKT cells in response to in vivo challenge with the cognate ligand α-galactosylceramide. Finally, transient E2 administration potentiated the previously described protective action of α-galactosylceramide treatment in NOD females. This study provides original evidence that E2 therapy strongly protects NOD mice from T1D and reveals the estrogen/iNKT cell axis as a new effective target to counteract diabetes onset at the stage of insulitis. Estrogen-based therapy should thus be considered for T1D prevention. PMID:26485613

  2. Estrogen Therapy Delays Autoimmune Diabetes and Promotes the Protective Efficiency of Natural Killer T-Cell Activation in Female Nonobese Diabetic Mice.

    PubMed

    Gourdy, Pierre; Bourgeois, Elvire A; Levescot, Anaïs; Pham, Linh; Riant, Elodie; Ahui, Marie-Louise; Damotte, Diane; Gombert, Jean-Marc; Bayard, Francis; Ohlsson, Claes; Arnal, Jean-François; Herbelin, André

    2016-01-01

    Therapeutic strategies focused on restoring immune tolerance remain the main avenue to prevent type 1 diabetes (T1D). Because estrogens potentiate FoxP3+ regulatory T cells (Treg) and invariant natural killer T (iNKT) cells, two regulatory lymphocyte populations that are functionally deficient in nonobese diabetic (NOD) mice, we investigated whether estradiol (E2) therapy influences the course of T1D in this model. To this end, female NOD mice were sc implanted with E2- or placebo-delivering pellets to explore the course of spontaneous and cyclophosphamide-induced diabetes. Treg-depleted and iNKT-cell-deficient (Jα18(-/-)) NOD mice were used to assess the respective involvement of these lymphocyte populations in E2 effects. Early E2 administration (from 4 wk of age) was found to preserve NOD mice from both spontaneous and cyclophosphamide-induced diabetes, and a complete protection was also observed throughout treatment when E2 treatment was initiated after the onset of insulitis (from 12 wk of age). This delayed E2 treatment remained fully effective in Treg-depleted mice but failed to entirely protect Jα18(-/-) mice. Accordingly, E2 administration was shown to restore the cytokine production of iNKT cells in response to in vivo challenge with the cognate ligand α-galactosylceramide. Finally, transient E2 administration potentiated the previously described protective action of α-galactosylceramide treatment in NOD females. This study provides original evidence that E2 therapy strongly protects NOD mice from T1D and reveals the estrogen/iNKT cell axis as a new effective target to counteract diabetes onset at the stage of insulitis. Estrogen-based therapy should thus be considered for T1D prevention.

  3. Comparison of cerebral microcirculation of alloxan diabetes and healthy mice using laser speckle contrast imaging

    NASA Astrophysics Data System (ADS)

    Timoshina, Polina A.; Shi, Rui; Zhang, Yang; Zhu, Dan; Semyachkina-Glushkovskaya, Oxana V.; Tuchin, Valery V.; Luo, Qingming

    2015-03-01

    The study of blood microcirculation is one of the most important problems of the medicine. This paper presents results of experimental study of cerebral blood flow microcirculation in mice with alloxan-induced diabetes using Temporal Laser Speckle Imaging (TLSI). Additionally, a direct effect of glucose water solution (concentration 20% and 45%) on blood flow microcirculation was studied. In the research, 20 white laboratory mice weighing 20-30 g were used. The TLSI method allows one to investigate time dependent scattering from the objects with complex dynamics, since it possesses greater temporal resolution. Results show that in brain of animal diabetic group diameter of sagittal vein is increased and the speed of blood flow reduced relative to the control group. Topical application of 20%- or 45%-glucose solutions also causes increase of diameter of blood vessels and slows down blood circulation. The results obtained show that diabetes development causes changes in the cerebral microcirculatory system and TLSI techniques can be effectively used to quantify these alterations.

  4. Renal protective effects of extracts from guava fruit (Psidium guajava L.) in diabetic mice.

    PubMed

    Lin, Chia-Yu; Lin, Chia-Yun; Yin, Mei-Chin

    2012-09-01

    This study analyzed the content of phenolic acids and flavonoids in extracts of guava fruit (Psidium guajava L.), and examined the renal protective effects of guava aqueous extract (GAE) and ethanol extract (GEE) in diabetic mice. GAE had more caffeic acid, myricetin, and quercetin; and GEE had more cinnamic, coumaric and ferulic acids. GAE or GEE at 1 and 2 % was supplied in diet for 12 weeks. GAE or GEE intake at 2 % significantly reduced glucose and blood urea nitrogen levels, increased insulin level in plasma of diabetic mice (p < 0.05). GAE or GEE treatments dose-dependently reserved glutathione content, retained activity of catalase and glutathione peroxidase, and decreased reactive oxygen species, interleukin (IL)-6, tumor necrosis factor-α and IL-1β levels in kidney (p < 0.05). GAE and GEE treatments at 2 % significantly declined renal N (ε)-(carboxymethyl)lysine, pentosidine and fructose levels (p < 0.05), and suppressed renal activity of aldose reductase (p < 0.05). These findings support that guava fruit could protect kidney against diabetic progression via its anti-oxidative, anti-inflammatory and anti-glycative effects.

  5. Inhibition of inflammation by astaxanthin alleviates cognition deficits in diabetic mice.

    PubMed

    Zhou, Xiaoyan; Zhang, Fang; Hu, Xiaotong; Chen, Jing; Wen, Xiangru; Sun, Ying; Liu, Yonghai; Tang, Renxian; Zheng, Kuiyang; Song, Yuanjian

    2015-11-01

    Neurons in the hippocampal and cortical functional regions are more susceptible to damage induced by hyperglycemia, which can result in severe spatial learning and memory impairment. Neuroprotection ameliorates cognitive impairment induced by hyperglycemia in diabetic encephalopathy (DE). Astaxanthin has been widely studied in diabetes mellitus and diabetic complications due to its hypoglycemic, antioxidant and anti-apoptotic effects. However, whether astaxanthin can alleviate cognition deficits induced by DE and its precise mechanisms remain undetermined. In this study, DE was induced by streptozotocin (STZ, 150 mg/kg) in ICR mice. We observed the effect of astaxanthin on cognition and investigated its potential mechanisms in DE mice. Results showed that astaxanthin treatment significantly decreased the latency and enhanced the distance and time spent in the target quadrant in the Morris water maze test. Furthermore, neuronal survival was significantly increased in the hippocampal CA3 region and the frontal cortex following treatment with astaxanthin. Meanwhile, immunoblotting was used to observe the nuclear translocation of nuclear factor-kappaB (NF-κB) p65 and the expression of tumor necrosis factor-α (TNF-α) in the hippocampus and frontal cortex. The results indicated that astaxanthin could inhibit NF-κB nuclear translocation and downregulate TNF-α expression in the hippocampus and frontal cortex. Overall, the present study implied that astaxanthin could improve cognition by protecting neurons against inflammation injury potentially through inhibiting the nuclear translocation of NF-κB and down-regulating TNF-α. PMID:26272354

  6. Prevention or early cure of type 1 diabetes by intranasal administration of gliadin in NOD mice.

    PubMed

    Funda, David P; Fundova, Petra; Hansen, Axel Kornerup; Buschard, Karsten

    2014-01-01

    Induction of long-term tolerance to β-cell autoantigens has been investigated both in animal models and in human type 1 diabetes (T1D) in order to prevent the disease. As regards external compounds, the dietary plant protein fraction has been associated with high penetrance of the disease, whereas gluten-free diets prevent T1D in animal models. Herewith we investigated whether intranasal (i.n.) administration of gliadin or gluten may arrest the diabetogenic process. I.n. administration of gliadin to 4-week-old NOD mice significantly reduced the diabetes incidence. Similarly, the insulitis was lowered. Intranasal gliadin also rescued a fraction of prediabetic 13-week-old NOD mice from progressing to clinical onset of diabetes compared to OVA-treated controls. Vaccination with i.n. gliadin led to an induction of CD4(+)Foxp3(+) T cells and even more significant induction of γδ T cells in mucosal, but not in non-mucosal lymphoid compartments. This prevention strategy was characterized by an increased proportion of IL-10 and a decreased proportion of IL-2, IL-4 and IFN-γ-positive CD4(+)Foxp3(+) T cells, and IFN-γ-positive γδ T cells, preferentially in mucosal lymphoid organs. In conclusion, i.n. vaccination with gliadin, an environmental antigen with possible etiological influence in T1D, may represent a novel, safer strategy for prevention or even early cure of T1D.

  7. Low-intensity vibration improves angiogenesis and wound healing in diabetic mice.

    PubMed

    Weinheimer-Haus, Eileen M; Judex, Stefan; Ennis, William J; Koh, Timothy J

    2014-01-01

    Chronic wounds represent a significant health problem, especially in diabetic patients. In the current study, we investigated a novel therapeutic approach to wound healing--whole body low-intensity vibration (LIV). LIV is anabolic for bone, by stimulating the release of growth factors, and modulating stem cell proliferation and differentiation. We hypothesized that LIV improves the delayed wound healing in diabetic mice by promoting a pro-healing wound environment. Diabetic db/db mice received excisional cutaneous wounds and were subjected to LIV (0.4 g at 45 Hz) for 30 min/d or a non-vibrated sham treatment (controls). Wound tissue was collected at 7 and 15 d post-wounding and wound healing, angiogenesis, growth factor levels and wound cell phenotypes were assessed. LIV increased angiogenesis and granulation tissue formation at day 7, and accelerated wound closure and re-epithelialization over days 7 and 15. LIV also reduced neutrophil accumulation and increased macrophage accumulation. In addition, LIV increased expression of pro-healing growth factors and chemokines (insulin-like growth factor-1, vascular endothelial growth factor and monocyte chemotactic protein-1) in wounds. Despite no evidence of a change in the phenotype of CD11b+ macrophages in wounds, LIV resulted in trends towards a less inflammatory phenotype in the CD11b- cells. Our findings indicate that LIV may exert beneficial effects on wound healing by enhancing angiogenesis and granulation tissue formation, and these changes are associated with increases in pro-angiogenic growth factors.

  8. Hypoglycemic, hypolipidemic and antioxidant effects of peptides from red deer antlers in streptozotocin-induced diabetic mice.

    PubMed

    Jiang, Ning; Zhang, Shuangjian; Zhu, Jing; Shang, Jing; Gao, Xiangdong

    2015-01-01

    Diabetes mellitus is a serious chronic metabolic disorder. To develop novel anti-diabetic drugs from nature sources has always been the focus of research. Red deer (Cervus elaphu Linnaeus) antler is one of the most famous Chinese traditional medicines. We found that the peptides of 5-10 kDa from red deer antlers (PRDA) promoted the growth of cultured rat islet cells. The purpose of this study was to investigate the anti-diabetic actions of PRDA in vivo and purify a pure active peptide. We therefore investigated the hypoglycemic, hypolipidemic and antioxidant effects of PRDA in streptozotocin-induced diabetic mice and isolated a pure anti-diabetic peptide. PRDA, given intraperitoneally (75, 150, or 300 μg/kg), significantly decreased the blood glucose levels, significantly increased the insulin concentrations, and remarkably improved the lipid metabolism in the diabetic mice. PRDA significantly increased the superoxide dismutase activity, catalase activity and the total antioxidant capacity in the serum and liver, and simultaneously decreased the malondialdehyde levels. The activities of hexokinase and pyruvate kinase, two important enzymes involved in glucose utilization, were also significantly increased in the liver of the PRDA-treated diabetic mice. Moreover, a novel anti-diabetic peptide isolated from PRDA significantly promoted the viability of cultured rat insulinoma cells. The molecular mass of the purified peptide was 7064.8 Da under mass spectrometry, and its N-terminal amino acid sequence was identified as LSPFTTKTYFPHFDLSHGSA. Thus, PRDA may be useful in managing the hyperglycemia, hyperlipidemia, and oxidative stress in diabetes, and the anti-diabetic peptide is a promising drug for the treatment of diabetes. PMID:25985857

  9. Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice

    PubMed Central

    Rieg, Jessica A. Dominguez; Chirasani, Venkat R.; Koepsell, Hermann; Senapati, Sanjib; Mahata, Sushil K.; Rieg, Timo

    2015-01-01

    The small intestine is the major site for nutrient absorption, which is critical in maintenance of euglycemia. Leptin, a key hormone involved in energy homeostasis, directly affects nutrient transport across the intestinal epithelium. Catestatin (CST), a 21-amino acid peptide derived from proprotein chromogranin A, has been shown to modulate leptin signaling. Therefore, we reasoned that leptin and CST could modulate intestinal Na+-glucose transporter 1 (SGLT1) expression in the context of obesity and diabetes. We found that hyperleptinemic db/db mice exhibit increased mucosal mass, associated with an enhanced proliferative response and decreased apoptosis in intestinal crypts, a finding absent in leptin deficient ob/ob mice. Intestinal SGLT1 abundance was significantly decreased in hyperleptinemic, but not leptin-deficient mice, indicating leptin regulation of SGLT1 expression. Phlorizin, a SGLT1/2 inhibitor, was without effect in an oral glucose tolerance test in db/db mice. The alterations in architecture and SGLT1 abundance were not accompanied by changes in the localization of intestinal alkaline phosphatase, indicating intact differentiation. Treatment of db/db mice with CST restored intestinal SGLT1 abundance and intestinal turnover, suggesting a cross-talk between leptin and CST, without affecting plasma leptin levels. Consistent with this hypothesis, we identified structural homology between CST and the AB-loop of leptin and protein-protein docking revealed binding of CST and leptin with the Ig-like binding site III of the leptin receptor. In summary, downregulation of SGLT1 in an obese type 2 diabetic mouse model with hyperleptinemia is presumably mediated via the short form of the leptin receptor and reduces overt hyperglycemia. PMID:26552046

  10. Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice.

    PubMed

    Dominguez Rieg, Jessica A; Chirasani, Venkat R; Koepsell, Hermann; Senapati, Sanjib; Mahata, Sushil K; Rieg, Timo

    2016-01-01

    The small intestine is the major site for nutrient absorption that is critical in maintenance of euglycemia. Leptin, a key hormone involved in energy homeostasis, directly affects nutrient transport across the intestinal epithelium. Catestatin (CST), a 21-amino acid peptide derived from proprotein chromogranin A, has been shown to modulate leptin signaling. Therefore, we reasoned that leptin and CST could modulate intestinal Na(+)-glucose transporter 1 (SGLT1) expression in the context of obesity and diabetes. We found that hyperleptinemic db/db mice exhibit increased mucosal mass, associated with an enhanced proliferative response and decreased apoptosis in intestinal crypts, a finding absent in leptin-deficient ob/ob mice. Intestinal SGLT1 abundance was significantly decreased in hyperleptinemic but not leptin-deficient mice, indicating leptin regulation of SGLT1 expression. Phlorizin, a SGLT1/2 inhibitor, was without effect in an oral glucose tolerance test in db/db mice. The alterations in architecture and SGLT1 abundance were not accompanied by changes in the localization of intestinal alkaline phosphatase, indicating intact differentiation. Treatment of db/db mice with CST restored intestinal SGLT1 abundance and intestinal turnover, suggesting a cross-talk between leptin and CST, without affecting plasma leptin levels. Consistent with this hypothesis, we identified structural homology between CST and the AB-loop of leptin and protein-protein docking revealed binding of CST and leptin with the Ig-like binding site-III of the leptin receptor. In summary, downregulation of SGLT1 in an obese type 2 diabetic mouse model with hyperleptinemia is presumably mediated via the short form of the leptin receptor and reduces overt hyperglycemia. PMID:26552046

  11. Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice.

    PubMed

    Dominguez Rieg, Jessica A; Chirasani, Venkat R; Koepsell, Hermann; Senapati, Sanjib; Mahata, Sushil K; Rieg, Timo

    2016-01-01

    The small intestine is the major site for nutrient absorption that is critical in maintenance of euglycemia. Leptin, a key hormone involved in energy homeostasis, directly affects nutrient transport across the intestinal epithelium. Catestatin (CST), a 21-amino acid peptide derived from proprotein chromogranin A, has been shown to modulate leptin signaling. Therefore, we reasoned that leptin and CST could modulate intestinal Na(+)-glucose transporter 1 (SGLT1) expression in the context of obesity and diabetes. We found that hyperleptinemic db/db mice exhibit increased mucosal mass, associated with an enhanced proliferative response and decreased apoptosis in intestinal crypts, a finding absent in leptin-deficient ob/ob mice. Intestinal SGLT1 abundance was significantly decreased in hyperleptinemic but not leptin-deficient mice, indicating leptin regulation of SGLT1 expression. Phlorizin, a SGLT1/2 inhibitor, was without effect in an oral glucose tolerance test in db/db mice. The alterations in architecture and SGLT1 abundance were not accompanied by changes in the localization of intestinal alkaline phosphatase, indicating intact differentiation. Treatment of db/db mice with CST restored intestinal SGLT1 abundance and intestinal turnover, suggesting a cross-talk between leptin and CST, without affecting plasma leptin levels. Consistent with this hypothesis, we identified structural homology between CST and the AB-loop of leptin and protein-protein docking revealed binding of CST and leptin with the Ig-like binding site-III of the leptin receptor. In summary, downregulation of SGLT1 in an obese type 2 diabetic mouse model with hyperleptinemia is presumably mediated via the short form of the leptin receptor and reduces overt hyperglycemia.

  12. Nobiletin improves hyperglycemia and insulin resistance in obese diabetic ob/ob mice.

    PubMed

    Lee, Young-Sil; Cha, Byung-Yoon; Saito, Kiyoto; Yamakawa, Hiroshi; Choi, Sun-Sil; Yamaguchi, Kohji; Yonezawa, Takayuki; Teruya, Toshiaki; Nagai, Kazuo; Woo, Je-Tae

    2010-06-01

    Nobiletin is a polymethoxylated flavone found in certain citrus fruits that exhibits various pharmacological effects including anti-inflammatory, antitumor and neuroprotective properties. The present study investigated the effects of nobiletin on insulin sensitivity in obese diabetic ob/ob mice, and the possible mechanisms involved. The ob/ob mice were treated with nobiletin (200mg/kg) for 5 weeks. Nobiletin significantly improved the plasma glucose levels, homeostasis model assessment index, glucose tolerance in an oral glucose tolerance test and plasma adiponectin levels. In white adipose tissue (WAT), nobiletin significantly decreased the mRNA expression levels of inflammatory adipokines such as interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 and increased the mRNA expression levels of adiponectin, peroxisome proliferator-activated receptor (PPAR)-gamma and its target genes. At the same time, nobiletin increased the glucose transporter (Glut) 4 expression levels in the whole plasma membrane, and Glut1 and phospho-Akt expression in the whole cell lysates in WAT and muscle. Nobiletin also increased Glut4 protein expression level in the whole cell lysates of the muscle. Taken together, the present results suggest that nobiletin improved the hyperglycemia and insulin resistance in obese diabetic ob/ob mice by regulating expression of Glut1 and Glut4 in WAT and muscle, and expression of adipokines in WAT.

  13. Transplantation of bone marrow derived cells promotes pancreatic islet repair in diabetic mice

    SciTech Connect

    Gao Xiaodong; Song Lujun; Shen Kuntang; Wang Hongshan; Niu Weixin Qin Xinyu

    2008-06-20

    The transplantation of bone marrow (BM) derived cells to initiate pancreatic regeneration is an attractive but as-yet unrealized strategy. Presently, BM derived cells from green fluorescent protein transgenic mice were transplanted into diabetic mice. Repair of diabetic islets was evidenced by reduction of hyperglycemia, increase in number of islets, and altered pancreatic histology. Cells in the pancreata of recipient mice co-expressed BrdU and insulin. Double staining revealed {beta} cells were in the process of proliferation. BrdU{sup +} insulin{sup -} PDX-1{sup +} cells, Ngn3{sup +} cells and insulin{sup +} glucagon{sup +} cells, which showed stem cells, were also found during {beta}-cell regeneration. The majority of transplanted cells were mobilized to the islet and ductal regions. In recipient pancreas, transplanted cells simultaneously expressed CD34 but did not express insulin, PDX-1, Ngn3, Nkx2.2, Nkx6.1, Pax4, Pax6, and CD45. It is concluded that BM derived cells especially CD34{sup +} cells can promote repair of pancreatic islets. Moreover, both proliferation of {beta} cells and differentiation of pancreatic stem cells contribute to the regeneration of {beta} cells.

  14. Hypoglycemic activity of Eriobotrya japonica seeds in type 2 diabetic rats and mice.

    PubMed

    Tanaka, Kazunari; Nishizono, Shoko; Makino, Nozomi; Tamaru, Shizuka; Terai, Osamu; Ikeda, Ikuo

    2008-03-01

    The hypoglycemic effects of Eriobotrya japonica seeds were investigated in type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and KK-A(y) mice. The rats and mice were fed on a diet containing 10% powdered Eriobotrya japonica seeds with the coat intact for 4 months. Although the blood glucose concentration in the OLETF rats fed on the control diet without Eriobotrya japonica seeds was increased with time, the concentration in the OLETF rats fed on the diet with Eriobotrya japonica seeds was consistently low throughout the experimental period and was comparable to the level in Long-Evans Tokushima Otsuka (LETO) rats which are normal non-diabetic rats. Serum insulin was significantly lower in the OLETF rats fed on the Eriobotrya japonica seed diet than in those fed on the control diet at the termination of the experimental period. Eriobotrya japonica seeds suppressed the increment of blood glucose for 4 months and also effectively improved the glucose tolerance in the KK-A(y) mice, these actions being mainly exerted by the ethanol extract of the seeds. These results suggest that Eriobotrya japonica seeds had a hypoglycemic property and the effect is attributable to the components extracted by ethanol.

  15. Effects of two antioxidants; α-lipoic acid and fisetin against diabetic cataract in mice.

    PubMed

    Kan, Emrah; Kiliçkan, Elif; Ayar, Ahmet; Çolak, Ramis

    2015-02-01

    The purpose of this study was to determine whether α-lipoic acid and fisetin have protective effects against cataract in a streptozotocin-induced experimental cataract model. Twenty-eight male BALB/C mice were made diabetic by the intraperitoneal administration of streptozotocin (200 mg/kg). Three weeks after induction of diabetes, mice were divided randomly into 4 groups in which each group contained 7 mice; fisetin-treated group (group 1), α-lipoic acid-treated group (group 2), fisetin placebo group (group 3), α-lipoic acid placebo group (group 4). Fisetin and α-lipoic acid were administered intraperitoneally weekly for 5 weeks. Cataract development was assessed at the end of 8 weeks by slit lamp examination, and cataract formation was graded using a scale. All groups developed at least grade 1 cataract formation. In the fisetin-treated group, the cataract stages were significantly lower than in the placebo group (p = 0.02). In the α-lipoic acid-treated group, the cataract stages were lower than in the placebo group but it did not reach to a significant value. Both fisetin and α-lipoic acid had a protective effect on cataract development in a streptozotocin-induced experimental cataract model. The protective effect of fisetin appears as though more effective than α-lipoic acid.

  16. Early Retinal Neuronal Dysfunction in Diabetic Mice: Reduced Light-Evoked Inhibition Increases Rod Pathway Signaling

    PubMed Central

    Moore-Dotson, Johnnie M.; Beckman, Jamie J.; Mazade, Reece E.; Hoon, Mrinalini; Bernstein, Adam S.; Romero-Aleshire, Melissa J.; Brooks, Heddwen L.; Eggers, Erika D.

    2016-01-01

    Purpose Recent studies suggest that the neural retinal response to light is compromised in diabetes. Electroretinogram studies suggest that the dim light retinal rod pathway is especially susceptible to diabetic damage. The purpose of this study was to determine whether diabetes alters rod pathway signaling. Methods Diabetes was induced in C57BL/6J mice by three intraperitoneal injections of streptozotocin (STZ; 75 mg/kg), and confirmed by blood glucose levels > 200 mg/dL. Six weeks after the first injection, whole-cell voltage clamp recordings of spontaneous and light-evoked inhibitory postsynaptic currents from rod bipolar cells were made in dark-adapted retinal slices. Light-evoked excitatory currents from rod bipolar and AII amacrine cells, and spontaneous excitatory currents from AII amacrine cells were also measured. Receptor inputs were pharmacologically isolated. Immunohistochemistry was performed on whole mounted retinas. Results Rod bipolar cells had reduced light-evoked inhibitory input from amacrine cells but no change in excitatory input from rod photoreceptors. Reduced light-evoked inhibition, mediated by both GABAA and GABAC receptors, increased rod bipolar cell output onto AII amacrine cells. Spontaneous release of GABA onto rod bipolar cells was increased, which may limit GABA availability for light-evoked release. These physiological changes occurred in the absence of retinal cell loss or changes in GABAA receptor expression levels. Conclusions Our results indicate that early diabetes causes deficits in the rod pathway leading to decreased light-evoked rod bipolar cell inhibition and increased rod pathway output that provide a basis for the development of early diabetic visual deficits. PMID:27028063

  17. Haptoglobin genotype is a determinant of survival and cardiac remodeling after myocardial infarction in diabetic mice

    PubMed Central

    Asaf, Roy; Blum, Shany; Roguin, Ariel; Kalet-Litman, Shiri; Kheir, Jad; Frisch, Avi; Miller-Lotan, Rachel; Levy, Andrew P

    2009-01-01

    Background We have recently demonstrated in man that a functional allelic polymorphism in the Haptoglobin (Hp) gene plays a major role in determining survival and congestive heart failure after myocardial infarction (MI). We sought to recapitulate the effect of Hp type on outcomes and cardiac remodeling after MI in transgenic mice. Methods The Hp 2 allele exists only in man. Wild type C57Bl/6 mice carry the Hp 1 allele with high homology to the human Hp 1 allele. We genetically engineered a murine Hp 2 allele and targeted its insertion by homologous recombination to the murine Hp locus to create Hp 2 mice. Diabetes Mellitus (DM) was induced with streptozotocin. MI was produced by occlusion of the left anterior descending artery in DM C57Bl/6 mice carrying the Hp 1 or Hp 2 allele. MI size was determined with TTC staining. Left ventricular (LV) function and dimensions were assessed by 2-dimensional echocardiography. Results In the absence of DM, Hp 1-1 and Hp 2-2 mice had similar LV dimensions and LV function. MI size was similar in DM Hp 1-1 and 2-2 mice 24 hours after MI (50.2 ± 2.1%and 46.9 ± 5.5%, respectively, p = 0.6). However, DM Hp 1-1 mice had a significantly lower mortality rate than DM Hp 2-2 mice 30 days after MI (HR 0.41, 95% CI (0.19–0.95), p = 0.037 by log rank). LV chamber dimensions were significantly increased in DM Hp 2-2 mice compared to DM Hp 1-1 mice 30 days after MI (0.196 ± 0.01 cm2 vs. 0.163 ± 0.01 cm2, respectively; p = 0.029). Conclusion In DM mice the Hp 2-2 genotype is associated with increased mortality and more severe cardiac remodeling 30 days after MI. PMID:19490627

  18. Genetic ablation of lymphocytes and cytokine signaling in nonobese diabetic mice prevents diet-induced obesity and insulin resistance.

    PubMed

    Friedline, Randall H; Ko, Hwi Jin; Jung, Dae Young; Lee, Yongjin; Bortell, Rita; Dagdeviren, Sezin; Patel, Payal R; Hu, Xiaodi; Inashima, Kunikazu; Kearns, Caitlyn; Tsitsilianos, Nicholas; Shafiq, Umber; Shultz, Leonard D; Lee, Ki Won; Greiner, Dale L; Kim, Jason K

    2016-03-01

    Obesity is characterized by a dysregulated immune system, which may causally associate with insulin resistance and type 2 diabetes. Despite widespread use of nonobese diabetic (NOD) mice, NOD with severe combined immunodeficiency (scid) mutation (SCID) mice, and SCID bearing a null mutation in the IL-2 common γ chain receptor (NSG) mice as animal models of human diseases including type 1 diabetes, the underlying metabolic effects of a genetically altered immune system are poorly understood. For this, we performed a comprehensive metabolic characterization of these mice fed chow or after 6 wk of a high-fat diet. We found that NOD mice had ∼50% less fat mass and were 2-fold more insulin sensitive, as measured by hyperinsulinemic-euglycemic clamp, than C57BL/6 wild-type mice. SCID mice were also more insulin sensitive with increased muscle glucose metabolism and resistant to diet-induced obesity due to increased energy expenditure (∼10%) and physical activity (∼40%) as measured by metabolic cages. NSG mice were completely protected from diet-induced obesity and insulin resistance with significant increases in glucose metabolism in peripheral organs. Our findings demonstrate an important role of genetic background, lymphocytes, and cytokine signaling in diet-induced obesity and insulin resistance.

  19. Spironolactone treatment attenuates vascular dysfunction in type 2 diabetic mice by decreasing oxidative stress and restoring NO/GC signaling

    PubMed Central

    Silva, Marcondes A. B.; Bruder-Nascimento, Thiago; Cau, Stefany B. A.; Lopes, Rheure A. M.; Mestriner, Fabiola L. A. C.; Fais, Rafael S.; Touyz, Rhian M.; Tostes, Rita C.

    2015-01-01

    Type 2 diabetes (DM2) increases the risk of cardiovascular disease. Aldosterone, which has pro-oxidative and pro-inflammatory effects in the cardiovascular system, is positively regulated in DM2. We assessed whether blockade of mineralocorticoid receptors (MR) with spironolactone decreases reactive oxygen species (ROS)-associated vascular dysfunction and improves vascular nitric oxide (NO) signaling in diabetes. Leptin receptor knockout [LepRdb/LepRdb (db/db)] mice, a model of DM2, and their counterpart controls [LepRdb/LepR+, (db/+) mice] received spironolactone (50 mg/kg body weight/day) or vehicle (ethanol 1%) via oral per gavage for 6 weeks. Spironolactone treatment abolished endothelial dysfunction and increased endothelial nitric oxide synthase (eNOS) phosphorylation (Ser1177) in arteries from db/db mice, determined by acetylcholine-induced relaxation and Western Blot analysis, respectively. MR antagonist therapy also abrogated augmented ROS-generation in aorta from diabetic mice, determined by lucigenin luminescence assay. Spironolactone treatment increased superoxide dismutase-1 and catalase expression, improved sodium nitroprusside and BAY 41-2272-induced relaxation, and increased soluble guanylyl cyclase (sGC) β subunit expression in arteries from db/db mice. Our results demonstrate that spironolactone decreases diabetes-associated vascular oxidative stress and prevents vascular dysfunction through processes involving increased expression of antioxidant enzymes and sGC. These findings further elucidate redox-sensitive mechanisms whereby spironolactone protects against vascular injury in diabetes. PMID:26500555

  20. Alleviation of streptozotocin-induced diabetes in nude mice by stem cells derived from human first trimester umbilical cord.

    PubMed

    Cao, M; Zhang, J B; Dong, D D; Mou, Y; Li, K; Fang, J; Wang, Z Y; Chen, C; Zhao, J; Yie, S M

    2015-10-16

    Cells isolated from human first trimester umbilical cord perivascular layer (hFTM-PV) tissues display the pluripotent characteristics of stem cells. In this study, we examined whether hFTM-PV cells can differentiate into islet-like clusters (ILCs) in vitro, and whether transplantation of the hFTM-PV cells with and without differentiation in vitro can alleviate diabetes in nude mice. The hFTM-PV cells were differentiated into ILCs in vitro through a simple stepwise culture protocol. To examine the in vivo effects of the cells, the hFTM-PV cells with and without differentiation in vitro were transplanted into the abdominal cavity of nude mice with streptozotocin (STZ)-induced diabetes. Blood glucose levels, body weight, and the survival probability of the diabetic nude mice were then statistically analyzed. The hFTM-PV cells were successfully induced into ILCs that could release insulin in response to elevated concentrations of glucose in vitro. In transplantation experiments, we observed that mice transplanted with the undifferentiated hFTM-PV cells, embryonic body-like cell aggregations, or ILCs all demonstrated normalized hyperglycemia and showed improved survival rate compared with those without cell transplantation. The hFTM-PV cells have the ability to differentiate into ILCs in vitro and transplantations of undifferentiated and differentiated cells can alleviate STZ-induced diabetes in nude mice. This may offer a potential cell source for stem cell-based therapy for treating diabetes in the future.

  1. Xenogenic transplantation of human breast adipose-derived stromal vascular fraction enhances recovery of erectile function in diabetic mice.

    PubMed

    Das, Nando Dulal; Song, Kang-Moon; Yin, Guo Nan; Batbold, Dulguun; Kwon, Mi-Hye; Kwon, Ki-Dong; Kim, Woo Jean; Kim, Yeon Soo; Ryu, Ji-Kan; Suh, Jun-Kyu

    2014-03-01

    The adipose tissue-derived stromal vascular fraction (SVF) is an ideal source of stem and stromal cells. The aim of this study was to examine whether and how xenogenic transplantation of human breast SVF restores erectile function in diabetic mice. Human SVF was isolated from five patients (age, 20-45 yr) undergoing reduction mammoplasty. Eight-week-old C57BL/6J mice were used, and diabetes was induced by intraperitoneal injection of streptozotocin. At 8 wk after induction of diabetes, the animals were randomly distributed into controls and diabetic mice treated with a single intracavernous injection of PBS, human SVF at different concentrations, or human SVF lysate. Two weeks later, erectile function was measured by cavernous nerve stimulation, and the penis was then harvested for biochemical examinations. Erectile function was significantly improved in diabetic mice treated with human SVF (2 × 10(5), 5 × 10(5), and 1 × 10(6) cells/20 μl) and SVF lysate. Human SVF treatment in diabetic mice significantly increased cavernous endothelial and smooth muscle cell contents, induced eNOS phosphorylation, and restored penile nNOS-positive nerve fibers. Human SVF lysate induced secretion of angiogenic factors and expression of their receptors. Human SVF did not increase serum levels of proinflammatory cytokines. A limitation of this study was that the exact composition of the human SVF was not examined. In summary, xenogenic transplantation of human SVF did not induce systemic inflammation and successfully improved erectile function in diabetic mice through enhanced penile angiogenesis and neural regeneration.

  2. Attenuation of atherosclerotic lesions in diabetic apolipoprotein E-deficient mice using gene silencing of macrophage migration inhibitory factor

    PubMed Central

    Sun, Hui; Zhang, XianJun; Zhao, Lei; Zhen, Xi; Huang, ShanYing; Wang, ShaSha; He, Hong; Liu, ZiMo; Xu, NaNa; Yang, FaLin; Qu, ZhongHua; Ma, ZhiYong; Zhang, Cheng; Zhang, Yun; Hu, Qin

    2015-01-01

    Macrophage migration inhibitory factor (MIF) involves the pathogenesis of atherosclerosis (AS) and increased plasma MIF levels in diabetes mellitus (DM) patients are associated with AS. Here, we have been suggested that MIF could be a critical contributor for the pathological process of diabetes-associated AS by using adenovirus-mediated RNA interference. First, streptozotocin (STZ)-induced diabetic animal model was constructed in 114 apolipoprotein E-deficient mice (apoE−/− mice) fed on a regular chow diet. Then, the animals were randomly divided into three groups: Adenovirus-mediated MIF interference (Ad-MIFi), Ad-enhanced green fluorescent protein (EGFP) and normal saline (NS) group (n ≈ 33/group). Non-diabetic apoE−/− mice (n = 35) were served as controls. Ad-MIFi, Ad-EGFP and NS were, respectively, injected into the tail vein of mice from Ad-MIFi, Ad-EGFP and NS group, which were injected repeatedly 4 weeks later. Physical, biochemical, morphological and molecular parameters were measured. The results showed that diabetic apoE−/− mice had significantly aggravated atherosclerotic lesions. MIF gene interference attenuated atherosclerotic lesions and stabilized atheromatous plaque, accompanied by the decreased macrophages and lipids deposition and inflammatory cytokines production, improved glucose intolerance and plasma cholesterol level, the decreased ratio of matrix matalloproteinase-2/tissue inhibitor of metalloproteinase-1 and plaque instability index. An increased expression of MIF and its ligand CD74 was also detected in the diabetic patients with coronary artery disease. The results suggest that MIF gene interference is able to inhibit atherosclerotic lesions and increase plaque stability in diabetic apoE−/−mice. MIF inhibition could be a novel and promising approach to the treatment of DM-associated AS. PMID:25661015

  3. SGLT2 inhibitor therapy improves blood glucose but does not prevent diabetic bone disease in diabetic DBA/2J male mice.

    PubMed

    Thrailkill, Kathryn M; Clay Bunn, R; Nyman, Jeffry S; Rettiganti, Mallikarjuna R; Cockrell, Gael E; Wahl, Elizabeth C; Uppuganti, Sasidhar; Lumpkin, Charles K; Fowlkes, John L

    2016-01-01

    Persons with type 1 and type 2 diabetes have increased fracture risk, attributed to deficits in the microarchitecture and strength of diabetic bone, thought to be mediated, in part, by the consequences of chronic hyperglycemia. Therefore, to examine the effects of a glucose-lowering SGLT2 inhibitor on blood glucose (BG) and bone homeostasis in a model of diabetic bone disease, male DBA/2J mice with or without streptozotocin (STZ)-induced hyperglycemia were fed chow containing the SGLT2 inhibitor, canagliflozin (CANA), or chow without drug, for 10weeks of therapy. Thereafter, serum bone biomarkers were measured, fracture resistance of cortical bone was assessed by μCT analysis and a three-point bending test of the femur, and vertebral bone strength was determined by compression testing. In the femur metaphysis and L6 vertebra, long-term diabetes (DM) induced deficits in trabecular bone microarchitecture. In the femur diaphysis, a decrease in cortical bone area, cortical thickness and minimal moment of inertia occurred in DM (p<0.0001, for all) while cortical porosity was increased (p<0.0001). These DM changes were associated with reduced fracture resistance (decreased material strength and toughness; decreased structural strength and rigidity; p<0.001 for all). Significant increases in PTH (p<0.0001), RatLAPs (p=0.0002), and urine calcium concentration (p<0.0001) were also seen in DM. Canagliflozin treatment improved BG in DM mice by ~35%, but did not improve microarchitectural parameters. Instead, in canagliflozin-treated diabetic mice, a further increase in RatLAPs was evident, possibly suggesting a drug-related intensification of bone resorption. Additionally, detrimental metaphyseal changes were noted in canagliflozin-treated control mice. Hence, diabetic bone disease was not favorably affected by canagliflozin treatment, perhaps due to insufficient glycemic improvement. Instead, in control mice, long-term exposure to SGLT2 inhibition was associated with

  4. Urtica dioica extract attenuates depressive like behavior and associative memory dysfunction in dexamethasone induced diabetic mice.

    PubMed

    Patel, Sita Sharan; Udayabanu, Malairaman

    2014-03-01

    Evidences suggest that glucocorticoids results in depression and is a risk factor for type 2 diabetes. Further diabetes induces oxidative stress and hippocampal dysfunction resulting in cognitive decline. Traditionally Urtica dioica has been used for diabetes mellitus and cognitive dysfunction. The present study investigated the effect of the hydroalcoholic extract of Urtica dioica leaves (50 and 100 mg/kg, p.o.) in dexamethasone (1 mg/kg, i.m.) induced diabetes and its associated complications such as depressive like behavior and cognitive dysfunction. We observed that mice administered with chronic dexamethasone resulted in hypercortisolemia, oxidative stress, depressive like behavior, cognitive impairment, hyperglycemia with reduced body weight, increased water intake and decreased hippocampal glucose transporter-4 (GLUT4) mRNA expression. Urtica dioica significantly reduced hyperglycemia, plasma corticosterone, oxidative stress and depressive like behavior as well as improved associative memory and hippocampal GLUT4 mRNA expression comparable to rosiglitazone (5 mg/kg, p.o.). Further, Urtica dioica insignificantly improved spatial memory and serum insulin. In conclusion, Urtica dioica reversed dexamethasone induced hyperglycemia and its associated complications such as depressive like behavior and cognitive dysfunction. PMID:24435938

  5. Protective Effects of Berberine on Renal Injury in Streptozotocin (STZ)-Induced Diabetic Mice

    PubMed Central

    Zhang, Xiuli; He, Hui; Liang, Dan; Jiang, Yan; Liang, Wei; Chi, Zhi-Hong; Ma, Jianfei

    2016-01-01

    Diabetic nephropathy (DN) is a serious diabetic complication with renal hypertrophy and expansion of extracellular matrices in renal fibrosis. Epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells may be involved in the main mechanism. Berberine (BBR) has been shown to have antifibrotic effects in liver, kidney and lung. However, the mechanism of cytoprotective effects of BBR in DN is still unclear. In this study, we investigated the curative effects of BBR on tubulointerstitial fibrosis in streptozotocin (STZ)-induced diabetic mice and the high glucose (HG)-induced EMT in NRK 52E cells. We found that BBR treatment attenuated renal fibrosis by activating the nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway in the diabetic kidneys. Further revealed that BBR abrogated HG-induced EMT and oxidative stress in relation not only with the activation of Nrf2 and two Nrf2-targeted antioxidative genes (NQO-1 and HO-1), but also with the suppressing the activation of TGF-β/Smad signaling pathway. Importantly, knockdown Nrf2 with siRNA not only abolished the BBR-induced expression of HO-1 and NQO-1 but also removed the inhibitory effect of BBR on HG-induced activation of TGF-β/Smad signaling as well as the anti-fibrosis effects. The data from present study suggest that BBR can ameliorate tubulointerstitial fibrosis in DN by activating Nrf2 pathway and inhibiting TGF-β/Smad/EMT signaling activity. PMID:27529235

  6. Urtica dioica extract attenuates depressive like behavior and associative memory dysfunction in dexamethasone induced diabetic mice.

    PubMed

    Patel, Sita Sharan; Udayabanu, Malairaman

    2014-03-01

    Evidences suggest that glucocorticoids results in depression and is a risk factor for type 2 diabetes. Further diabetes induces oxidative stress and hippocampal dysfunction resulting in cognitive decline. Traditionally Urtica dioica has been used for diabetes mellitus and cognitive dysfunction. The present study investigated the effect of the hydroalcoholic extract of Urtica dioica leaves (50 and 100 mg/kg, p.o.) in dexamethasone (1 mg/kg, i.m.) induced diabetes and its associated complications such as depressive like behavior and cognitive dysfunction. We observed that mice administered with chronic dexamethasone resulted in hypercortisolemia, oxidative stress, depressive like behavior, cognitive impairment, hyperglycemia with reduced body weight, increased water intake and decreased hippocampal glucose transporter-4 (GLUT4) mRNA expression. Urtica dioica significantly reduced hyperglycemia, plasma corticosterone, oxidative stress and depressive like behavior as well as improved associative memory and hippocampal GLUT4 mRNA expression comparable to rosiglitazone (5 mg/kg, p.o.). Further, Urtica dioica insignificantly improved spatial memory and serum insulin. In conclusion, Urtica dioica reversed dexamethasone induced hyperglycemia and its associated complications such as depressive like behavior and cognitive dysfunction.

  7. Protective Effects of Berberine on Renal Injury in Streptozotocin (STZ)-Induced Diabetic Mice.

    PubMed

    Zhang, Xiuli; He, Hui; Liang, Dan; Jiang, Yan; Liang, Wei; Chi, Zhi-Hong; Ma, Jianfei

    2016-01-01

    Diabetic nephropathy (DN) is a serious diabetic complication with renal hypertrophy and expansion of extracellular matrices in renal fibrosis. Epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells may be involved in the main mechanism. Berberine (BBR) has been shown to have antifibrotic effects in liver, kidney and lung. However, the mechanism of cytoprotective effects of BBR in DN is still unclear. In this study, we investigated the curative effects of BBR on tubulointerstitial fibrosis in streptozotocin (STZ)-induced diabetic mice and the high glucose (HG)-induced EMT in NRK 52E cells. We found that BBR treatment attenuated renal fibrosis by activating the nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway in the diabetic kidneys. Further revealed that BBR abrogated HG-induced EMT and oxidative stress in relation not only with the activation of Nrf2 and two Nrf2-targeted antioxidative genes (NQO-1 and HO-1), but also with the suppressing the activation of TGF-β/Smad signaling pathway. Importantly, knockdown Nrf2 with siRNA not only abolished the BBR-induced expression of HO-1 and NQO-1 but also removed the inhibitory effect of BBR on HG-induced activation of TGF-β/Smad signaling as well as the anti-fibrosis effects. The data from present study suggest that BBR can ameliorate tubulointerstitial fibrosis in DN by activating Nrf2 pathway and inhibiting TGF-β/Smad/EMT signaling activity. PMID:27529235

  8. Low-Dose Radiation Activates Akt and Nrf2 in the Kidney of Diabetic Mice: A Potential Mechanism to Prevent Diabetic Nephropathy

    PubMed Central

    Xing, Xiao; Zhang, Chi; Shao, Minglong; Tong, Qingyue; Zhang, Guirong; Li, Cai; Cheng, Jie; Jin, Shunzi; Ma, Jisheng; Wang, Guanjun; Li, Xiaokun; Cai, Lu

    2012-01-01

    Repetitive exposure of diabetic mice to low-dose radiation (LDR) at 25 mGy could significantly attenuate diabetes-induced renal inflammation, oxidative damage, remodeling, and dysfunction, for which, however, the underlying mechanism remained unknown. The present study explored the effects of LDR on the expression and function of Akt and Nrf2 in the kidney of diabetic mice. C57BL/6J mice were used to induce type 1 diabetes with multiple low-dose streptozotocin. Diabetic and age-matched control mice were irradiated with whole body X-rays at either single 25 mGy and 75 mGy or accumulated 75 mGy (25 mGy daily for 3 days) and then sacrificed at 1–12 h for examining renal Akt phosphorylation and Nrf2 expression and function. We found that 75 mGy of X-rays can stimulate Akt signaling pathway and upregulate Nrf2 expression and function in diabetic kidneys; single exposure of 25 mGy did not, but three exposures to 25 mGy of X-rays could offer a similar effect as single exposure to 75 mGy on the stimulation of Akt phosphorylation and the upregulation of Nrf2 expression and transcription function. These results suggest that single 75 mGy or multiple 25 mGy of X-rays can stimulate Akt phosphorylation and upregulate Nrf2 expression and function, which may explain the prevention of LDR against the diabetic nephropathy mentioned above. PMID:23227273

  9. Diabetes-induced loss of gastric ICC accompanied by up-regulation of natriuretic peptide signaling pathways in STZ-induced diabetic mice.

    PubMed

    Wu, Yi-Song; Lu, Hong-Li; Huang, Xu; Liu, Dong-Hai; Meng, Xiang-Min; Guo, Xin; Kim, Young-chul; Xu, Wen-Xie

    2013-02-01

    Our previous study demonstrated that natriuretic peptides (NPs) play an inhibitory role in regulation of gastric smooth muscle motility. However, it is not clear whether NPs are involved in diabetics-induced loss of gastric interstitial cell of Cajal (ICC). The present study was designed to investigate the relationship between diabetics-induced loss of gastric ICC and natriuretic peptide signaling pathway in streptozotocin (STZ)-induced diabetic mice. The results showed that the protein expression levels of c-Kit and membrane-bound stem cell factor (mSCF) in gastric smooth muscle layers were decreased in STZ-induced diabetic mice. However, both mRNA and protein expression levels of natriuretic peptide receptor (NPR)-A, B and C were increased in the same place of the diabetic mice. The amplitude of spontaneous contraction in gastric antral smooth muscles was inhibited by C-type natriuretic peptide (CNP) dose-dependently and the inhibitory effect was potentiated in diabetic mice. Pretreatment of the cultured gastric smooth muscle cells (GSMCs) with different concentration of CNP can significantly decrease the mSCF expression level. 8-Bromoguanosine-3',5'-cyclomo-nophosphate (8-Br-cGMP), a membrane permeable cGMP analog, mimicked the effect of CNP but not cANF (a specific NPR-C agonist). Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay showed that high concentration of cANF (10(-6) mol/L) inhibited cell proliferation in cultured GSMCs. These findings suggest that up-regulation of NPs/NPR-A, B/cGMP and NPs/NPR-C signaling pathways may be involved in diabetes-induced loss of gastric ICC.

  10. Ganglioside GM3 synthase depletion reverses neuropathic pain and small fiber neuropathy in diet-induced diabetic mice

    PubMed Central

    Jayaraj, Nirupa D; Wilson, Heather M; Ren, Dongjun; Flood, Kelsey; Wang, Xiao-Qi; Shum, Andrew; Miller, Richard J; Paller, Amy S

    2016-01-01

    Background Small fiber neuropathy is a well-recognized complication of type 2 diabetes and has been shown to be responsible for both neuropathic pain and impaired wound healing. In previous studies, we have demonstrated that ganglioside GM3 depletion by knockdown of GM3 synthase fully reverses impaired wound healing in diabetic mice. However, the role of GM3 in neuropathic pain and small fiber neuropathy in diabetes is unknown. Purpose Determine whether GM3 depletion is able to reverse neuropathic pain and small fibers neuropathy and the mechanism of the reversal. Results We demonstrate that GM3 synthase knockout and the resultant GM3 depletion rescues the denervation in mouse footpad skin and fully reverses the neuropathic pain in diet-induced obese diabetic mice. In cultured dorsal root ganglia from diet-induced diabetic mice, GM3 depletion protects against increased intracellular calcium influx in vitro. Conclusions These studies establish ganglioside GM3 as a new candidate responsible for neuropathic pain and small fiber neuropathy in diabetes. Moreover, these observations indicate that systemic or topically applied interventions aimed at depleting GM3 may improve both the painful neuropathy and the wound healing impairment in diabetes by protecting against nerve end terminal degeneration, providing a disease-modifying approach to this common, currently intractable medical issue. PMID:27590073

  11. Effect of diet-induced obesity or type 1 or type 2 diabetes on corneal nerves and peripheral neuropathy in C57Bl/6J mice.

    PubMed

    Yorek, Matthew S; Obrosov, Alexander; Shevalye, Hanna; Holmes, Amey; Harper, Matthew M; Kardon, Randy H; Yorek, Mark A

    2015-03-01

    We determined the impact diet-induced obesity (DIO) and types 1 and 2 diabetes have on peripheral neuropathy with emphasis on corneal nerve structural changes in C57Bl/6J mice. Endpoints examined included nerve conduction velocity, response to thermal and mechanical stimuli and innervation of the skin and cornea. DIO mice and to a greater extent type 2 diabetic mice were insulin resistant. DIO and both types 1 and 2 diabetic mice developed motor and sensory nerve conduction deficits. In the cornea of DIO and type 2 diabetic mice there was a decrease in sub-epithelial corneal nerves, innervation of the corneal epithelium, and corneal sensitivity. Type 1 diabetic mice did not present with any significant changes in corneal nerve structure until after 20 weeks of hyperglycemia. DIO and type 2 diabetic mice developed corneal structural damage more rapidly than type 1 diabetic mice although hemoglobin A1 C values were significantly higher in type 1 diabetic mice. This suggests that DIO with or without hyperglycemia contributes to development and progression of peripheral neuropathy and nerve structural damage in the cornea.

  12. Toll-Like Receptor 3 Is Critical for Coxsackievirus B4-Induced Type 1 Diabetes in Female NOD Mice

    PubMed Central

    Thuma, Jean R.; Courreges, Maria C.; Benencia, Fabian; James, Calvin B.L.; Malgor, Ramiro; Kantake, Noriko; Mudd, William; Denlinger, Nathan; Nolan, Bret; Wen, Li; Schwartz, Frank L.

    2015-01-01

    Group B coxsackieviruses (CVBs) are involved in triggering some cases of type 1 diabetes mellitus (T1DM). However, the molecular mechanism(s) responsible for this remain elusive. Toll-like receptor 3 (TLR3), a receptor that recognizes viral double-stranded RNA, is hypothesized to play a role in virus-induced T1DM, although this hypothesis is yet to be substantiated. The objective of this study was to directly investigate the role of TLR3 in CVB-triggered T1DM in nonobese diabetic (NOD) mice, a mouse model of human T1DM that is widely used to study both spontaneous autoimmune and viral-induced T1DM. As such, we infected female wild-type (TLR3+/+) and TLR3 knockout (TLR3−/−) NOD mice with CVB4 and compared the incidence of diabetes in CVB4-infected mice with that of uninfected counterparts. We also evaluated the islets of uninfected and CVB4-infected wild-type and TLR3 knockout NOD mice by immunohistochemistry and insulitis scoring. TLR3 knockout mice were markedly protected from CVB4-induced diabetes compared with CVB4-infected wild-type mice. CVB4-induced T-lymphocyte-mediated insulitis was also significantly less severe in TLR3 knockout mice compared with wild-type mice. No differences in insulitis were observed between uninfected animals, either wild-type or TLR3 knockout mice. These data demonstrate for the first time that TLR3 is 1) critical for CVB4-induced T1DM, and 2) modulates CVB4-induced insulitis in genetically prone NOD mice. PMID:25422874

  13. Food restriction by intermittent fasting induces diabetes and obesity and aggravates spontaneous atherosclerosis development in hypercholesterolaemic mice.

    PubMed

    Dorighello, Gabriel G; Rovani, Juliana C; Luhman, Christopher J F; Paim, Bruno A; Raposo, Helena F; Vercesi, Anibal E; Oliveira, Helena C F

    2014-03-28

    Different regimens of food restriction have been associated with protection against obesity, diabetes and CVD. In the present study, we hypothesised that food restriction would bring benefits to atherosclerosis- and diabetes-prone hypercholesterolaemic LDL-receptor knockout mice. For this purpose, 2-month-old mice were submitted to an intermittent fasting (IF) regimen (fasting every other day) over a 3-month period, which resulted in an overall 20 % reduction in food intake. Contrary to our expectation, epididymal and carcass fat depots and adipocyte size were significantly enlarged by 15, 72 and 68 %, respectively, in the IF mice compared with the ad libitum-fed mice. Accordingly, plasma levels of leptin were 50 % higher in the IF mice than in the ad libitum-fed mice. In addition, the IF mice showed increased plasma levels of total cholesterol (37 %), VLDL-cholesterol (195 %) and LDL-cholesterol (50 %). As expected, in wild-type mice, the IF regimen decreased plasma cholesterol levels and epididymal fat mass. Glucose homeostasis was also disturbed by the IF regimen in LDL-receptor knockout mice. Elevated levels of glycaemia (40 %), insulinaemia (50 %), glucose intolerance and insulin resistance were observed in the IF mice. Systemic inflammatory markers, TNF-α and C-reactive protein, were significantly increased and spontaneous atherosclerosis development were markedly increased (3-fold) in the IF mice. In conclusion, the IF regimen induced obesity and diabetes and worsened the development of spontaneous atherosclerosis in LDL-receptor knockout mice. Although being efficient in a wild-type background, this type of food restriction is not beneficial in the context of genetic hypercholesterolaemia.

  14. Food restriction by intermittent fasting induces diabetes and obesity and aggravates spontaneous atherosclerosis development in hypercholesterolaemic mice.

    PubMed

    Dorighello, Gabriel G; Rovani, Juliana C; Luhman, Christopher J F; Paim, Bruno A; Raposo, Helena F; Vercesi, Anibal E; Oliveira, Helena C F

    2014-03-28

    Different regimens of food restriction have been associated with protection against obesity, diabetes and CVD. In the present study, we hypothesised that food restriction would bring benefits to atherosclerosis- and diabetes-prone hypercholesterolaemic LDL-receptor knockout mice. For this purpose, 2-month-old mice were submitted to an intermittent fasting (IF) regimen (fasting every other day) over a 3-month period, which resulted in an overall 20 % reduction in food intake. Contrary to our expectation, epididymal and carcass fat depots and adipocyte size were significantly enlarged by 15, 72 and 68 %, respectively, in the IF mice compared with the ad libitum-fed mice. Accordingly, plasma levels of leptin were 50 % higher in the IF mice than in the ad libitum-fed mice. In addition, the IF mice showed increased plasma levels of total cholesterol (37 %), VLDL-cholesterol (195 %) and LDL-cholesterol (50 %). As expected, in wild-type mice, the IF regimen decreased plasma cholesterol levels and epididymal fat mass. Glucose homeostasis was also disturbed by the IF regimen in LDL-receptor knockout mice. Elevated levels of glycaemia (40 %), insulinaemia (50 %), glucose intolerance and insulin resistance were observed in the IF mice. Systemic inflammatory markers, TNF-α and C-reactive protein, were significantly increased and spontaneous atherosclerosis development were markedly increased (3-fold) in the IF mice. In conclusion, the IF regimen induced obesity and diabetes and worsened the development of spontaneous atherosclerosis in LDL-receptor knockout mice. Although being efficient in a wild-type background, this type of food restriction is not beneficial in the context of genetic hypercholesterolaemia. PMID:24176004

  15. Probucol inhibited Nox2 expression and attenuated podocyte injury in type 2 diabetic nephropathy of db/db mice.

    PubMed

    Zhou, Guangyu; Wang, Yanqiu; He, Ping; Li, Detian

    2013-01-01

    The present study was conducted to investigate the effects of probucol on the progression of diabetic nephropathy and the underlying mechanism in type 2 diabetic db/db mice. Eight weeks db/db mice were treated with regular diet or probucol-containing diet (1%) for 12 weeks. Non-diabetic db/m mice were used as controls. We examined body weight, blood glucose, and urinary albumin. At 20 weeks, experimental mice were sacrificed and their blood and kidneys were extracted for the analysis of blood chemistry, kidney histology, oxidative stress marker, and podocyte marker. As a result, 24 h urinary albumin excretions were reduced after probucol treatment. There were improvements of extracellular matrix accumulation and fibronectin and collagen IV deposition in glomeruli in the probucol-treated db/db mice. The reduction of nephrin and the loss of podocytes were effectively prevented by probucol in db/db mice. Furthermore, probucol significantly decreased the production of thiobarbituric acid-reactive substances (TBARS), an index of reactive oxygen species (ROS) generation and down-regulated the expression of Nox2. Taken together, our findings support that probucol may have the potential to protect against type 2 diabetic nephropathy via amelioration of podocyte injury and reduction of oxidative stress.

  16. Evaluation of Chios mastic gum on lipid and glucose metabolism in diabetic mice.

    PubMed

    Georgiadis, Ioannis; Karatzas, Theodore; Korou, Laskarina-Maria; Agrogiannis, George; Vlachos, Ioannis S; Pantopoulou, Alkisti; Tzanetakou, Irene P; Katsilambros, Nikolaos; Perrea, Despina N

    2014-03-01

    Chios mastic gum (MG), a resin produced from Pistacia lentiscus var. Chia, is reported to possess beneficial cardiovascular and hepatoprotective properties. This study investigated the effect of crude Chios MG on metabolic parameters in diabetic mice. Streptozotocin-induced diabetic 12-week-old male C57bl/6 mice were assigned to three groups: NC (n=9) control; LdM (n=9) animals receiving low dose mastic for 8 weeks (20 mg/kg body weight [BW]); and HdM (n=9) animals receiving high dose mastic (500 mg/kg BW) for the same period. Serum lipid and glucose levels were determined at baseline, at 4 and 8 weeks. Serum total protein, adiponectin, and resistin levels were also measured at the end of the experiment. Histopathological examination for liver, kidney, aorta, and heart lesions was performed. After 4 weeks, MG administration resulted in decreased serum glucose and triglyceride levels in both LdM and HdM, whereas BW levels were reduced in LdM group compared with controls. At the end of the experiment, LdM presented significantly lower serum glucose, cholesterol, low-density lipoprotein cholesterol, and triglyceride levels and improved high-density lipoprotein cholesterol levels compared with control group. HdM group had ameliorated serum triglyceride levels. Hepatic steatosis observed in control group was partially reversed in LdM and HdM groups. MG administered in low dosages improves glucose and lipid disturbances in diabetic mice while alleviating hepatic damage. PMID:24404977

  17. Perforin facilitates beta cell killing and regulates autoreactive CD8+ T-cell responses to antigen in mouse models of type 1 diabetes.

    PubMed

    Trivedi, Prerak; Graham, Kate L; Krishnamurthy, Balasubramaninan; Fynch, Stacey; Slattery, Robyn M; Kay, Thomas W H; Thomas, Helen E

    2016-04-01

    In type 1 diabetes, cytotoxic CD8(+) T lymphocytes (CTLs) directly interact with pancreatic beta cells through major histocompatibility complex class I. An immune synapse facilitates delivery of cytotoxic granules, comprised mainly of granzymes and perforin. Perforin deficiency protects the majority of non-obese diabetic (NOD) mice from autoimmune diabetes. Intriguingly perforin deficiency does not prevent diabetes in CD8(+) T-cell receptor transgenic NOD8.3 mice. We therefore investigated the importance of perforin-dependent killing via CTL-beta cell contact in autoimmune diabetes. Perforin-deficient CTL from NOD mice or from NOD8.3 mice were significantly less efficient at adoptive transfer of autoimmune diabetes into NODRag1(-/-) mice, confirming that perforin is essential to facilitate beta cell destruction. However, increasing the number of transferred in vitro-activated perforin-deficient 8.3 T cells reversed the phenotype and resulted in diabetes. Perforin-deficient NOD8.3 T cells were present in increased proportion in islets, and proliferated more in response to antigen in vivo indicating that perforin may regulate the activation of CTLs, possibly by controlling cytokine production. This was confirmed when we examined the requirement for direct interaction between beta cells and CD8(+) T cells in NOD8.3 mice, in which beta cells specifically lack major histocompatibility complex (MHC) class I through conditional deletion of β2-microglobulin. Although diabetes was significantly reduced, 40% of these mice developed diabetes, indicating that NOD8.3 T cells can kill beta cells in the absence of direct interaction. Our data indicate that although perforin delivery is the main mechanism that CTL use to destroy beta cells, they can employ alternative mechanisms to induce diabetes in a perforin-independent manner.

  18. Perforin facilitates beta cell killing and regulates autoreactive CD8+ T-cell responses to antigen in mouse models of type 1 diabetes.

    PubMed

    Trivedi, Prerak; Graham, Kate L; Krishnamurthy, Balasubramaninan; Fynch, Stacey; Slattery, Robyn M; Kay, Thomas W H; Thomas, Helen E

    2016-04-01

    In type 1 diabetes, cytotoxic CD8(+) T lymphocytes (CTLs) directly interact with pancreatic beta cells through major histocompatibility complex class I. An immune synapse facilitates delivery of cytotoxic granules, comprised mainly of granzymes and perforin. Perforin deficiency protects the majority of non-obese diabetic (NOD) mice from autoimmune diabetes. Intriguingly perforin deficiency does not prevent diabetes in CD8(+) T-cell receptor transgenic NOD8.3 mice. We therefore investigated the importance of perforin-dependent killing via CTL-beta cell contact in autoimmune diabetes. Perforin-deficient CTL from NOD mice or from NOD8.3 mice were significantly less efficient at adoptive transfer of autoimmune diabetes into NODRag1(-/-) mice, confirming that perforin is essential to facilitate beta cell destruction. However, increasing the number of transferred in vitro-activated perforin-deficient 8.3 T cells reversed the phenotype and resulted in diabetes. Perforin-deficient NOD8.3 T cells were present in increased proportion in islets, and proliferated more in response to antigen in vivo indicating that perforin may regulate the activation of CTLs, possibly by controlling cytokine production. This was confirmed when we examined the requirement for direct interaction between beta cells and CD8(+) T cells in NOD8.3 mice, in which beta cells specifically lack major histocompatibility complex (MHC) class I through conditional deletion of β2-microglobulin. Although diabetes was significantly reduced, 40% of these mice developed diabetes, indicating that NOD8.3 T cells can kill beta cells in the absence of direct interaction. Our data indicate that although perforin delivery is the main mechanism that CTL use to destroy beta cells, they can employ alternative mechanisms to induce diabetes in a perforin-independent manner. PMID:26446877

  19. Curcumin ameliorates autoimmune diabetes. Evidence in accelerated murine models of type 1 diabetes

    PubMed Central

    Castro, C N; Barcala Tabarrozzi, A E; Winnewisser, J; Gimeno, M L; Antunica Noguerol, M; Liberman, A C; Paz, D A; Dewey, R A; Perone, M J

    2014-01-01

    Type 1 diabetes (T1DM) is a T cell-mediated autoimmune disease that selectively destroys pancreatic β cells. The only possible cure for T1DM is to control autoimmunity against β cell-specific antigens. We explored whether the natural compound curcumin, with anti-oxidant and anti-inflammatory activities, might down-regulate the T cell response that destroys pancreatic β cells to improve disease outcome in autoimmune diabetes. We employed two accelerated autoimmune diabetes models: (i) cyclophosphamide (CYP) administration to non-obese diabetic (NOD) mice and (ii) adoptive transfer of diabetogenic splenocytes into NODscid mice. Curcumin treatment led to significant delay of disease onset, and in some instances prevented autoimmune diabetes by inhibiting pancreatic leucocyte infiltration and preserving insulin-expressing cells. To investigate the mechanisms of protection we studied the effect of curcumin on key immune cell populations involved in the pathogenesis of the disease. Curcumin modulates the T lymphocyte response impairing proliferation and interferon (IFN)-γ production through modulation of T-box expressed in T cells (T-bet), a key transcription factor for proinflammatory T helper type 1 (Th1) lymphocyte differentiation, both at the transcriptional and translational levels. Also, curcumin reduces nuclear factor (NF)-κB activation in T cell receptor (TCR)-stimulated NOD lymphocytes. In addition, curcumin impairs the T cell stimulatory function of dendritic cells with reduced secretion of proinflammatory cytokines and nitric oxide (NO) and low surface expression of co-stimulatory molecules, leading to an overall diminished antigen-presenting cell activity. These in-vitro effects correlated with ex-vivo analysis of cells obtained from curcumin-treated mice during the course of autoimmune diabetes. These findings reveal an effective therapeutic effect of curcumin in autoimmune diabetes by its actions on key immune cells responsible for β cell death. PMID

  20. Ameliorative effect of dietary genistein on diabetes induced hyper-inflammation and oxidative stress during early stage of wound healing in alloxan induced diabetic mice.

    PubMed

    Eo, Hyeyoon; Lee, Hea-Ji; Lim, Yunsook

    2016-09-23

    Among the diabetic complications, diabetic foot ulcer due to delayed wound healing is one of the most significant clinical problems. Early inflammatory stage is important for better prognosis during wound healing. Thus, regulation of inflammatory response during early stage of wound healing is main target for complete cutaneous recovery. This study investigated the role of genistein supplementation in inflammation and oxidative stress, which are related to NLRP3 inflammasome, NFκB and Nrf2 activation, during cutaneous wound healing in alloxan-induced diabetic mice. Mice with diabetes with fasting blood glucose (FBG) levels > 250 mg/dl were fed diets with AIN-93G rodent diet containing 0%, 0.025% (LG) or 0.1% (HG) genistein. After 2 weeks of genistein supplementation, excisional wounds were made by biopsy punches (4 mm). Genistein supplementation improved fasting glucose levels and wound closure rate. Moreover, genistein supplementation restored NLRP3 inflammasome (NLRP3, ASC and caspase-1) at the basal level and ameliorated both inflammation (TNFα, iNOS, COX2 and NFκB) and antioxidant defense system (Nrf2, HO-1, GPx, and catalase) during early stage of wound healing in diabetic mice. Taken together, genistein supplementation would be a potential therapeutic nutrient in prevention and treatment of delayed wound healing by modulation of inflammation and oxidative stress during inflammatory stage.

  1. Recovery from diabetes in neonatal mice after a low-dose streptozotocin treatment

    SciTech Connect

    Kataoka, Masateru; Kawamuro, Yuki; Shiraki, Nobuaki; Miki, Rika; Sakano, Daisuke; Yoshida, Tetsu; Yasukawa, Takanori; Kume, Kazuhiko; Kume, Shoen

    2013-01-18

    Highlights: ► We monitored long-term beta cell regeneration in neonatal mice treated with low dose STZ. ► Low-dose STZ neonatal female mice recovered blood glucose in 150 days. ► Glucose intolerance of the STZ treated mice significantly improved in 150 days. -- Abstract: Administration of streptozotocin (STZ) induces destruction of β-cells and is widely used as an experimental animal model of type I diabetes. In neonatal rat, after low-doses of STZ-mediated destruction of β-cells, β-cells regeneration occurs and reversal of hyperglycemia was observed. However, in neonatal mice, β-cell regeneration seems to occur much slowly compared to that observed in the rat. Here, we described the time dependent quantitative changes in β-cell mass during a spontaneous slow recovery of diabetes induced in a low-dose STZ mice model. We then investigated the underlying mechanisms and analyzed the cell source for the recovery of β-cells. We showed here that postnatal day 7 (P7) female mice treated with 50 mg/kg STZ underwent the destruction of a large proportion of β-cells and developed hyperglycemia. The blood glucose increased gradually and reached a peak level at 500 mg/dl on day 35–50. This was followed by a spontaneous regeneration of β-cells. A reversal of non-fasting blood glucose to the control value was observed within 150 days. However, the mice still showed impaired glucose tolerance on day 150 and day 220, although a significant improvement was observed on day 150. Quantification of the β-cell mass revealed that the β-cell mass increased significantly between day 100 and day 150. On day 150 and day 220, the β-cell mass was approximately 23% and 48.5% of the control, respectively. Of the insulin-positive cells, 10% turned out to be PCNA-positive proliferating cells. Our results demonstrated that, β-cell duplication is one of the cell sources for β-cell regeneration.

  2. Effect of pregabalin on contextual memory deficits and inflammatory state-related protein expression in streptozotocin-induced diabetic mice.

    PubMed

    Sałat, Kinga; Gdula-Argasińska, Joanna; Malikowska, Natalia; Podkowa, Adrian; Lipkowska, Anna; Librowski, Tadeusz

    2016-06-01

    Diabetes mellitus is a metabolic disease characterized by hyperglycemia due to defects in insulin secretion or its action. Complications from long-term diabetes consist of numerous biochemical, molecular, and functional tissue alterations, including inflammation, oxidative stress, and neuropathic pain. There is also a link between diabetes mellitus and vascular dementia or Alzheimer's disease. Hence, it is important to treat diabetic complications using drugs which do not aggravate symptoms induced by the disease itself. Pregabalin is widely used for the treatment of diabetic neuropathic pain, but little is known about its impact on cognition or inflammation-related proteins in diabetic patients. Thus, this study aimed to evaluate the effect of intraperitoneal (ip) pregabalin on contextual memory and the expression of inflammatory state-related proteins in the brains of diabetic, streptozotocin (STZ)-treated mice. STZ (200 mg/kg, ip) was used to induce diabetes mellitus. To assess the impact of pregabalin (10 mg/kg) on contextual memory, a passive avoidance task was applied. Locomotor and exploratory activities in pregabalin-treated diabetic mice were assessed by using activity cages. Using Western blot analysis, the expression of cyclooxygenase-2 (COX-2), cytosolic prostaglandin E synthase (cPGES), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), nuclear factor-ĸB (NF-ĸB) p50 and p65, aryl hydrocarbon receptor (AhR), as well as glucose transporter type-4 (GLUT4) was assessed in mouse brains after pregabalin treatment. Pregabalin did not aggravate STZ-induced learning deficits in vivo or influence animals' locomotor activity. We observed significantly lower expression of COX-2, cPGES, and NF-κB p50 subunit, and higher expression of AhR and Nrf2 in the brains of pregabalin-treated mice in comparison to STZ-treated controls, which suggested immunomodulatory and anti-inflammatory effects of pregabalin. Antioxidant properties of pregabalin in the brains of

  3. Peer Victimization as a Predictor of Depression and Body Mass Index in Obese and Non-Obese Adolescents

    ERIC Educational Resources Information Center

    Adams, Ryan E.; Bukowski, William M.

    2008-01-01

    Background: The current study examined the pathway from peer victimization to depressive symptoms and body mass index (BMI) as mediated by self-concept for physical appearance in both obese and non-obese adolescents. It was thought that this pathway would be particularly important for obese adolescents because, compared to non-obese adolescents,…

  4. Plasma zinc status and membrane lipid composition in genetically diabetic mice (db/db)

    SciTech Connect

    Burke, J.P.; Fenton, M.R.

    1986-03-05

    Sex and age matched diabetic C57BL/Ks-db+/db+ mice (db/db) were sacrificed at eight weeks of age. Plasma samples were collected and zinc levels determined. Livers were excised and mitochondrial and microsomal membranes prepared. Aliquots of membrane fractions were subjected to lipid extraction and cholesterol (Cl), phospholipid (PL) and fatty acid analysis (FA) performed. Plasma zinc levels in db/db mice were elevated 25% compared to m/m controls (148.8+/-8.1 ..mu..g/dl vs. 118.9+/-14.9 ..mu..g/dl). Cholesterol and PL levels remained unchanged in both mitochondrial and microsomal membranes. Analysis of PL composition from db/db mitochondria by two dimensional thin layer chromatography revealed no change in the percentage of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) but a 40% decrease in cardiolipin. Slight increases were observed in the percentage of phosphatidylserine and phosphatidylinositol (PS+PI) in microsomes isolated from db/db mice. Fatty acid analysis of microsomal PC and PE showed a decrease of 28% in the 18:1/18:0 ratio as well as a 21% decrease in the ratio of 20:4/18:2 in db/db animals. Analysis of succinate dehydrogenase (mitochondrial) and glucose-6-phosphatase (microsomal) revealed significant decreases in activity in livers of db/db mice. The altered zinc metabolism as well as the changes in membrane lipid composition suggest that this may be a model to study the role of zinc in membrane structure.

  5. Systemic immune modulation induced by alcoholic beverage intake in obese-diabetes (db/db) mice.

    PubMed

    Lee, Hyunah; Jang, Ik-Soon; Park, Junsoo; Kim, Seol-Hee; Baek, So-Young; Go, Sung-Ho; Lee, Seung-Hoon

    2013-03-01

    Alcohol over-consumption is generally immunosuppressive. In this study, the effects of single or repetitive alcohol administration on the systemic immunity of db/db mice were observed to clarify the possible mechanisms for the increased susceptibility of obese individuals to alcohol-related immunological health problems. Alcohol (as a form of commercially available 20% distilled-alcoholic beverage) was orally administered one-time or seven times over 2 weeks to db/db mice and normal C57BL/6J mice. Immunologic alterations were analyzed by observation of body weight and animal activity, along with proportional changes of splenocytes for natural killer cells, macrophages, and T and B lymphocytes. Modulation of plasma cytokine level and immune-related genes were also ascertained by micro-bead assay and a microarray method, respectively. The immune micro-environment of db/db mice was an inflammatory state and adaptive cellular immunity was significantly suppressed. Low-dose alcohol administration reversed the immune response, decreasing inflammatory responses and the increment of adaptive immunity mainly related to CD4(+) T cells, but not CD8(+) T cells, to normal background levels. Systemic immune modulation due to alcohol administration in the obese-diabetic mouse model may be useful in the understanding of the induction mechanism, which will aid the development of therapeutics for related secondary diseases. PMID:23261674

  6. Lack of p47(phox) in Akita Diabetic Mice Is Associated with Interstitial Pneumonia, Fibrosis, and Oral Inflammation.

    PubMed

    Zamakhchari, Mai F; Sima, Corneliu; Sama, Kishore; Fine, Noah; Glogauer, Michael; Van Dyke, Thomas E; Gyurko, Robert

    2016-03-01

    Excess reactive oxygen species production is central to the development of diabetic complications. The contribution of leukocyte reactive oxygen species produced by the NADPH oxidase to altered inflammatory responses associated with uncontrolled hyperglycemia is poorly understood. To get insight into the role of phagocytic superoxide in the onset of diabetic complications, we used a model of periodontitis in mice with chronic hyperglycemia and lack of leukocyte p47(phox) (Akita/Ncf1) bred from C57BL/6-Ins2(Akita)/J (Akita) and neutrophil cytosolic factor 1 knockout (Ncf1) mice. Akita/Nfc1 mice showed progressive cachexia starting at early age and increased mortality by six months. Their lungs developed infiltrative interstitial lesions that obliterated air spaces as early as 12 weeks when fungal colonization of lungs also was observed. Neutrophils of Akita/Ncf1 mice had normal degranulation and phagocytic efficiency when compared with wild-type mice. Although Akita/Ncf1 mice had increased prevalence of oral infections and more severe periodontitis compared with wild-type mice, bone loss was only marginally higher compared with Akita and Ncf1 null mice. Altogether these results indicate that lack of leukocyte superoxide production in mice with chronic hyperglycemia results in interstitial pneumonia and increased susceptibility to infections. PMID:26747235

  7. Sustained expression of GLP-1 receptor differentially modulates β-cell functions in diabetic and nondiabetic mice.

    PubMed

    Kubo, Fumiyo; Miyatsuka, Takeshi; Sasaki, Shugo; Takahara, Mitsuyoshi; Yamamoto, Yuichi; Shimo, Naoki; Watada, Hirotaka; Kaneto, Hideaki; Gannon, Maureen; Matsuoka, Taka-aki; Shimomura, Iichiro

    2016-02-26

    Glucagon-like peptide 1 (GLP-1) has been shown to play important roles in maintaining β-cell functions, such as insulin secretion and proliferation. While expression levels of GLP-1 receptor (Glp1r) are compromised in the islets of diabetic rodents, it remains unclear when and to what degree Glp1r mRNA levels are decreased during the progression of diabetes. In this study, we performed real-time PCR with the islets of db/db diabetic mice at different ages, and found that the expression levels of Glp1r were comparable to those of the islets of nondiabetic db/misty controls at the age of four weeks, and were significantly decreased at the age of eight and 12 weeks. To investigate whether restored expression of Glp1r affects the diabetic phenotypes, we generated the transgenic mouse model Pdx1(PB)-CreER(TM); CAG-CAT-Glp1r (βGlp1r) that allows for induction of Glp1r expression specifically in β cells. Whereas the expression of exogenous Glp1r had no measurable effect on glucose tolerance in nondiabetic βGlp1r;db/misty mice, βGlp1r;db/db mice exhibited higher glucose and lower insulin levels in blood on glucose challenge test than control db/db littermates. In contrast, four weeks of treatment with exendin-4 improved the glucose profiles and increased serum insulin levels in βGlp1r;db/db mice, to significantly higher levels than those in control db/db mice. These differential effects of exogenous Glp1r in nondiabetic and diabetic mice suggest that downregulation of Glp1r might be required to slow the progression of β-cell failure under diabetic conditions. PMID:26854076

  8. Extract of Ginkgo Biloba Ameliorates Streptozotocin-Induced Type 1 Diabetes Mellitus and High-Fat Diet-Induced Type 2 Diabetes Mellitus in Mice.

    PubMed

    Rhee, Ki-Jong; Lee, Chang Gun; Kim, Sung Woo; Gim, Dong-Hyeon; Kim, Hyun-Cheol; Jung, Bae Dong

    2015-01-01

    Diabetes mellitus (DM) is caused by either destruction of pancreatic β-cells (type 1 DM) or unresponsiveness to insulin (type 2 DM). Conventional therapies for diabetes mellitus have been developed but still needs improvement. Many diabetic patients have complemented conventional therapy with alternative methods including oral supplementation of natural products. In this study, we assessed whether Ginkgo biloba extract (EGb) 761 could provide beneficial effects in the streptozotocin-induced type 1 DM and high-fat diet-induced type 2 DM murine model system. For the type 1 DM model, streptozotocin-induced mice were orally administered EGb 761 for 10 days prior to streptozotocin injection and then again administered EGb 761 for an additional 10 days. Streptozotocin-treated mice administered EGb 761 exhibited lower blood triglyceride levels, lower blood glucose levels and higher blood insulin levels compared to streptozotocin-treated mice. Furthermore, liver LPL and liver PPAR-α were increased whereas IL-1β and TNF-α were decreased in streptozotocin-injected mice treated with EGb 761 compared to mice injected with streptozotocin alone. For the type 2 DM model, mice were given high-fat diet for 60 days and then orally administered EGb 761 every other day for 80 days. We found that mice given a high-fat diet and EGb 761 showed decreased blood triglyceride levels, increased liver LPL, increased liver PPAR-α and decreased body weight compared to mice given high-fat diet alone. These results suggest that EGb 761 can exert protective effects in both type 1 and type 2 DM murine models.

  9. Methanolic Root Extract of Rauwolfia serpentina Benth Improves the Glycemic, Antiatherogenic, and Cardioprotective Indices in Alloxan-Induced Diabetic Mice

    PubMed Central

    Azmi, Muhammad Bilal; Qureshi, Shamim A.

    2012-01-01

    The aim of the study was to evaluate the phytochemistry and the effect of methanolic root extract (MREt) of Rauwolfia serpentina on alloxan-induced diabetic Wister male mice. Mice were divided in control (distilled water at 1 mL/kg) and alloxan-induced diabetic mice which subdivided into diabetic (distilled water at 1 mL/kg), negative (0.05% dimethyl sulfoxide at 1 mL/kg), positive (glibenclamide at 5 mg/kg) controls, and three test groups (MREt at 10, 30, and 60 mg/kg). All treatments were given orally for 14 days. Qualitatively MREt showed the presence of alkaloids, carbohydrates, flavonoids, glycosides, cardiac glycosides, phlobatannins, resins, saponins, steroids, tannins, and triterpenoids, while quantitatively extract was rich in total phenols. The flavonoids, saponins and alkaloids were also determined in root powder. MREt found effective in improving the body weights, glucose and insulin levels, insulin/glucose ratio, glycosylated and total hemoglobin in test groups as compared to diabetic control. Similarly, significantly decreased levels of total cholesterol, triglycerides, low-density lipoprotein (LDL-c), and very low-density lipoprotein (VLDL-c) cholesterols were found in test groups. Significant lipolysis with improved glycogenesis was also found in liver tissues of all test groups. ALT levels were found normal in all groups. Thus, MREt improves the glycemic, antiatherogenic, coronary risk, and cardioprotective indices in alloxan-induced diabetic mice. PMID:23365565

  10. Co-regulation of SREBP-1 and mTOR ameliorates lipid accumulation in kidney of diabetic mice.

    PubMed

    Wang, Hui; Zhu, Lin; Hao, Jun; Duan, Huijun; Liu, Shuxia; Zhao, Song; Liu, Qingjuan; Liu, Wei

    2015-08-01

    SREBP-1 and mTOR have been proved to involve in renal lipid metabolism of diabetes mellitus. In the present study, we investigated the effect of co-regulation of SREBP-1 and mTOR on renal lipid metabolism using diabetic mice and cultured renal tubular cells. The results showed that compared with those in high glucose-stimulated HKC cells single transfected with shRNA-SREBP-1 vector, the level of SREBP-1 protein were significantly reduced by 64.1% followed by decreased FASN mRNA, ACC mRNA, ADRP protein and lipid droplets in HKC cells co-transfected with shRNA-SREBP-1 vector and kinase-dead mTOR vector. Furthermore, diabetic mice co-injected with shRNA-SREBP-1 vector and kinase-dead mTOR vector showed that renal SREBP-1 protein, FASN mRNA and ACC mRNA were respectively decreased by 34.6%, 45.9%, 22.0% in comparison with those in diabetic mice single injected with shRNA-SREBP-1 vector accompanied by reduced ADRP protein and triglyceride content. In the end our study suggests that co-regulation of SREBP-1 and mTOR in kidney of diabetic mice is more effective in lowering renal lipogenesis than only regulation of SREBP-1. PMID:26112216

  11. Protective effect of thymol on high fat diet induced diabetic nephropathy in C57BL/6J mice.

    PubMed

    Saravanan, Settu; Pari, Leelevinothan

    2016-02-01

    Obesity is one of several factors implicated in chronic kidney disease (CKD). Thymol, a monoterpene phenolic compound found in the oils of thyme with multiple biological properties especially antidiabetic activity. The present study was undertaken to evaluate the thymol against diabetic nephropathy by high fat diet (HFD)-induced diabetic C57BL/6J mice. After 10 weeks of continuous dietary intervention, HFD (fat- 35.2%) to mice presented characteristic features of progressive nephropathy by significant increased in kidney weight, blood, and urinary parameters, glomerulosclerosis, oxidative stress, hyperlipidemia and subsequent renal injuries. After intragastric administration of thymol (40 mg/kg BW) daily for the subsequent 5 weeks significantly decreased the blood, urinary parameters and kidney weight. Thymol inhibited the activation of transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor (VEGF). Also, significantly increased the antioxidants and suppresses the lipid peroxidation markers in erythrocytes and kidney tissue compared to the diabetic mice. Thymol downregulated the expression level of sterol regulatory element binding protein-1c (SREBP-1c) and reduced the lipid accumulation in renal. Histopathological study of kidney tissues showed that extracellular mesangial matrix expansion, glomerulosclerosis in diabetic mice were suppressed by thymol. Further, our results indicate that administration of thymol afforded remarkable protection against HFD-induced diabetic nephropathy. PMID:26680107

  12. Proinsulin-producing, hyperglycemia-induced adipose tissue macrophages underlie insulin resistance in high fat-fed diabetic mice.

    PubMed

    Buras, Eric Dale; Yang, Lina; Saha, Pradip; Kim, Jongoh; Mehta, Pooja; Yang, Yisheng; Hilsenbeck, Susan; Kojima, Hideto; Chen, Wenhao; Smith, C Wayne; Chan, Lawrence

    2015-08-01

    Adipose tissue macrophages (ATMs) play an important role in the pathogenesis of obese type 2 diabetes. High-fat diet (HFD)-induced obesity has been shown to lead to ATM accumulation in rodents; however, the impact of hyperglycemia on ATM dynamics in HFD-fed type 2 diabetic models has not been studied. We previously showed that hyperglycemia induces the appearance of proinsulin (PI)-producing proinflammatory bone marrow (BM)-derived cells (PI-BMDCs) in rodents. We fed a 60% HFD to C57BL6/J mice to produce an obese type 2 diabetes model. Absent in chow-fed animals, PI-BMDCs account for 60% of the ATMs in the type 2 diabetic mice. The PI-ATM subset expresses TNF-α and other inflammatory markers, and is highly enriched within crownlike structures (CLSs). We found that amelioration of hyperglycemia by different hypoglycemic agents forestalled PI-producing ATM accumulation and adipose inflammation in these animals. We developed a diphtheria toxin receptor-based strategy to selectively ablate PI-BMDCs among ATMs. Application of the maneuver in HFD-fed type 2 diabetic mice was found to lead to near total disappearance of complex CLSs and reversal of insulin resistance and hepatosteatosis in these animals. In sum, we have identified a novel ATM subset in type 2 diabetic rodents that underlies systemic insulin resistance. PMID:25953849

  13. Importance of sulfur-containing metabolites in discriminating fecal extracts between normal and type-2 diabetic mice.

    PubMed

    Walker, Alesia; Lucio, Marianna; Pfitzner, Barbara; Scheerer, Markus F; Neschen, Susanne; de Angelis, Martin Hrabě; Hartmann, Anton; Schmitt-Kopplin, Philippe

    2014-10-01

    A metabolic disorder such as Type-2 Diabetes mellitus (T2DM) is a complex disease induced by genetic, environmental, and nutritional factors. The db/db mouse model, bearing a nonfunctional leptin receptor, is widely used to investigate the pathophysiology of T2DM. Fecal extracts of db/db and wild-type littermates were studied to unravel a broad spectrum of new and relevant metabolites related to T2DM as proxies of the interplay of gut microbiome and murine metabolomes. The nontargeted metabolomics approach consists of an integrated analytical concept of high-resolution mass spectrometry FT-ICR-MS, followed by UPLC-TOF-MS/MS experiments. We demonstrate that a metabolic disorder such as T2DM affects the gastrointestinal tract environment, thereby influencing different metabolic pathways and their respective metabolites in diabetic mice. Fatty acids, bile acids concerning cholic and deoxycholic acid, and steroid metabolism were highly discriminative comparing fecal meta-metabolomes of wt and db/db mice. Furthermore, sulfur-(S)-containing metabolites including N-acyl taurines were altered in diabetic mice, enabling us to focus on S-containing metabolites, especially the sulfate and taurine conjugates of bile and fatty acids. Different sulfate containing bile acids including sulfocholic acid, oxocholic acid sulfate, taurocholic acid sulfate, and cyprinol sulfate were significantly altered in diabetic mice. Moreover, we identified 12 new sulfate and taurine conjugates of hydroxylated fatty acids with significant importance in T2DM metabolism in db/db mice. PMID:24991707

  14. Protective Effect of Topiramate on Hyperglycemia-Induced Cerebral Oxidative Stress, Pericyte Loss and Learning Behavior in Diabetic Mice

    PubMed Central

    Price, Tulin O.; Farr, Susan A.; Niehoff, Michael L.; Ercal, Nuran; Morley, John E.; Shah, Gul N.

    2015-01-01

    Diabetes mellitus-associated damage to the microvasculature of the brain is caused by hyperglycemia-induced oxidative stress, which results in pericyte loss, blood-brain barrier disruption, and impaired cognitive function. Oxidative stress, in diabetes, is caused by reactive oxygen species produced during accelerated respiration (mitochondrial oxidative metabolism of glucose). The rate of respiration is regulated by mitochondrial carbonic anhydrases (CAs). Inhibition of these enzymes protects the brain from diabetic damage. Previously, we reported that topiramate, a mitochondrial CA inhibitor, at a dose of 50 mg/kg/day protects the brain in diabetes by reducing oxidative stress and restoring pericyte numbers. Topiramate has high affinity for both mitochondrial CAs; therefore, it is conceivable that a much lower dose may inhibit these enzymes and thus protect the brain from hyperglycemia-induced oxidative damage. Therefore, in an effort to reduce the toxicity associated with higher doses of topiramate, the current study was designed to investigate the effect of 1.0 mg/kg topiramate on reducing oxidative stress, restoring pericyte numbers in the brain, and improving the impaired learning behavior in diabetic mouse. Diabetes was induced by a one-time injection of streptozotocin and topiramate was administered daily for 12 weeks. Levels of oxidative stress, reduced glutathione (GSH) and 4-hydroxy-2-trans-nonenal (HNE) were measured in the brain and pericyte/endothelial cell ratios in isolated brain microvessels. Learning behavior was assessed by T-maze foot shock avoidance test. A significant decrease in GSH (control, 12.2 ± 0.4 vs. diabetic, 10.8 ± 0.4 vs. diabetic + topiramate, 12.6 ± 0.6, p<0.05) and an increase in HNE (control, 100 ± 4.2, vs. diabetic, 127.3 ± 8.8 vs. diabetic + topiramate, 93.9 ± 8.4 p<0.05) in diabetic mice were corrected by topiramate treatment. Topiramate treatment also resulted in restoration of pericyte numbers in diabetic mice (control

  15. Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM

    PubMed Central

    Ma, Dan; Shield, Julian P.H.; Dean, Wendy; Leclerc, Isabelle; Knauf, Claude; Burcelin, Rémy; Rutter, Guy A.; Kelsey, Gavin

    2004-01-01

    Transient neonatal diabetes mellitus (TNDM) is a rare inherited diabetic syndrome apparent in the first weeks of life and again during early adulthood. The relative contributions of reduced islet β cell number and impaired β cell function to the observed hypoinsulinemia are unclear. The inheritance pattern of this imprinted disorder implicates overexpression of one or both genes within the TNDM locus: ZAC, which encodes a proapoptotic zinc finger protein, and HYMAI, which encodes an untranslated mRNA. To investigate the consequences for pancreatic function, we have developed a high-copy transgenic mouse line, TNDM29, carrying the human TNDM locus. TNDM29 neonates display hyperglycemia, and older adults, impaired glucose tolerance. Neonatal hyperglycemia occurs only on paternal transmission, analogous to paternal dependence of TNDM in humans. Embryonic pancreata of TNDM29 mice showed reductions in expression of endocrine differentiation factors and numbers of insulin-staining structures. By contrast, β cell mass was normal or elevated at all postnatal stages, whereas pancreatic insulin content in neonates and peak serum insulin levels after glucose infusion in adults were reduced. Expression of human ZAC and HYMAI in these transgenic mice thus recapitulates key features of TNDM and implicates impaired development of the endocrine pancreas and β cell function in disease pathogenesis. PMID:15286800

  16. Gastric Bypass Surgery Reverses Diabetic Phenotypes in Bdnf-Deficient Mice.

    PubMed

    Jiang, Shujun; Wang, Qinghua; Huang, Zan; Song, Anying; Peng, Yu; Hou, Siyuan; Guo, Shiying; Zhu, Weiyun; Yan, Sheng; Lin, Zhaoyu; Gao, Xiang

    2016-08-01

    Duodenum-jejunum gastric bypass (DJB) has been used to treat morbid diabetic patients. However, neither the suitability among patients nor the mechanisms of this surgical treatment is clear. Previously, we reported a new mouse strain named Timo as type 2 diabetes model caused by brain-derived neurotrophic factor (Bdnf) deficiency. In this study, we found that DJB on Timo mice reversed their metabolic abnormalities without altering the expression of Bdnf. Glucose tolerance and insulin sensitivity were improved greatly, along with reduction of fat accumulation in liver and white adipose tissue. The gut flora population was altered by DJB with increased proportion of Firmicutes and decreased Actinobacteria and Proteobacteria in the ileum after surgery. Systemic inflammation in Timo mice was greatly suppressed with less macrophage infiltration and lower tumor necrosis factor-α levels in liver and white adipose tissue after surgery. Interestingly, the alteration of gut microflora abundance and improved metabolism preceded the inflammation alleviation after DJB surgery. These results suggested that DJB can reverse Bdnf deficiency-associated metabolic abnormality. In addition, the reduced inflammation may not be the initial cause for the DJB-associated metabolic and microbiota alterations. The increased BDNF protein levels in hypothalamus and hippocampus may result from microbiota change after DJB surgery. PMID:27418549

  17. Autoimmune diabetes can be induced in transgenic major histocompatibility complex class II-deficient mice

    PubMed Central

    1993-01-01

    Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease marked by hyperglycemia and mononuclear cell infiltration of insulin- producing beta islet cells. Predisposition to IDDM in humans has been linked to the class II major histocompatibility complex (MHC), and islet cells often become aberrantly class II positive during the course of the disease. We have used two recently described transgenic lines to investigate the role of class II molecules and CD4+ T cells in the onset of autoimmune insulitis. Mice that are class II deficient secondary to a targeted disruption of the A beta b gene were bred to mice carrying a transgene for the lymphocytic choriomenigitis virus (LCMV) glycoprotein (GP) targeted to the endocrine pancreas. Our results indicate that class II-deficient animals with and without the GP transgene produce a normal cytotoxic T lymphocyte response to whole LCMV. After infection with LCMV, GP-transgenic class II-deficient animals develop hyperglycemia as rapidly as their class II-positive littermates. Histologic examination of tissue sections from GP- transgenic class II-deficient animals reveals lymphocytic infiltrates of the pancreatic islets that are distinguishable from those of their class II-positive littermates only by the absence of infiltrating CD4+ T cells. These results suggest that in this model of autoimmune diabetes, CD4+ T cells and MHC class II molecules are not required for the development of disease. PMID:8101862

  18. Deletion of miR-150 Exacerbates Retinal Vascular Overgrowth in High-Fat-Diet Induced Diabetic Mice

    PubMed Central

    Shi, Liheng; Kim, Andy Jeesu; Chang, Richard Cheng-An; Chang, Janet Ya-An; Ying, Wei; Ko, Michael L.; Zhou, Beiyan; Ko, Gladys Yi-Ping

    2016-01-01

    Diabetic retinopathy (DR) is the leading cause of blindness among American adults above 40 years old. The vascular complication in DR is a major cause of visual impairment, making finding therapeutic targets to block pathological angiogenesis a primary goal for developing DR treatments. MicroRNAs (miRs) have been proposed as diagnostic biomarkers and potential therapeutic targets for various ocular diseases including DR. In diabetic animals, the expression levels of several miRs, including miR-150, are altered. The expression of miR-150 is significantly suppressed in pathological neovascularization in mice with hyperoxia-induced retinopathy. The purpose of this study was to investigate the functional role of miR-150 in the development of retinal microvasculature complications in high-fat-diet (HFD) induced type 2 diabetic mice. Wild type (WT) and miR-150 null mutant (miR-150-/-) male mice were given a HFD (59% fat calories) or normal chow diet. Chronic HFD caused a decrease of serum miR-150 in WT mice. Mice on HFD for 7 months (both WT and miR-150-/-) had significant decreases in retinal light responses measured by electroretinograms (ERGs). The retinal neovascularization in miR-150-/--HFD mice was significantly higher compared to their age matched WT-HFD mice, which indicates that miR-150 null mutation exacerbates chronic HFD-induced neovascularization in the retina. Overexpression of miR-150 in cultured endothelial cells caused a significant reduction of vascular endothelial growth factor receptor 2 (VEGFR2) protein levels. Hence, deletion of miR-150 significantly increased the retinal pathological angiogenesis in HFD induced type 2 diabetic mice, which was in part through VEGFR2. PMID:27304911

  19. Impaired Leptomeningeal Collateral Flow Contributes to the Poor Outcome following Experimental Stroke in the Type 2 Diabetic Mice

    PubMed Central

    Akamatsu, Yosuke; Nishijima, Yasuo; Lee, Chih Cheng; Yang, Shih Yen; Shi, Lei; An, Lin; Wang, Ruikang K.; Tominaga, Teiji

    2015-01-01

    Collateral status is an independent predictor of stroke outcome. However, the spatiotemporal manner in which collateral flow maintains cerebral perfusion during cerebral ischemia is poorly understood. Diabetes exacerbates ischemic brain damage, although the impact of diabetes on collateral dynamics remains to be established. Using Doppler optical coherent tomography, a robust recruitment of leptomeningeal collateral flow was detected immediately after middle cerebral artery (MCA) occlusion in C57BL/6 mice, and it continued to grow over the course of 1 week. In contrast, an impairment of collateral recruitment was evident in the Type 2 diabetic db/db mice, which coincided with a worse stroke outcome compared with their normoglycemic counterpart db/+, despite their equally well-collateralized leptomeningeal anastomoses. Similar to the wild-type mice, both db/+ and db/db mice underwent collateral growth 7 d after MCA stroke, although db/db mice still exhibited significantly reduced retrograde flow into the MCA territory chronically. Acutely induced hyperglycemia in the db/+ mice did not impair collateral flow after stroke, suggesting that the state of hyperglycemia alone was not sufficient to impact collateral flow. Human albumin was efficacious in improving collateral flow and outcome after stroke in the db/db mice, enabling perfusion to proximal MCA territory that was usually not reached by retrograde flow from anterior cerebral artery without treatment. Our results suggest that the impaired collateral status contributes to the exacerbated ischemic injury in mice with Type 2 diabetes, and modulation of collateral flow has beneficial effects on stroke outcome among these subjects. PMID:25740515

  20. Proteasome inhibitors, including curcumin, improve pancreatic β-cell function and insulin sensitivity in diabetic mice

    PubMed Central

    Weisberg, S; Leibel, R; Tortoriello, D V

    2016-01-01

    Background: Type 2 diabetes stems from obesity-associated insulin resistance, and in the genetically susceptible, concomitant pancreatic β-cell failure can occur, which further exacerbates hyperglycemia. Recent work by our group and others has shown that the natural polyphenol curcumin attenuates the development of insulin resistance and hyperglycemia in mouse models of hyperinsulinemic or compensated type 2 diabetes. Although several potential downstream molecular targets of curcumin exist, it is now recognized to be a direct inhibitor of proteasome activity. We now show that curcumin also prevents β-cell failure in a mouse model of uncompensated obesity-related insulin resistance (Leprdb/db on the Kaliss background). Results: In this instance, dietary supplementation with curcumin prevented hyperglycemia, increased insulin production and lean body mass, and prolonged lifespan. In addition, we show that short-term in vivo treatment with low dosages of two molecularly distinct proteasome inhibitors celastrol and epoxomicin reverse hyperglycemia in mice with β-cell failure by increasing insulin production and insulin sensitivity. Conclusions: These studies suggest that proteasome inhibitors may prove useful for patients with diabetes by improving both β-cell function and relieving insulin resistance. PMID:27110686

  1. Update on animal models of diabetic retinopathy: from molecular approaches to mice and higher mammals

    PubMed Central

    Robinson, Remya; Barathi, Veluchamy A.; Chaurasia, Shyam S.; Wong, Tien Y.; Kern, Timothy S.

    2012-01-01

    Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and one of the major causes of blindness worldwide. The pathogenesis of DR has been investigated using several animal models of diabetes. These models have been generated by pharmacological induction, feeding a galactose diet, and spontaneously by selective inbreeding or genetic modification. Among the available animal models, rodents have been studied most extensively owing to their short generation time and the inherited hyperglycemia and/or obesity that affect certain strains. In particular, mice have proven useful for studying DR and evaluating novel therapies because of their amenability to genetic manipulation. Mouse models suitable for replicating the early, non-proliferative stages of the retinopathy have been characterized, but no animal model has yet been found to demonstrate all of the vascular and neural complications that are associated with the advanced, proliferative stages of DR that occur in humans. In this review, we summarize commonly used animal models of DR, and briefly outline the in vivo imaging techniques used for characterization of DR in these models. Through highlighting the ocular pathological findings, clinical implications, advantages and disadvantages of these models, we provide essential information for planning experimental studies of DR that will lead to new strategies for its prevention and treatment. PMID:22730475

  2. Fenofibrate increases cardiac autophagy via FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of Type 1 diabetic mice.

    PubMed

    Zhang, Jingjing; Cheng, Yanli; Gu, Junlian; Wang, Shudong; Zhou, Shanshan; Wang, Yuehui; Tan, Yi; Feng, Wenke; Fu, Yaowen; Mellen, Nicholas; Cheng, Rui; Ma, Jianxing; Zhang, Chi; Li, Zhanquan; Cai, Lu

    2016-04-01

    Fenofibrate (FF), as a peroxisome-proliferator-activated receptor α (PPARα) agonist, has been used clinically for decades to lower lipid levels. In the present study, we examined whether FF can be repurposed to prevent the pathogenesi of the heart in Type 1 diabetes and to describe the underlying mechanism of its action. Streptozotocin (STZ)-induced diabetic mice and their age-matched control mice were treated with vehicle or FF by gavage every other day for 3 or 6 months. FF prevented diabetes-induced cardiac dysfunction (e.g. decreased ejection fraction and hypertrophy), inflammation and remodelling. FF also increased cardiac expression of fibroblast growth factor 21 (FGF21) and sirtuin 1 (Sirt1) in non-diabetic and diabetic conditions. Deletion of FGF21 gene (FGF21-KO) worsened diabetes-induced pathogenic effects in the heart. FF treatment prevented heart deterioration in the wild-type diabetic mice, but could not do so in the FGF21-KO diabetic mice although the systemic lipid profile was lowered in both wild-type and FGF21-KO diabetic mice. Mechanistically, FF treatment prevented diabetes-impaired autophagy, reflected by increased microtubule-associated protein 1A/1B-light chain 3, in the wild-type diabetic mice but not in the FGF21-KO diabetic mice. Studies with H9C2 cells in vitro demonstrated that exposure to high glucose (HG) significantly increased inflammatory response, oxidative stress and pro-fibrotic response and also significantly inhibited autophagy. These effects of HG were prevented by FF treatment. Inhibition of either autophagy by 3-methyladenine (3MA) or Sirt1 by sirtinol (SI) abolished FF's prevention of HG-induced effects. These results suggested that FF could prevent Type 1 diabetes-induced pathological and functional abnormalities of the heart by increasing FGF21 that may up-regulate Sirt1-mediated autophagy. PMID:26795437

  3. Glucose metabolism and insulin sensitivity in transgenic mice overexpressing leptin with lethal yellow agouti mutation: usefulness of leptin for the treatment of obesity-associated diabetes.

    PubMed

    Masuzaki, H; Ogawa, Y; Aizawa-Abe, M; Hosoda, K; Suga, J; Ebihara, K; Satoh, N; Iwai, H; Inoue, G; Nishimura, H; Yoshimasa, Y; Nakao, K

    1999-08-01

    Leptin acts as an adipocyte-derived blood-borne satiety factor that can increase glucose metabolism. To elucidate the therapeutic implications of leptin for obesity-associated diabetes, we crossed transgenic skinny mice overexpressing leptin (Tg/+), which we have developed recently, and lethal yellow KKAy mice (Ay/+), a genetic model for obesity-diabetes syndrome, and examined the metabolic phenotypes of F1 animals. At 6 weeks of age, plasma leptin concentrations in Tg/+ mice with the Ay allele (Tg/+:Ay/+) were significantly higher than those in Ay/+ mice. Although no significant differences in body weight were noted among Tg/+:Ay/+ mice, Ay/+ mice, and their wild-type lean littermates (+/+), glucose and insulin tolerance tests revealed increased glucose tolerance and insulin sensitivity in Tg/+:Ay/+ compared with Ay/+ mice. However, at 12 weeks of age, when plasma leptin concentrations in Ay/+ mice were comparable to those in Tg/+:Ay/+ mice, Tg/+:Ay/+ mice developed obesity-diabetes syndrome similar to that of Ay/+ mice. Body weights of 12-week-old Tg/+:Ay/+ and Ay/+ mice were reduced to those of +/+ mice by a 3-week food restriction; when plasma leptin concentrations remained high in Tg/+:Ay/+ mice but were markedly reduced in Ay/+ and +/+ mice, glucose tolerance and insulin sensitivity in Tg/+:Ay/+ mice were markedly improved as compared with Ay/+ and +/+ mice. The present study demonstrates that hyperleptinemia can delay the onset of impaired glucose metabolism and accelerate the recovery from diabetes during caloric restriction in Tg/+:Ay/+ mice, thereby suggesting the potential usefulness of leptin in combination with a long-term caloric restriction for the treatment of obesity-associated diabetes.

  4. Lectin from Crataeva tapia Bark Improves Tissue Damages and Plasma Hyperglycemia in Alloxan-Induced Diabetic Mice

    PubMed Central

    da Rocha, Amanda Alves; Araújo, Tiago Ferreira da Silva; da Fonseca, Caíque Silveira Martins; da Mota, Diógenes Luís; de Medeiros, Paloma Lys; Paiva, Patrícia Maria Guedes; Coelho, Luana Cassandra Breitenbach Barroso; Correia, Maria Tereza dos Santos; Lima, Vera Lúcia de Menezes

    2013-01-01

    Crataeva tapia is a plant popularly used for diabetes treatment, in Brazil. Progressive decline in renal and hepatic functions has been described in patients with diabetes mellitus, and mortality rate is increased in patients with chronic liver and renal disease. This study aimed to evaluate whether Crataeva tapia bark lectin (CrataBL) improves hyperglycemia and renal and hepatic damage in diabetic mice. CrataBL was purified by ion exchange chromatography on CM-cellulose, and intraperitoneal administration of CrataBL to alloxan-induced diabetic mice at dose of 10 mg/Kg/day and 20 mg/Kg/day for 10 days significantly reduced serum glucose levels by 14.9% and 55.9%, respectively. Serum urea, creatinine, aspartate aminotransferase, and alanine aminotransferase were also significantly reduced after treatment with both doses of CrataBL. Furthermore, histological analysis of liver, kidney, and pancreas revealed an improvement in the tissue morphology upon treatment with CrataBL. The results suggest that CrataBL has a beneficial hypoglycemic activity and improves the renal and hepatic complications of diabetes. Therefore, this lectin may be a promising agent for the treatment of diabetes, and this might be the basis for its use in the folk medicine as an alternative treatment to manage diabetes-related complications such as hyperglycemia and tissue damage. PMID:24324521

  5. Involvement of Spinal Angiotensin II System in Streptozotocin-Induced Diabetic Neuropathic Pain in Mice.

    PubMed

    Ogata, Yoshiki; Nemoto, Wataru; Nakagawasai, Osamu; Yamagata, Ryota; Tadano, Takeshi; Tan-No, Koichi

    2016-09-01

    Renin-angiotensin system (RAS) activity increases under hyperglycemic states, and is thought to be involved in diabetic complications. We previously demonstrated that angiotensin (Ang) II, a main bioactive component of the RAS, might act as a neurotransmitter and/or neuromodulator in the transmission of nociceptive information in the spinal cord. Here, we examined whether the spinal Ang II system is responsible for diabetic neuropathic pain induced by streptozotocin (STZ). Tactile allodynia was observed concurrently with an increase in blood glucose levels the day after mice received STZ (200 mg/kg, i.v.) injections. Tactile allodynia on day 14 was dose-dependently inhibited by intrathecal administration of losartan, an Ang II type 1 (AT1) receptor antagonist, but not by PD123319, an AT2 receptor antagonist. In the lumbar dorsal spinal cord, the expression of Ang II, Ang converting enzyme (ACE), and phospho-p38 mitogen-activated protein kinase (MAPK) were all significantly increased on day 14 after STZ injection compared with vehicle-treated controls, whereas no differences were observed among AT1 receptors or angiotensinogen levels. Moreover, the increase in phospho-p38 MAPK was significantly inhibited by intrathecal administration of losartan. These results indicate that the expression of spinal ACE increased in STZ-induced diabetic mice, which in turn led to an increase in Ang II levels and tactile allodynia. This increase in spinal Ang II was accompanied by the phosphorylation of p38 MAPK, which was shown to be mediated by AT1 receptors.

  6. Involvement of Spinal Angiotensin II System in Streptozotocin-Induced Diabetic Neuropathic Pain in Mice.

    PubMed

    Ogata, Yoshiki; Nemoto, Wataru; Nakagawasai, Osamu; Yamagata, Ryota; Tadano, Takeshi; Tan-No, Koichi

    2016-09-01

    Renin-angiotensin system (RAS) activity increases under hyperglycemic states, and is thought to be involved in diabetic complications. We previously demonstrated that angiotensin (Ang) II, a main bioactive component of the RAS, might act as a neurotransmitter and/or neuromodulator in the transmission of nociceptive information in the spinal cord. Here, we examined whether the spinal Ang II system is responsible for diabetic neuropathic pain induced by streptozotocin (STZ). Tactile allodynia was observed concurrently with an increase in blood glucose levels the day after mice received STZ (200 mg/kg, i.v.) injections. Tactile allodynia on day 14 was dose-dependently inhibited by intrathecal administration of losartan, an Ang II type 1 (AT1) receptor antagonist, but not by PD123319, an AT2 receptor antagonist. In the lumbar dorsal spinal cord, the expression of Ang II, Ang converting enzyme (ACE), and phospho-p38 mitogen-activated protein kinase (MAPK) were all significantly increased on day 14 after STZ injection compared with vehicle-treated controls, whereas no differences were observed among AT1 receptors or angiotensinogen levels. Moreover, the increase in phospho-p38 MAPK was significantly inhibited by intrathecal administration of losartan. These results indicate that the expression of spinal ACE increased in STZ-induced diabetic mice, which in turn led to an increase in Ang II levels and tactile allodynia. This increase in spinal Ang II was accompanied by the phosphorylation of p38 MAPK, which was shown to be mediated by AT1 receptors. PMID:27401876

  7. Brugia malayi soluble and excretory-secretory proteins attenuate development of streptozotocin-induced type 1 diabetes in mice.

    PubMed

    Amdare, N; Khatri, V; Yadav, R S P; Tarnekar, A; Goswami, K; Reddy, M V R

    2015-12-01

    Understanding the modulation of the host-immune system by pathogens-like filarial parasites offers an alternate approach to prevent autoimmune diseases. In this study, we have shown that treatment with filarial proteins prior to or after the clinical onset of streptozotocin-induced type-1 diabetes (T1D) can ameliorate the severity of disease in BALB/c mice. Pre-treatment with Brugia malayi adult soluble (Bm A S) or microfilarial excretory-secretory (Bm mf ES) or microfilarial soluble (Bm mf S) antigens followed by induction of diabetes led to lowering of fasting blood glucose levels with as many as 57.5-62.5% of mice remaining nondiabetic. These proteins were more effective when they were used to treat the mice with established T1D as 62.5-71.5% of the mice turned to be nondiabetic. Histopathological examination of pancreas of treated mice showed minor inflammatory changes in pancreatic islet cell architecture. The therapeutic effect was found to be associated with the decreased production of cytokines TNF-α & IFN-γ and increased production of IL-10 in the culture supernatants of splenocytes of treated mice. A switch in the production of anti-insulin antibodies from IgG2a to IgG1 isotype was also seen. Together these results provide a proof towards utilizing the filarial derived proteins as novel anti-diabetic therapeutics.

  8. Chronic Ingestion of Advanced Glycation End Products Induces Degenerative Spinal Changes and Hypertrophy in Aging Pre-Diabetic Mice

    PubMed Central

    Illien-Jünger, Svenja; Lu, Young; Qureshi, Sheeraz A.; Hecht, Andrew C.; Cai, Weijing; Vlassara, Helen; Striker, Gary E.; Iatridis, James C.

    2015-01-01

    Intervertebral disc (IVD) degeneration and pathological spinal changes are major causes of back pain, which is the top cause of global disability. Obese and diabetic individuals are at increased risk for back pain and musculoskeletal complications. Modern diets contain high levels of advanced glycation end products (AGEs), cyto-toxic components which are known contributors to obesity, diabetes and accelerated aging pathologies. There is little information about potential effects of AGE rich diet on spinal pathology, which may be a contributing cause for back pain which is common in obese and diabetic individuals. This study investigated the role of specific AGE precursors (e.g. methylglyoxal-derivatives (MG)) on IVD and vertebral pathologies in aging C57BL6 mice that were fed isocaloric diets with standard (dMG+) or reduced amounts of MG derivatives (dMG-; containing 60-70% less dMG). dMG+ mice exhibited a pre-diabetic phenotype, as they were insulin resistant but not hyperglycemic. Vertebrae of dMG+ mice displayed increased cortical-thickness and cortical-area, greater MG-AGE accumulation and ectopic calcification in vertebral endplates. IVD morphology of dMG+ mice exhibited ectopic calcification, hypertrophic differentiation and glycosaminoglycan loss relative to dMG- mice. Overall, chronic exposure to dietary AGEs promoted age-accelerated IVD degeneration and vertebral alterations involving ectopic calcification which occurred in parallel with insulin resistance, and which were prevented with dMG- diet. This study described a new mouse model for diet-induced spinal degeneration, and results were in support of the hypothesis that chronic AGE ingestion could be a factor contributing to a pre-diabetic state, ectopic calcifications in spinal tissues, and musculoskeletal complications that are more generally known to occur with chronic diabetic conditions. PMID:25668621

  9. α-Cell Dysfunctions and Molecular Alterations in Male Insulinopenic Diabetic Mice Are Not Completely Corrected by Insulin.

    PubMed

    Dusaulcy, Rodolphe; Handgraaf, Sandra; Heddad-Masson, Mounia; Visentin, Florian; Vesin, Christian; Reimann, Franck; Gribble, Fiona; Philippe, Jacques; Gosmain, Yvan

    2016-02-01

    Glucagon and α-cell dysfunction are critical in the development of hyperglycemia during diabetes both in humans and rodents. We hypothesized that α-cell dysfunction leading to dysregulated glucagon secretion in diabetes is due to both a lack of insulin and intrinsic defects. To characterize α-cell dysfunction in diabetes, we used glucagon-Venus transgenic male mice and induced insulinopenic hyperglycemia by streptozotocin administration leading to alterations of glucagon secretion. We investigated the in vivo impact of insulinopenic hyperglycemia on glucagon-producing cells using FACS-sorted α-cells from control and diabetic mice. We demonstrate that increased glucagonemia in diabetic mice is mainly due to increases of glucagon release and biosynthesis per cell compared with controls without changes in α-cell mass. We identified genes coding for proteins involved in glucagon biosynthesis and secretion, α-cell differentiation, and potential stress markers such as the glucagon, Arx, MafB, cMaf, Brain4, Foxa1, Foxa3, HNF4α, TCF7L2, Glut1, Sglt2, Cav2.1, Cav2.2, Nav1.7, Kir6.2/Sur1, Pten, IR, NeuroD1, GPR40, and Sumo1 genes, which were abnormally regulated in diabetic mice. Importantly, insulin treatment partially corrected α-cell function and expression of genes coding for proglucagon, or involved in glucagon secretion, glucose transport and insulin signaling but not those coding for cMAF, FOXA1, and α-cell differentiation markers as well as GPR40, NEUROD1, CAV2.1, and SUMO1. Our results indicate that insulinopenic diabetes induce marked α-cell dysfunction and molecular alteration, which are only partially corrected by in vivo insulin treatment. PMID:26696123

  10. Renoprotective Effect of Gemigliptin, a Dipeptidyl Peptidase-4 Inhibitor, in Streptozotocin-Induced Type 1 Diabetic Mice

    PubMed Central

    Jung, Gwon-Soo; Jeon, Jae-Han; Choe, Mi Sun; Kim, Sung-Woo; Lee, In-Kyu

    2016-01-01

    Background Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the treatment of patients with type 2 diabetes and have proven protective effects on diabetic kidney disease (DKD). Whether DPP-4 inhibitors have renoprotective effects on insulin-deficient type 1 diabetes has not been comprehensively examined. The aim of this study was to determine whether gemigliptin, a new DPP-4 inhibitor, has renoprotective effects in streptozotocin (STZ)-induced type 1 diabetic mice. Methods Diabetes was induced by intraperitoneal administration of a single dose of STZ. Mice with diabetes were treated without or with gemigliptin (300 mg/kg) for 8 weeks. Morphological changes of the glomerular basement membrane (GBM) were observed by electron microscopy and periodic-acid Schiff staining. In addition, we measured blood glucose and urinary albumin excretion and evaluated fibrotic markers using immunohistochemical staining, quantitative reverse transcription polymerase chain reaction analysis, and Western blot analysis. Results Gemigliptin did not reduce the blood glucose levels of STZ-treated mice. In gemigliptin-treated mice with STZ, a significant reduction in urinary albumin excretion and GBM thickness was observed. Immunohistological examination revealed that gemigliptin attenuated renal fibrosis induced by STZ and decreased extracellular matrix protein levels, including those of type I collagen and fibronectin, and Smad3 phosphorylation. In cultured rat renal cells, gemigliptin inhibited transforming growth factor β-stimulated type I collagen and fibronectin mRNA and protein levels via down-regulation of Smad3 phosphorylation. Conclusion Our data demonstrate that gemigliptin has renoprotective effects on DKD, regardless of its glucose-lowering effect, suggesting that it could be used to prevent DKD, including in patients with type 1 diabetes. PMID:27098503

  11. Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice

    SciTech Connect

    Li, Yuan-Yuan; Yu, Li-Fang; Zhang, Li-Na; Qiu, Bei-Ying; Su, Ming-Bo; Wu, Fang; Chen, Da-Kai; Pang, Tao; Gu, Min; Zhang, Wei; Ma, Wei-Ping; Jiang, Hao-Wen; Li, Jing-Ya Nan, Fa-Jun Li, Jia

    2013-12-01

    AMP-activated protein kinase (AMPK), which is a pivotal guardian of whole-body energy metabolism, has become an attractive therapeutic target for metabolic syndrome. Previously, using a homogeneous scintillation proximity assay, we identified the small-molecule AMPK activator C24 from an optimization based on the original allosteric activator PT1. In this paper, the AMPK activation mechanism of C24 and its potential beneficial effects on glucose and lipid metabolism on db/db mice were investigated. C24 allosterically stimulated inactive AMPK α subunit truncations and activated AMPK heterotrimers by antagonizing autoinhibition. In primary hepatocytes, C24 increased the phosphorylation of AMPK downstream target acetyl-CoA carboxylase dose-dependently without changing intracellular AMP/ATP ratio, indicating its allosteric activation in cells. Through activating AMPK, C24 decreased glucose output by down-regulating mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in primary hepatocytes. C24 also decreased the triglyceride and cholesterol contents in HepG2 cells. Due to its improved bioavailability, chronic oral treatment with multiple doses of C24 significantly reduced blood glucose and lipid levels in plasma, and improved the glucose tolerance of diabetic db/db mice. The hepatic transcriptional levels of PEPCK and G6Pase were reduced. These results demonstrate that this orally effective activator of AMPK represents a novel approach to the treatment of metabolic syndrome. - Highlights: • C24 activates AMPK through antagonizing autoinhibition within α subunit. • C24 activates AMPK in hepatocytes and decreases glucose output via AMPK. • C24 exerts beneficial effects on diabetic db/db mice. • C24 represents a novel therapeutic for treatment of metabolic syndrome.

  12. Microarray profiling of gene expression patterns in glomerular cells of astaxanthin-treated diabetic mice: a nutrigenomic approach.

    PubMed

    Naito, Yuji; Uchiyama, Kazuhiko; Mizushima, Katsura; Kuroda, Masaaki; Akagiri, Satomi; Takagi, Tomohisa; Handa, Osamu; Kokura, Satoshi; Yoshida, Norimasa; Ichikawa, Hiroshi; Takahashi, Jiro; Yoshikawa, Toshikazu

    2006-10-01

    We have demonstrated that astaxanthin reduces glomerular oxidative stress as well as inhibits the increase in urinary albumin in diabetic db/db mice. The aim of the present study was to determine the gene expression patterns in the glomerular cells of the diabetic mouse kidney, and to investigate the effects of astaxanthin on the expression of these genes using a high-density DNA microarray. The diet administered to the astaxanthin-supplementation group was prepared by mixing a control powder with astaxanthin at a concentration of 0.02%. Glomerular cells were obtained from the kidneys of mice by laser capture microdissection. Preparation of cRNA and target hybridization were performed according to the Affymetrix GeneChip eukaryotic small sample target labeling assay protocol. The gene expression profile was evaluated by the mouse expression set 430A GeneChip. Array data analysis was carried out using Affymetrix GeneChip operating and Ingenuity Pathway analysis software. Comparison between diabetic db/db and non-diabetic db/m mice revealed that 779 probes (3.1%) were significantly affected, i.e. 550 probes were up-regulated, and 229 probes were down-regulated, both at levels of >/=1.5-fold in the diabetic mice. Ingenuity signal analysis of 550 up-regulated probes revealed the mitochondrial oxidative phosphorylation pathway as the most significantly affected caronical pathway. The affected genes were associated with complexes I, III, and IV located on the mitochondrial inner membrane, and the expression levels of these genes were decreased in mice treated with astaxanthin as compared to the levels in the control mice. In addition, the expression of many genes associated with oxidative stress, collagen synthesis, and transforming growth factor-beta signaling was enhanced in the diabetic mice, and this enhancement was slightly inhibited in the astaxanthin-treated mice. In conclusion, this genome-wide nutrigenomics approach provided insight into genes and putative

  13. Differential proteomic analysis of the pancreas of diabetic db/db mice reveals the proteins involved in the development of complications of diabetes mellitus.

    PubMed

    Pérez-Vázquez, Victoriano; Guzmán-Flores, Juan M; Mares-Álvarez, Daniela; Hernández-Ortiz, Magdalena; Macías-Cervantes, Maciste H; Ramírez-Emiliano, Joel; Encarnación-Guevara, Sergio

    2014-01-01

    Type 2 diabetes mellitus is characterized by hyperglycemia and insulin-resistance. Diabetes results from pancreatic inability to secrete the insulin needed to overcome this resistance. We analyzed the protein profile from the pancreas of ten-week old diabetic db/db and wild type mice through proteomics. Pancreatic proteins were separated in two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and significant changes in db/db mice respect to wild type mice were observed in 27 proteins. Twenty five proteins were identified by matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) and their interactions were analyzed using search tool for the retrieval of interacting genes/proteins (STRING) and database for annotation, visualization and integrated discovery (DAVID). Some of these proteins were Pancreatic α-amylase, Cytochrome b5, Lithostathine-1, Lithostathine-2, Chymotrypsinogen B, Peroxiredoxin-4, Aspartyl aminopeptidase, Endoplasmin, and others, which are involved in the metabolism of carbohydrates and proteins, as well as in oxidative stress, and inflammation. Remarkably, these are mostly endoplasmic reticulum proteins related to peptidase activity, i.e., they are involved in proteolysis, glucose catabolism and in the tumor necrosis factor-mediated signaling pathway. These results suggest mechanisms for insulin resistance, and the chronic inflammatory state observed in diabetes.

  14. Renoprotective Effects of Atorvastatin in Diabetic Mice: Downregulation of RhoA and Upregulation of Akt/GSK3.

    PubMed

    Bruder-Nascimento, Thiago; Callera, Glaucia; Montezano, Augusto Cesar; Antunes, Tayze T; He, Ying; Cat, Aurelie Nguyen Dinh; Ferreira, Nathanne S; Barreto, Pedro A; Olivon, Vânia C; Tostes, Rita C; Touyz, Rhian M

    2016-01-01

    Potential benefits of statins in the treatment of chronic kidney disease beyond lipid-lowering effects have been described. However, molecular mechanisms involved in renoprotective actions of statins have not been fully elucidated. We questioned whether statins influence development of diabetic nephropathy through reactive oxygen species, RhoA and Akt/GSK3 pathway, known to be important in renal pathology. Diabetic mice (db/db) and their control counterparts (db/+) were treated with atorvastatin (10 mg/Kg/day, p.o., for 2 weeks). Diabetes-associated renal injury was characterized by albuminuria (albumin:creatinine ratio, db/+: 3.2 ± 0.6 vs. db/db: 12.5 ± 3.1*; *P<0.05), increased glomerular/mesangial surface area, and kidney hypertrophy. Renal injury was attenuated in atorvastatin-treated db/db mice. Increased ROS generation in the renal cortex of db/db