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.

Nonobese Diabetic (NOD) Mice Congenic for a Targeted Deletion of 12/15-Lipoxygenase Are Protected From Autoimmune Diabetes

PubMed Central

McDuffie, Marcia; Maybee, Nelly A.; Keller, Susanna R.; Stevens, Brian K.; Garmey, James C.; Morris, Margaret A.; Kropf, Elizabeth; Rival, Claudia; Ma, Kaiwen; Carter, Jeffrey D.; Tersey, Sarah A.; Nunemaker, Craig S.; Nadler, Jerry L.

2010-01-01

OBJECTIVE 12/15-lipoxygenase (12/15-LO), one of a family of fatty acid oxidoreductase enzymes, reacts with polyenoic fatty acids to produce proinflammatory lipids. 12/15-LO is expressed in macrophages and pancreatic β-cells. It enhances interleukin 12 production by macrophages, and several of its products induce apoptosis of β-cells at nanomolar concentrations in vitro. We had previously demonstrated a role for 12/15-LO in β-cell damage in the streptozotocin model of diabetes. Since the gene encoding 12/15-LO (gene designation Alox15) lies within the Idd4 diabetes susceptibility interval in NOD mice, we hypothesized that 12/15-LO is also a key regulator of diabetes susceptibility in the NOD mouse. RESEARCH DESIGN AND METHODS We developed NOD mice carrying an inactivated 12/15-LO locus (NOD-Alox15null) using a “speed congenic” protocol, and the mice were monitored for development of insulitis and diabetes. RESULTS NOD mice deficient in 12/15-LO develop diabetes at a markedly reduced rate compared with NOD mice (2.5 vs. >60% in females by 30 weeks). Nondiabetic female NOD-Alox15null mice demonstrate improved glucose tolerance, as well as significantly reduced severity of insulitis and improved β-cell mass, when compared with age-matched nondiabetic NOD females. Disease resistance is associated with decreased numbers of islet-infiltrating activated macrophages at 4 weeks of age in NOD-Alox15null mice, preceding the development of insulitis. Subsequently, islet-associated infiltrates are characterized by decreased numbers of CD4+ T cells and increased Foxp3+ cells. CONCLUSIONS These results suggest an important role for 12/15-LO in conferring susceptibility to autoimmune diabetes in NOD mice through its effects on macrophage recruitment or activation. PMID:17940120

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jin, Yulan; Purohit, Sharad; Department of Pathology, Medical College of Georgia, Georgia Health Sciences University, GA

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 inmore » 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.« less

Exposure to bisphenol A, but not phthalates, increases spontaneous diabetes type 1 development in NOD mice.

PubMed

Bodin, Johanna; Kocbach Bølling, Anette; Wendt, Anna; Eliasson, Lena; Becher, Rune; Kuper, Frieke; Løvik, Martinus; Nygaard, Unni Cecilie

2015-01-01

Type 1 diabetes mellitus (T1DM) is an autoimmune destruction of insulin producing pancreatic beta-cells due to a genetic predisposition and can be triggered by environmental factors. We have previously shown that bisphenol A (BPA) accelerates the spontaneous development of diabetes in non-obese diabetic (NOD) mice. Here, we hypothesized that oral exposure to a mixture of the endocrine disruptors BPA and phthalates, relevant for human exposure, would accelerate diabetes development compared to BPA alone. NOD mice were exposed to BPA (1 mg/l), a mixture of phthalates (DEHP 1 mg/l, DBP 0.2 mg/l, BBP 10 mg/l and DiBP 20 mg/l) or a combination of BPA and the phthalate mixture through drinking water from conception and throughout life. Previous observations that BPA exposure increased the prevalence of diabetes and insulitis and decreased the number of tissue resident macrophages in pancreas were confirmed, and extended by demonstrating that BPA exposure also impaired the phagocytic activity of peritoneal macrophages. None of these effects were observed after phthalate exposure alone. The phthalate exposure in combination with BPA seemed to dampen the BPA effects on macrophage number and function as well as diabetes development, but not insulitis development. Exposure to BPA alone or in combination with phthalates decreased cytokine release (TNFα, IL-6, IL-10, IFNγ, IL-4) from in vitro stimulated splenocytes and lymph node cells, indicating systemic changes in immune function. In conclusion, exposure to BPA, but not to phthalates or mixed exposure to BPA and phthalates, accelerated diabetes development in NOD mice, apparently in part via systemic immune alterations including decreased macrophage function.

Prophylactic fenbendazole therapy does not affect the incidence and onset of type 1 diabetes in non-obese diabetic mice.

PubMed

Franke, Deanna D H; Shirwan, Haval

2006-03-01

Fenbendazole (FBZ) is a common, highly efficacious broad-spectrum anthelmintic drug used to treat and limit rodent pinworm infections. However, the effect of its prophylactic use on the immune response of rodents is largely undefined. The non-obese diabetic (NOD) mouse is a model commonly used to study type 1 diabetes (T1D). Parasitic infections will inhibit diabetes development in NOD mice; thus, in the presence of contamination, prophylactic treatment with anthelmintics must be considered to maintain experimental research. Herein, we investigated the prophylactic use of FBZ in NOD mice to determine its effect on the incidence and onset of diabetes, lymphocyte sub-populations and T cell proliferative responses. NOD mice were separated into control and treatment groups. The treatment group received a diet containing FBZ. Animals were monitored for the incidence and onset of T1D. At matched time points, diabetic and non-diabetic mice were killed and splenic lymphocytes analyzed for various cell sub-populations and mitogen-induced proliferative responses using flow cytometry. Treated and control mice were monitored >23 weeks with no detectable effects on the incidence or onset of diabetes. Moreover, no significant differences were detected in lymphocyte sub-populations and mitogen-induced CD4(+) and CD8(+) proliferative responses between control and treatment groups. These results suggest that prophylactic FBZ treatment does not significantly alter the incidence or onset of diabetes in NOD mice. The prophylactic use of FBZ, therefore, presents a viable approach for the prevention of pinworm infection in precious experimental animals with substantial scientific and economic benefits.

Gut microbial markers are associated with diabetes onset, regulatory imbalance, and IFN-γ level in NOD mice.

PubMed

Krych, Ł; Nielsen, D S; Hansen, A K; Hansen, C H F

2015-01-01

Gut microbiota regulated imbalances in the host's immune profile seem to be an important factor in the etiology of type 1 diabetes (T1D), and identifying bacterial markers for T1D may therefore be useful in diagnosis and prevention of T1D. The aim of the present study was to investigate the link between the early gut microbiota and immune parameters of non-obese diabetic (NOD) mice in order to select alleged bacterial markers of T1D. Gut microbial composition in feces was analyzed with 454/FLX Titanium (Roche) pyro-sequencing and correlated with diabetes onset age and immune cell populations measured in diabetic and non-diabetic mice at 30 weeks of age. The early gut microbiota composition was found to be different between NOD mice that later in life were classified as diabetic or non-diabetic. Those differences were further associated with changes in FoxP3(+) regulatory T cells, CD11b(+) dendritic cells, and IFN-γ production. The model proposed in this work suggests that operational taxonomic units classified to S24-7, Prevotella, and an unknown Bacteriodales (all Bacteroidetes) act in favor of diabetes protection whereas members of Lachnospiraceae, Ruminococcus, and Oscillospira (all Firmicutes) promote pathogenesis.

Transmaternal bisphenol A exposure accelerates diabetes type 1 development in NOD mice.

PubMed

Bodin, Johanna; Bølling, Anette Kocbach; Becher, Rune; Kuper, Frieke; Løvik, Martinus; Nygaard, Unni Cecilie

2014-02-01

Diabetes mellitus type 1 is an autoimmune disease with a genetic predisposition that is triggered by environmental factors during early life. Epidemiological studies show that bisphenol A (BPA), an endocrine disruptor, has been detected in about 90% of all analyzed human urine samples. In this study, BPA was found to increase the severity of insulitis and the incidence of diabetes in female non obese diabetic (NOD) mice offspring after transmaternal exposure through the dams' drinking water (0, 0.1, 1, and 10mg/l). Both the severity of insulitis in the pancreatic islets at 11 weeks of age and the diabetes prevalence at 20 weeks were significantly increased for female offspring in the highest exposure group compared to the control group. Increased numbers of apoptotic cells, a reduction in tissue resident macrophages and an increase in regulatory T cells were observed in islets prior to insulitis development in transmaternally exposed offspring. The detectable apoptotic cells were identified as mostly glucagon producing alpha-cells but also tissue resident macrophages and beta-cells. In the local (pancreatic) lymph node neither regulatory T cell nor NKT cell populations were affected by maternal BPA exposure. Maternal BPA exposure may have induced systemic immune changes in offspring, as evidenced by alterations in LPS- and ConA-induced cytokine secretion in splenocytes. In conclusion, transmaternal BPA exposure, in utero and through lactation, accelerated the spontaneous diabetes development in NOD mice. This acceleration appeared to be related to early life modulatory effects on the immune system, resulting in adverse effects later in life.

Cholinergic anti-inflammatory pathway in the non-obese diabetic mouse model.

PubMed

Koopman, F A; Vosters, J L; Roescher, N; Broekstra, N; Tak, P P; Vervoordeldonk, M J

2015-10-01

Activation of the cholinergic anti-inflammatory pathway (CAP) has been shown to reduce inflammation in animal models, while abrogation of the pathway increases inflammation. We investigated whether modulation of CAP influences inflammation in the non-obese diabetic (NOD) mouse model for Sjögren's syndrome and type 1 diabetes. The alpha-7 nicotinic acetylcholine receptor (α7nAChR) was stimulated with AR-R17779 or nicotine in NOD mice. In a second study, unilateral cervical vagotomy was performed. α7nAChR expression, focus scores, and salivary flow were evaluated in salivary glands (SG) and insulitis score in the pancreas. Cytokines were measured in serum and SG. α7nAChR was expressed on myoepithelial cells in SG. Monocyte chemotactic protein-1 levels were reduced in SG after AR-R17779 treatment and tumor necrosis factor production was increased in the SG of the vagotomy group compared to controls. Focus score and salivary flow were unaffected. NOD mice developed diabetes more rapidly after vagotomy, but at completion of the study there were no statistically significant differences in number of mice that developed diabetes or in insulitis scores. Intervention of the CAP in NOD mice leads to minimal changes in inflammatory cytokines, but did not affect overall inflammation and function of SG or development of diabetes. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Type 1 diabetes in NOD mice unaffected by mast cell deficiency.

PubMed

Gutierrez, Dario A; Fu, Wenxian; Schonefeldt, Susann; Feyerabend, Thorsten B; Ortiz-Lopez, Adriana; Lampi, Yulia; Liston, Adrian; Mathis, Diane; Rodewald, Hans-Reimer

2014-11-01

Mast cells have been invoked as important players in immune responses associated with autoimmune diseases. Based on in vitro studies, or in vivo through the use of Kit mutant mice, mast cells have been suggested to play immunological roles in direct antigen presentation to both CD4(+) and CD8(+) T cells, in the regulation of T-cell and dendritic cell migration to lymph nodes, and in Th1 versus Th2 polarization, all of which could significantly impact the immune response against self-antigens in autoimmune disease, including type 1 diabetes (T1D). Until now, the role of mast cells in the onset and incidence of T1D has only been indirectly tested through the use of low-specificity mast cell inhibitors and activators, and published studies reported contrasting results. Our three laboratories have generated independently two strains of mast cell-deficient nonobese diabetic (NOD) mice, NOD.Cpa3(Cre/+) (Heidelberg) and NOD.Kit(W-sh/W-sh) (Leuven and Boston), to address the effects of mast cell deficiency on the development of T1D in the NOD strain. Our collective data demonstrate that both incidence and progression of T1D in NOD mice are independent of mast cells. Moreover, analysis of pancreatic lymph node cells indicated that lack of mast cells has no discernible effect on the autoimmune response, which involves both innate and adaptive immune components. Our results demonstrate that mast cells are not involved in T1D in the NOD strain, making their role in this process nonessential and excluding them as potential therapeutic targets. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Comparative genetics: synergizing human and NOD mouse studies for identifying genetic causation of type 1 diabetes.

PubMed

Driver, John P; Chen, Yi-Guang; Mathews, Clayton E

2012-01-01

Although once widely anticipated to unlock how human type 1 diabetes (T1D) develops, extensive study of the nonobese diabetic (NOD) mouse has failed to yield effective treatments for patients with the disease. This has led many to question the usefulness of this animal model. While criticism about the differences between NOD and human T1D is legitimate, in many cases disease in both species results from perturbations modulated by the same genes or different genes that function within the same biological pathways. Like in humans, unusual polymorphisms within an MHC class II molecule contributes the most T1D risk in NOD mice. This insight supports the validity of this model and suggests the NOD has been improperly utilized to study how to cure or prevent disease in patients. Indeed, clinical trials are far from administering T1D therapeutics to humans at the same concentration ranges and pathological states that inhibit disease in NOD mice. Until these obstacles are overcome it is premature to label the NOD mouse a poor surrogate to test agents that cure or prevent T1D. An additional criticism of the NOD mouse is the past difficulty in identifying genes underlying T1D using conventional mapping studies. However, most of the few diabetogenic alleles identified to date appear relevant to the human disorder. This suggests that rather than abandoning genetic studies in NOD mice, future efforts should focus on improving the efficiency with which diabetes susceptibility genes are detected. The current review highlights why the NOD mouse remains a relevant and valuable tool to understand the genes and their interactions that promote autoimmune diabetes and therapeutics that inhibit this disease. It also describes a new range of technologies that will likely transform how the NOD mouse is used to uncover the genetic causes of T1D for years to come.

Upregulating CD4+CD25+FOXP3+ regulatory T cells in pancreatic lymph nodes in diabetic NOD mice by adjuvant immunotherapy.

PubMed

Tian, Bole; Hao, Jianqiang; Zhang, Yu; Tian, Lei; Yi, Huimin; O'Brien, Timothy D; Sutherland, David E R; Hering, Bernhard J; Guo, Zhiguang

2009-01-27

Immunotherapy with Complete Freund's adjuvant (CFA) is effective in ameliorating autoimmunity in diabetic nonobese diabetic (NOD) mice. We investigated whether CFA treatment up-regulates CD4+CD25+Foxp3+ regulatory T cells and increases transforming growth factor (TGF)-beta1 production in diabetic NOD mice. New-onset diabetic NOD mice were treated with CFA and exendin-4, a potent analog of glucagon-like peptide-1. Reversal of diabetes was determined by monitoring blood glucose level. Ameliorating autoimmunity through immunoregulation was assessed by adoptive transfer. Regulatory T cells in the peripheral blood, spleen, thymus, and pancreatic nodes were measured. TGF-beta1 in plasma and the insulin content in the pancreas were also measured. Immunostainings for insulin and BrdU were performed. New-onset diabetes could be reversed in 38% of NOD mice treated with CFA alone and in 86% of NOD mice treated with both CFA and exendin-4. Diabetes adoptive transfer by splenocytes from CFA-treated NOD mice was delayed. The percentage of CD4+CD25+Foxp3+ regulatory T cells in the pancreatic lymph nodes of CFA-treated NOD mice was significantly increased at 1, 5, and 15 to 17 weeks after treatment. TGF-beta1 in the plasma of CFA-treated NOD mice was also significantly increased. Combining CFA with exendin-4 treatment significantly increased the insulin content and the numbers of insulin and BrdU double-labeled beta cells in the islets. Our results demonstrated that CFA treatment ameliorates autoimmunity in diabetic NOD mice by up-regulating CD4=CD25+Foxp3+ regulatory T cells and increasing TGF-beta1 production. Exendin-4 enhanced the effect of CFA on reversing diabetes in NOD mice by stimulating beta-cell replication.

Activation of CD1d-restricted T cells protects NOD mice from developing diabetes by regulating dendritic cell subsets

PubMed Central

Naumov, Yuri N.; Bahjat, Keith S.; Gausling, Rudolph; Abraham, Roshini; Exley, Mark A.; Koezuka, Yasuhiko; Balk, Steven B.; Strominger, Jack L.; Clare-Salzer, Michael; Wilson, S. Brian

2001-01-01

CD1d-restricted invariant NKT (iNKT) cells are immunoregulatory cells whose loss exacerbates diabetes in nonobese diabetic (NOD) female mice. Here, we show that the relative numbers of iNKT cells from the pancreatic islets of NOD mice decrease at the time of conversion from peri-insulitis to invasive insulitis and diabetes. Conversely, NOD male mice who have a low incidence of diabetes showed an increased frequency of iNKT cells. Moreover, administration of α-galactosylceramide, a potent activating ligand presented by CD1d, ameliorated the development of diabetes in NOD female mice and resulted in the accumulation of iNKT cells and myeloid dendritic cells (DC) in pancreatic lymph nodes (PLN), but not in inguinal lymph nodes. Strikingly, injection of NOD female mice with myeloid DC isolated from the PLN, but not those from the inguinal lymph nodes, completely prevented diabetes. Thus, the immunoregulatory role of iNKT cells is manifested by the recruitment of tolerogenic myeloid DC to the PLN and the inhibition of ongoing autoimmune inflammation. PMID:11707602

Exaggerated Increases in Microglia Proliferation, Brain Inflammatory Response and Sickness Behaviour upon Lipopolysaccharide Stimulation in Non-Obese Diabetic Mice.

PubMed

McGuiness, Barry; Gibney, Sinead M; Beumer, Wouter; Versnel, Marjan A; Sillaber, Inge; Harkin, Andrew; Drexhage, Hemmo A

2016-01-01

The non-obese diabetic (NOD) mouse, an established model for autoimmune diabetes, shows an exaggerated reaction of pancreas macrophages to inflammatory stimuli. NOD mice also display anxiety when immune-stimulated. Chronic mild brain inflammation and a pro-inflammatory microglial activation is critical in psychiatric behaviour. To explore brain/microglial activation and behaviour in NOD mice at steady state and after systemic lipopolysaccharide (LPS) injection. Affymetrix analysis on purified microglia of pre-diabetic NOD mice (8-10 weeks) and control mice (C57BL/6 and CD1 mice, the parental non-autoimmune strain) at steady state and after systemic LPS (100 μg/kg) administration. Quantitative PCR was performed on the hypothalamus for immune activation markers (IL-1β, IFNγ and TNFα) and growth factors (BDNF and PDGF). Behavioural profiling of NOD, CD1, BALB/c and C57BL/6 mice at steady state was conducted and sickness behaviour/anxiety in NOD and CD1 mice was monitored before and after LPS injection. Genome analysis revealed cell cycle/cell death and survival aberrancies of NOD microglia, substantiated as higher proliferation on BrdU staining. Inflammation signs were absent. NOD mice had a hyper-reactive response to novel environments with some signs of anxiety. LPS injection induced a higher expression of microglial activation markers, a higher brain pro-inflammatory set point (IFNγ, IDO) and a reduced expression of BDNF and PDGF after immune stimulation in NOD mice. NOD mice displayed exaggerated and prolonged sickness behaviour after LPS administration. After stimulation with LPS, NOD mice display an increased microglial proliferation and an exaggerated inflammatory brain response with reduced BDNF and PDGF expression and increased sickness behaviour as compared to controls. © 2016 S. Karger AG, Basel.

The Role of NOD Mice in Type 1 Diabetes Research: Lessons from the Past and Recommendations for the Future.

PubMed

Chen, Yi-Guang; Mathews, Clayton E; Driver, John P

2018-01-01

For more than 35 years, the NOD mouse has been the primary animal model for studying autoimmune diabetes. During this time, striking similarities to the human disease have been uncovered. In both species, unusual polymorphisms in a major histocompatibility complex (MHC) class II molecule confer the most disease risk, disease is caused by perturbations by the same genes or different genes in the same biological pathways and that diabetes onset is preceded by the presence of circulating autoreactive T cells and autoantibodies that recognize many of the same islet antigens. However, the relevance of the NOD model is frequently challenged due to past failures translating therapies from NOD mice to humans and because the appearance of insulitis in mice and some patients is different. Nevertheless, the NOD mouse remains a pillar of autoimmune diabetes research for its usefulness as a preclinical model and because it provides access to invasive procedures as well as tissues that are rarely procured from patients or controls. The current article is focused on approaches to improve the NOD mouse by addressing reasons why immune therapies have failed to translate from mice to humans. We also propose new strategies for mixing and editing the NOD genome to improve the model in ways that will better advance our understanding of human diabetes. As proof of concept, we report that diabetes is completely suppressed in a knock-in NOD strain with a serine to aspartic acid substitution at position 57 in the MHC class II Aβ. This supports that similar non-aspartic acid substitutions at residue 57 of variants of the human class II HLA-DQβ homolog confer diabetes risk.

The Role of NOD Mice in Type 1 Diabetes Research: Lessons from the Past and Recommendations for the Future

PubMed Central

Chen, Yi-Guang; Mathews, Clayton E.; Driver, John P.

2018-01-01

For more than 35 years, the NOD mouse has been the primary animal model for studying autoimmune diabetes. During this time, striking similarities to the human disease have been uncovered. In both species, unusual polymorphisms in a major histocompatibility complex (MHC) class II molecule confer the most disease risk, disease is caused by perturbations by the same genes or different genes in the same biological pathways and that diabetes onset is preceded by the presence of circulating autoreactive T cells and autoantibodies that recognize many of the same islet antigens. However, the relevance of the NOD model is frequently challenged due to past failures translating therapies from NOD mice to humans and because the appearance of insulitis in mice and some patients is different. Nevertheless, the NOD mouse remains a pillar of autoimmune diabetes research for its usefulness as a preclinical model and because it provides access to invasive procedures as well as tissues that are rarely procured from patients or controls. The current article is focused on approaches to improve the NOD mouse by addressing reasons why immune therapies have failed to translate from mice to humans. We also propose new strategies for mixing and editing the NOD genome to improve the model in ways that will better advance our understanding of human diabetes. As proof of concept, we report that diabetes is completely suppressed in a knock-in NOD strain with a serine to aspartic acid substitution at position 57 in the MHC class II Aβ. This supports that similar non-aspartic acid substitutions at residue 57 of variants of the human class II HLA-DQβ homolog confer diabetes risk. PMID:29527189

A quantitative comparison of rates of phagocytosis and digestion of apoptotic cells by macrophages from normal (BALB/c) and diabetes-prone (NOD) mice.

PubMed

Marée, Athanasius F M; Komba, Mitsuhiro; Finegood, Diane T; Edelstein-Keshet, Leah

2008-01-01

Macrophages play an important role in clearing apoptotic debris from tissue. Defective or reduced clearance, seen, for instance, in non-obese diabetic (NOD) mice, has been correlated with initiation of autoimmune (Type 1) diabetes (T1D) (O'Brien BA, Huang Y, Geng X, Dutz JP, Finegood DT. Diabetes 51: 2481-2488, 2002). To validate such a link, it is essential to quantify the reduced clearance (for example, by comparison to BALB/c control mice) and to determine which elements of that clearance are impaired. Recently, we fit data for the time course of in vitro macrophage feeding experiments to basic models of macrophage clearance dynamics, thus quantifying kinetics of uptake and digestion of apoptotic cells in both mouse strains (Marée AFM, Komba M, Dyck C, Łabeçki M, Finegood DT, Edelstein-Keshet L. J Theor Biol 233: 533-551, 2005). In the cycle of modeling and experimental investigation, we identified the importance of 1) measuring short-, intermediate-, and long-time data (to increase the accuracy of parameter fits), and 2) designing experiments with distinct observable regimes, including engulfment-only and digestion-only phases. Here, we report on new results from experiments so designed. In comparing macrophages from the two strains, we find that NOD macrophage engulfment of apoptotic cells is 5.5 times slower than BALB/c controls. Significantly, our new data demonstrate that digestion is at least two times slower in NOD, in contrast with previous conclusions. Moreover, new data enable us to detect an acceleration in engulfment (after the first engulfment) in both strains, but much smaller in NOD macrophages.

Reduction of T cell receptor diversity in NOD mice prevents development of type 1 diabetes but not Sjögren's syndrome.

PubMed

Kern, Joanna; Drutel, Robert; Leanhart, Silvia; Bogacz, Marek; Pacholczyk, Rafal

2014-01-01

Non-obese diabetic (NOD) mice are well-established models of independently developing spontaneous autoimmune diseases, Sjögren's syndrome (SS) and type 1 diabetes (T1D). The key determining factor for T1D is the strong association with particular MHCII molecule and recognition by diabetogenic T cell receptor (TCR) of an insulin peptide presented in the context of I-Ag7 molecule. For SS the association with MHCII polymorphism is weaker and TCR diversity involved in the onset of the autoimmune phase of SS remains poorly understood. To compare the impact of TCR diversity reduction on the development of both diseases we generated two lines of TCR transgenic NOD mice. One line expresses transgenic TCRβ chain originated from a pathogenically irrelevant TCR, and the second line additionally expresses transgenic TCRαmini locus. Analysis of TCR sequences on NOD background reveals lower TCR diversity on Treg cells not only in the thymus, but also in the periphery. This reduction in diversity does not affect conventional CD4+ T cells, as compared to the TCRmini repertoire on B6 background. Interestingly, neither transgenic TCRβ nor TCRmini mice develop diabetes, which we show is due to lack of insulin B:9-23 specific T cells in the periphery. Conversely SS develops in both lines, with full glandular infiltration, production of autoantibodies and hyposalivation. It shows that SS development is not as sensitive to limited availability of TCR specificities as T1D, which suggests wider range of possible TCR/peptide/MHC interactions driving autoimmunity in SS.

Major histocompatibility complex class I-deficient NOD-B2mnull mice are diabetes and insulitis resistant.

PubMed

Serreze, D V; Leiter, E H; Christianson, G J; Greiner, D; Roopenian, D C

1994-03-01

Specific allelic combinations within the class II region of the major histocompatibility complex (MHC) represent a major genetic component for susceptibility to autoimmune insulin-dependent diabetes mellitus (IDDM) in humans. We produced and used a stock of NOD/Lt mice congenic for a functionally inactivated beta 2-microglobulin (B2mnull) locus to assess whether there was an absolute requirement for MHC class I expression and/or CD8+ T-cells in diabetogenesis. These NOD-B2mnull mice do not express cell surface MHC class I molecules or produce detectable levels of CD8+ T-cells and are diabetes and insulitis resistant. Previous results from transgenic mouse models indicated that intracellular accumulation of MHC class I molecules negatively affects pancreatic beta-cell function and can result in the development of nonautoimmune insulin-dependent diabetes mellitus (IDDM). MHC class I molecules have been shown to accumulate intracellularly in the presence of a disrupted B2m locus, but this mutation does not negatively affect plasma insulin levels in either NOD/Lt mice or in those of a mixed 129 and C57BL/6 genetic background. Interestingly, 14% of the male mice in this mixed background did develop hyperinsulinemia (> 1,500 pM) independent of the disrupted B2m locus, suggesting that these mice could conceivably develop insulin-resistant diabetes. However, none of these mice became diabetic at up to 22 months of age. Thus, elimination of cell surface MHC class I expression with a disrupted B2m gene blocks autoimmune diabetes in NOD/Lt mice, without engendering a separate, distinct form of glucose intolerance.

Metastable Pluripotent States in NOD Mouse Derived ES Cells

PubMed Central

Hanna, Jacob; Markoulaki, Styliani; Mitalipova, Maisam; Cheng, Albert W.; Cassady, John P.; Staerk, Judith; Carey, Bryce W.; Lengner, Christopher J.; Foreman, Ruth; Love, Jennifer; Gao, Qing; Kim, Jongpil; Jaenisch, Rudolf

2009-01-01

Embryonic stem (ES) cells are isolated from the inner cell mass (ICM) of blastocysts, whereas epiblast stem cells (EpiSCs) are derived from the post-implantation epiblast and display a restricted developmental potential. Here we characterize pluripotent states in the non-obese diabetic (NOD) mouse strain, which prior to this study was considered “non-permissive” for ES cell derivation. We find that NOD stem cells can be stabilized by providing constitutive expression of Klf4 or c-Myc or small molecules that can replace these factors during in vitro reprogramming. The NOD ES and iPS cells appear “metastable”, as they acquire an alternative EpiSC-like identity after removal of the exogenous factors, while their reintroduction converts the cells back to ICM-like pluripotency. Our findings suggest that stem cells from different genetic backgrounds can assume distinct states of pluripotency in vitro, the stability of which is regulated by endogenous genetic determinants and can be modified by exogenous factors. PMID:19427283

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

Fornari, Thais A; Donate, Paula B; Assis, Amanda F; 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.

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

Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria.

PubMed

Riera, Marta; Anguiano, Lidia; Clotet, Sergi; Roca-Ho, Heleia; Rebull, Marta; Pascual, Julio; Soler, Maria Jose

2016-03-15

Circulating and renal activity of angiotensin-converting enzyme 2 (ACE2) is increased in non-obese diabetic (NOD) mice. Because paricalcitol has been reported to protect against diabetic nephropathy, we investigated the role of paricalcitol in modulating ACE2 in these mice. In addition, renal ADAM17, a metalloprotease implied in ACE2 shedding, was assessed. NOD female and non-diabetic control mice were studied for 21 days after diabetes onset and divided into various treatment groups. Diabetic animals received either vehicle; 0.4 or 0.8 μg/kg paricalcitol, aliskiren, or a combination of paricalcitol and aliskiren. We then studied the effect of paricalcitol on ACE2 expression in proximal tubular epithelial cells. Paricalcitol alone or in combination with aliskiren resulted in significantly reduced circulating ACE2 activity in NOD mice but there were no changes in urinary albumin excretion. Serum renin activity was significantly decreased in mice that received aliskiren but no effect was found when paricalcitol was used alone. Renal content of ADAM17 was significantly decreased in animals that received a high dose of paricalcitol. Renal and circulating oxidative stress (quantified by plasma H2O2 levels and immunolocalization of nitrotyrosine) were reduced in high-dose paricalcitol-treated mice compared with non-treated diabetic mice. In culture, paricalcitol incubation resulted in a significant increase in ACE2 expression compared with nontreated cells. In NOD mice with type 1 diabetes, paricalcitol modulates ACE2 activity, ADAM17, and oxidative stress renal content independently from the glycemic profile and urinary albumin excretion. In tubular cells, paricalcitol may modulate ACE2 by blocking its shedding. In the early stage of diabetic nephropathy, paricalcitol treatment counterbalances the effect of diabetes on circulating ACE2 activity. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard

Elevated systemic glutamic acid level in the non-obese diabetic mouse is Idd linked and induces beta cell apoptosis.

PubMed

Banday, Viqar Showkat; Lejon, Kristina

2017-02-01

Although type 1 diabetes (T1D) is a T-cell-mediated disease in the effector stage, the mechanism behind the initial beta cell assault is less understood. Metabolomic differences, including elevated levels of glutamic acid, have been observed in patients with T1D before disease onset, as well as in pre-diabetic non-obese diabetic (NOD) mice. Increased levels of glutamic acid damage both neurons and beta cells, implying that this could contribute to the initial events of T1D pathogenesis. We investigated the underlying genetic factors and consequences of the increased levels of glutamic acid in NOD mice. Serum glutamic acid levels from a (NOD×B6)F 2 cohort (n = 182) were measured. By genome-wide and Idd region targeted microsatellite mapping, genetic association was detected for six regions including Idd2, Idd4 and Idd22. In silico analysis of potential enzymes and transporters located in and around the mapped regions that are involved in glutamic acid metabolism consisted of alanine aminotransferase, glutamic-oxaloacetic transaminase, aldehyde dehydrogenase 18 family, alutamyl-prolyl-tRNA synthetase, glutamic acid transporters GLAST and EAAC1. Increased EAAC1 protein expression was observed in lysates from livers of NOD mice compared with B6 mice. Functional consequence of the elevated glutamic acid level in NOD mice was tested by culturing NOD. Rag2 -/- Langerhans' islets with glutamic acid. Induction of apoptosis of the islets was detected upon glutamic acid challenge using TUNEL assay. Our results support the notion that a dysregulated metabolome could contribute to the initiation of T1D. We suggest that targeting of the increased glutamic acid in pre-diabetic patients could be used as a potential therapy. © 2016 John Wiley & Sons Ltd.

New-onset diabetes mellitus after heart transplantation in children - Incidence and risk factors.

PubMed

Sehgal, Swati; Bock, Matthew J; Louks Palac, Hannah; Brickman, Wendy J; Gossett, Jeffrey G; Marino, Bradley S; Backer, Carl L; Pahl, Elfriede

2016-11-01

Diabetes mellitus is a recognized complication of SOT in adults and is associated with decreased graft and patient survival. Little is known about NOD in pediatric HT recipients. We aimed to characterize the incidence and describe risk factors for development of NOD after HT in children. Children who developed diabetes after HT were identified from the OPTN database. Demographic and clinical data before and after transplant were compared between patients with and without NOD. A total of 2056 children were included, 56% were male, 54% were Caucasian, and 62% had cardiomyopathy prior to HT. NOD developed in 219 children (11%) after HT. The incidence of NOD was 2.4, 9.0, and 10.4% at one, five, and 10 yr after HT, respectively. Obesity (HR: 4.32), dialysis prior to transplant (HR: 2.38), African American race (HR: 1.86), transplant before year 2000 (HR: 1.82), female gender (HR: 1.68), and older age at transplant (HR: 1.28) were independent predictors of NOD. The major modifiable risk factor for NOD is obesity, imparting the maximum hazard. Improved surveillance for diabetes in high-risk patients and specific prevention and intervention strategies are imperative in this population. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Anti-FcεR1 antibody injections activate basophils and mast cells and delay Type I diabetes onset in NOD mice

PubMed Central

Larson, David; Torrero, Marina N.; Mueller, Ellen; Shi, Yinghui; Killoran, Kristin

2012-01-01

Mounting evidence suggests that helminth infections protect against autoimmune diseases. As helminths cause chronic IgE-mediated activation of basophils and mast cells we hypothesized that continuous activation of these cells could prevents diabetes onset in nonobese diabetic (NOD) mice in the absence of infection. Anti-FcεR1 activated basophils and mast cells and resulted in the release of IL-4 and histamine into the bloodstream. Anti-FcεR1-treated NOD mice showed a type 2 shift in insulin-specific antibody production and exhibited significant delays in diabetes onset. IL-4 responses played a partial role as the protective effect of anti-FcεR1 therapy was diminished in IL-4-deficient NOD mice. In contrast, histamine signaling was not required as anti-FcεR1-mediated protection was not reduced in mice treated with histamine receptor blockers. These results demonstrate that anti-FcεR1 therapy delays diabetes onset in NOD mice and suggest that chronic basophil and mast cell activation may represent a new avenue of therapy for Th1-associated autoimmune diseases. PMID:21920822

Specific destruction of islet transplants in NOD<-->C57BL/6 and NOD<-->C3H/Tif embryo aggregation chimeras irrespective of allelic differences in beta-cell antigens.

PubMed

Leijon, K; Hillörn, V; Bergqvist, I; Holmberg, D

1995-06-01

We have tested the hypothesis that allelic differences in the antigens expressed by the beta-cells of the islets of Langerhans influence the development of insulitis in the non-obese diabetic (NOD) mouse. Islets of Langerhans from NOD, C57BL/6 and C3H/Tif mice were transplanted under the kidney capsule of NOD<-->C57BL/6 and NOD<-->C3H/Tif embryo aggregation (EA) chimeras and the infiltration was scored 5-7 weeks later. Mononuclear cell infiltration of pancreatic islets was observed in 60% of the NOD<-->C57BL/6 and in 55% of the NOD<-->C3H/Tif EA chimeras. All transplanted EA chimeras that developed insulitis also displayed mononuclear cell infiltrates in the transplants, irrespective of the origin of the transplanted islets. In contrast, no infiltration of transplants was detected in EA chimeras scoring negative for insulitis. These results demonstrate that the specific destruction of islet transplants does not require the expression of NOD specific antigens by the islets. Moreover, the beta-cell destruction appears not to be restricted to NOD-MHC. The correlation between insulitis and transplant beta-cell destruction suggests the possibility that the development of insulitis is a prerequisite for transplant specific destruction. MHC restricted destruction may, therefore, precede the beta-cell destruction of transplanted islets. The chimerism among the mononuclear cells infiltrating the islet transplants was found to correlate with the overall haematopoetic chimerism in each of the individual EA chimeras. This observation suggests that NOD bone marrow, as well as non-NOD bone marrow, generates cells contributing to the beta-cell destruction process.

Akkermansia muciniphila induces gut microbiota remodelling and controls islet autoimmunity in NOD mice.

PubMed

Hänninen, Arno; Toivonen, Raine; Pöysti, Sakari; Belzer, Clara; Plovier, Hubert; Ouwerkerk, Janneke P; Emani, Rohini; Cani, Patrice D; De Vos, Willem M

2017-12-21

Intestinal microbiota is implicated in the pathogenesis of autoimmune type 1 diabetes in humans and in non-obese diabetic (NOD) mice, but evidence on its causality and on the role of individual microbiota members is limited. We investigated if different diabetes incidence in two NOD colonies was due to microbiota differences and aimed to identify individual microbiota members with potential significance. We profiled intestinal microbiota between two NOD mouse colonies showing high or low diabetes incidence by 16S ribosomal RNA gene sequencing and colonised the high-incidence colony with the microbiota of the low-incidence colony. Based on unaltered incidence, we identified a few taxa which were not effectively transferred and thereafter, transferred experimentally one of these to test its potential significance. Although the high-incidence colony adopted most microbial taxa present in the low-incidence colony, diabetes incidence remained unaltered. Among the few taxa which were not transferred, Akkermansia muciniphila was identified. As A. muciniphila abundancy is inversely correlated to the risk of developing type 1 diabetes-related autoantibodies, we transferred A. muciniphila experimentally to the high-incidence colony. A. muciniphila transfer promoted mucus production and increased expression of antimicrobial peptide Reg3γ , outcompeted Ruminococcus torques from the microbiota, lowered serum endotoxin levels and islet toll-like receptor expression, promoted regulatory immunity and delayed diabetes development. Transfer of the whole microbiota may not reduce diabetes incidence despite a major change in gut microbiota, but single symbionts such as A. muciniphila with beneficial metabolic and immune signalling effects may reduce diabetes incidence when administered as a probiotic. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly

Rotavirus Activates Lymphocytes from Non-Obese Diabetic Mice by Triggering Toll-Like Receptor 7 Signaling and Interferon Production in Plasmacytoid Dendritic Cells

PubMed Central

Pane, Jessica A.; Webster, Nicole L.; Coulson, Barbara S.

2014-01-01

It has been proposed that rotavirus infection promotes the progression of genetically-predisposed children to type 1 diabetes, a chronic autoimmune disease marked by infiltration of activated lymphocytes into pancreatic islets. Non-obese diabetic (NOD) mice provide a model for the human disease. Infection of adult NOD mice with rhesus monkey rotavirus (RRV) accelerates diabetes onset, without evidence of pancreatic infection. Rather, RRV spreads to the pancreatic and mesenteric lymph nodes where its association with antigen-presenting cells, including dendritic cells, induces cellular maturation. RRV infection increases levels of the class I major histocompatibility complex on B cells and proinflammatory cytokine expression by T cells at these sites. In autoimmunity-resistant mice and human mononuclear cells from blood, rotavirus-exposed plasmacytoid dendritic cells contribute to bystander polyclonal B cell activation through type I interferon expression. Here we tested the hypothesis that rotavirus induces bystander activation of lymphocytes from NOD mice by provoking dendritic cell activation and proinflammatory cytokine secretion. NOD mouse splenocytes were stimulated with rotavirus and assessed for activation by flow cytometry. This stimulation activated antigen-presenting cells and B cells independently of virus strain and replicative ability. Instead, activation depended on virus dose and was prevented by blockade of virus decapsidation, inhibition of endosomal acidification and interference with signaling through Toll-like receptor 7 and the type I interferon receptor. Plasmacytoid dendritic cells were more efficiently activated than conventional dendritic cells by RRV, and contributed to the activation of B and T cells, including islet-autoreactive CD8+ T cells. Thus, a double-stranded RNA virus can induce Toll-like receptor 7 signaling, resulting in lymphocyte activation. Our findings suggest that bystander activation mediated by type I interferon

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

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

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

Spontaneous osteosarcoma of the femur in a non-obese diabetic mouse

PubMed Central

Hong, Sunhwa; Lee, Hyun-A; Choe, Ohmok; Chung, Youngho

2011-01-01

An abnormal swelling was identified in the distal portion of the right femur in a 1-year-old non-obese diabetic (NOD) mouse. Grossly, a large mass of the distal femur was observed in the right femur. Lesions were poorly marginated, associated with destruction of the cancellous and cortical elements of the bone, and showed ossification within the soft tissue component. Histologically, the tumor was identified as a poorly differentiated sarcoma. Histopathologic examination of the bone masses revealed invasive proliferation of poorly differentiated neoplastic mesenchymal cells forming streams, bundles, and nests, which resulted in destruction of normal bone. Neoplastic cells exhibited random variation in cellular appearance and arrangement, as well as matrix composition and abundance. Haphazard and often intermingling patterns of osteogenic, chondroblastic, lipoblastic, and angiogenic tissues were present. Larger areas of neoplastic bone and hyaline cartilage contained multiple large areas of hemorrhage and necrosis bordered by neoplastic cells. The mass was diagnosed as an osteosarcoma. To our knowledge, this is the first spontaneous osteosarcoma in an NOD mouse. PMID:21998615

Comparative Pathogenesis of Autoimmune Diabetes in Humans, NOD Mice, and Canines: Has a Valuable Animal Model of Type 1 Diabetes Been Overlooked?

PubMed Central

O’Kell, Allison L.; Wasserfall, Clive; Catchpole, Brian; Davison, Lucy J.; Hess, Rebecka S.; Kushner, Jake A.

2017-01-01

Despite decades of research in humans and mouse models of disease, substantial gaps remain in our understanding of pathogenic mechanisms underlying the development of type 1 diabetes. Furthermore, translation of therapies from preclinical efforts capable of delaying or halting β-cell destruction has been limited. Hence, a pressing need exists to identify alternative animal models that reflect human disease. Canine insulin deficiency diabetes is, in some cases, considered to follow autoimmune pathogenesis, similar to NOD mice and humans, characterized by hyperglycemia requiring lifelong exogenous insulin therapy. Also similar to human type 1 diabetes, the canonical canine disorder appears to be increasing in prevalence. Whereas islet architecture in rodents is distinctly different from humans, canine pancreatic endocrine cell distribution is more similar. Differences in breed susceptibility alongside associations with MHC and other canine immune response genes parallel that of different ethnic groups within the human population, a potential benefit over NOD mice. The impact of environment on disease development also favors canine over rodent models. Herein, we consider the potential for canine diabetes to provide valuable insights for human type 1 diabetes in terms of pancreatic histopathology, impairment of β-cell function and mass, islet inflammation (i.e., insulitis), and autoantibodies specific for β-cell antigens. PMID:28533295

Degradable polymeric carrier for the delivery of IL-10 plasmid DNA to prevent autoimmune insulitis of NOD mice.

PubMed

Koh, J J; Ko, K S; Lee, M; Han, S; Park, J S; Kim, S W

2000-12-01

Recently, we have reported that biodegradable poly [alpha-(4-aminobutyl)-L-glycolic acid] (PAGA) can condense and protect plasmid DNA from DNase I. In this study, we investigated whether the systemic administration of pCAGGS mouse IL-10 (mIL-10) expression plasmid complexed with PAGA can reduce the development of insulitis in non-obese diabetic (NOD) mice. PAGA/mIL-10 plasmid complexes were stable for more than 60 min, but the naked DNA was destroyed within 10 min by DNase I. The PAGA/DNA complexes were injected into the tail vein of 3-week-old NOD mice. Serum mIL-10 level peaked at 5 days after injection, and could be detected for more than 9 weeks. The prevalence of severe insulitis on 12-week-old NOD mice was markedly reduced by the intravenous injection of PAGA/DNA complex (15.7%) compared with that of naked DNA injection (34.5%) and non-treated controls (90.9%). In conclusion, systemic administration of pCAGGS mIL-10 plasmid/PAGA complexes can reduce the severity of insulitis in NOD mice. This study shows that the PAGA/DNA complex has the potential for the prevention of autoimmune diabetes mellitus. Gene Therapy (2000) 7, 2099-2104.

Inhibition of autoimmune diabetes in NOD mice with serum from streptococcal preparation (OK-432)-injected mice.

PubMed Central

Seino, H; Satoh, J; Shintani, S; Takahashi, K; Zhu, X P; Masuda, T; Nobunaga, T; Saito, M; Terano, Y; Toyota, T

1991-01-01

We have recently reported that systemic and chronic administration of recombinant tumour necrosis factor alpha (TNF-alpha), as well as streptococcal preparation (OK-432), inhibits development of insulin-dependent diabetes mellitus (IDDM) in NOD mice and BB rats, models of IDDM. In this study we examined whether serum containing endogenous TNF induced by OK-432 injection could inhibit IDDM in NOD mice. Treatment twice a week from 4 weeks of age with OK-432-injected mouse serum, which contained endogenous TNF (75U), but not IL-1, IL-2 and interferon-gamma (IFN-gamma) activity, reduced the intensity of insulitis and significantly inhibited the cumulative incidence of diabetes by 28 weeks of age in NOD mice, as compared with the incidence in non-treated mice (P less than 0.01) and in mice treated with control serum (P less than 0.02). This inhibitory effect of the serum was diminished, although not significantly, by neutralization of serum TNF activity with anti-mouse TNF antibody. In the mice treated with the serum from OK-432-injected mice, Thy-1.2+ or CD8+ spleen cells decreased (P less than 0.01) and surface-Ig+ (S-Ig+) cells increased (P less than 0.05), whereas the proliferative response of spleen cells to concanavalin A (P less than 0.01) and lipopolysaccharide (P less than 0.05) increased. The results indicate that the inhibition by OK-432 treatment of IDDM in NOD mice was partially mediated by serum factors including endogenous TNF. PMID:1747949

Long-term reversal of diabetes in non-obese diabetic mice by liver-directed gene therapy.

PubMed

Ren, Binhai; O'Brien, Bronwyn A; Byrne, Michelle R; Ch'ng, Edwin; Gatt, Prudence N; Swan, M Anne; Nassif, Najah T; Wei, Ming Q; Gijsbers, Rik; Debyser, Zeger; Simpson, Ann M

2013-01-01

Type 1 diabetes (T1D) results from an autoimmune attack against the insulin-producing β-cells of the pancreas. The present study aimed to reverse T1D by gene therapy. We used a novel surgical technique, which involves isolating the liver from the circulation before the delivery of a lentiviral vector carrying furin-cleavable human insulin (INS-FUR) or empty vector to the livers of diabetic non-obese diabetic mice (NOD). This was compared with the direct injection of the vector into the portal circulation. Mice were monitored for body weight and blood glucose. Intravenous glucose tolerance tests were performed. Expression of insulin and pancreatic transcription factors was determined by the reverse transcriptase-polymerase chain reaction and immunohistochemistry and immunoelectron microscopy was used to localise insulin. Using the novel surgical technique, we achieved long-term transduction (42% efficiency) of hepatocytes, restored normoglycaemia for 150 days (experimental endpoint) and re-established normal glucose tolerance. We showed the expression of β-cell transcription factors, murine insulin, glucagon and somatostatin, and hepatic storage of insulin in granules. The expression of hepatic markers, C/EBP-β, G6PC, AAT and GLUI was down-regulated in INS-FUR-treated livers. Liver function tests remained normal, with no evidence of intrahepatic inflammation or autoimmune destruction of the insulin-secreting liver tissue. By comparison, direct injection of INS-FUR reduced blood glucose levels, and no pancreatic transdifferentiation or normal glucose tolerance was observed. This gene therapy protocol has, for the first time, permanently reversed T1D with normal glucose tolerance in NOD mice and, as such, represents a novel therapeutic strategy for the treatment of T1D. Copyright © 2013 John Wiley & Sons, Ltd.

Guillain Barré Syndrome is induced in Non-Obese Diabetic (NOD) mice following Campylobacter jejuni infection and is exacerbated by antibiotics.

PubMed

St Charles, J L; Bell, J A; Gadsden, B J; Malik, A; Cooke, H; Van de Grift, L K; Kim, H Y; Smith, E J; Mansfield, L S

2017-02-01

Campylobacter jejuni is a leading cause of bacterial gastroenteritis linked to several serious autoimmune sequelae such as the peripheral neuropathies Guillain Barré syndrome (GBS) and Miller Fisher syndrome (MFS). We hypothesized that GBS and MFS can result in NOD wild type (WT) mice or their congenic interleukin (IL)-10 or B7-2 knockouts secondary to C. jejuni infection. Mice were gavaged orally with C. jejuni strains HB93-13 and 260.94 from patients with GBS or CF93-6 from a patient with MFS and assessed for clinical neurological signs and phenotypes, anti-ganglioside antibodies, and cellular infiltrates and lesions in gut and peripheral nerve tissues. Significant increases in autoantibodies against single gangliosides (GM1, GQ1b, GD1a) occurred in infected NOD mice of all genotypes, although the isotypes varied (NOD WT had IgG1, IgG3; NOD B7-2 -/- had IgG3; NOD IL-10 -/- had IgG1, IgG3, IgG2a). Infected NOD WT and NOD IL-10 -/- mice also produced anti-ganglioside antibodies of the IgG1 isotype directed against a mixture of GM1/GQ1b gangliosides. Phenotypic tests showed significant differences between treatment groups of all mouse genotypes. Peripheral nerve lesions with macrophage infiltrates were significantly increased in infected mice of NOD WT and IL-10 -/- genotypes compared to sham-inoculated controls, while lesions with T cell infiltrates were significantly increased in infected mice of the NOD B7-2 -/- genotype compared to sham-inoculated controls. In both infected and sham inoculated NOD IL-10 -/- mice, antibiotic treatment exacerbated neurological signs, lesions and the amount and number of different isotypes of antiganglioside autoantibodies produced. Thus, inducible mouse models of post-C. jejuni GBS are feasible and can be characterized based on evaluation of three factors-onset of GBS clinical signs/phenotypes, anti-ganglioside autoantibodies and nerve lesions. Based on these factors we characterized 1) NOD B-7 -/- mice as an acute

Novel Humanized mice to test Therapeutics for Human Type 1 Diabetes

DTIC Science & Technology

2014-01-06

performed in non- obese diabetic (NOD) mice, the closest animal model for human T1D, have identified different immune cells involved in pancreatic β-cell...periphery. Each MHC class II chain contributes to the formation of a groove where the peptide is embedded (78). 17 The polygenetic factor underlying...diabetes mellitus in non- obese diabetic mice by transgenes encoding modified I-A beta-chain or normal I-E alpha-chain. Nature 345:727-9 63. Marek

Prevention of Autoimmune Diabetes and Induction of β-Cell Proliferation in NOD Mice by Hyperbaric Oxygen Therapy

PubMed Central

Faleo, Gaetano; Fotino, Carmen; Bocca, Nicola; Molano, R. Damaris; Zahr-Akrawi, Elsie; Molina, Judith; Villate, Susana; Umland, Oliver; Skyler, Jay S.; Bayer, Allison L.; Ricordi, Camillo; Pileggi, Antonello

2012-01-01

We evaluated the effects of hyperbaric oxygen therapy (HOT) on autoimmune diabetes development in nonobese diabetic (NOD) mice. Animals received no treatment or daily 60-min HOT 100% oxygen (HOT-100%) at 2.0 atmospheres absolute and were monitored for diabetes onset, insulitis, infiltrating cells, immune cell function, and β-cell apoptosis and proliferation. Cyclophosphamide-induced diabetes onset was reduced from 85.3% in controls to 48% after HOT-100% (P < 0.005) and paralleled by lower insulitis. Spontaneous diabetes incidence reduced from 85% in controls to 65% in HOT-100% (P = 0.01). Prediabetic mice receiving HOT-100% showed lower insulitis scores, reduced T-cell proliferation upon stimulation in vitro (P < 0.03), increased CD62L expression in T cells (P < 0.04), reduced costimulation markers (CD40, DC80, and CD86), and reduced major histocompatibility complex class II expression in dendritic cells (DCs) (P < 0.025), compared with controls. After autoimmunity was established, HOT was less effective. HOT-100% yielded reduced apoptosis (transferase-mediated dUTP nick-end labeling-positive insulin-positive cells; P < 0.01) and increased proliferation (bromodeoxyuridine incorporation; P < 0.001) of insulin-positive cells compared with controls. HOT reduces autoimmune diabetes incidence in NOD mice via increased resting T cells and reduced activation of DCs with preservation of β-cell mass resulting from decreased apoptosis and increased proliferation. The safety profile and noninvasiveness makes HOT an appealing adjuvant therapy for diabetes prevention and intervention trials. PMID:22566533

PD-L1–Driven Tolerance Protects Neurogenin3-Induced Islet Neogenesis to Reverse Established Type 1 Diabetes in NOD Mice

PubMed Central

Li, Rongying; Lee, Jeongkyung; Kim, Mi-sun; Liu, Victoria; Moulik, Mousumi; Li, Haiyan; Yi, Qing; Xie, Aini; Chen, Wenhao; Yang, Lina; Li, Yimin; Tsai, Tsung Huang; Oka, Kazuhiro

2015-01-01

A breakdown in self-tolerance underlies autoimmune destruction of β-cells and type 1 diabetes. A cure by restoring β-cell mass is limited by the availability of transplantable β-cells and the need for chronic immunosuppression. Evidence indicates that inhibiting costimulation through the PD-1/PD-L1 pathway is central to immune tolerance. We therefore tested whether induction of islet neogenesis in the liver, protected by PD-L1–driven tolerance, reverses diabetes in NOD mice. We demonstrated a robust induction of neo-islets in the liver of diabetic NOD mice by gene transfer of Neurogenin3, the islet-defining factor, along with betacellulin, an islet growth factor. These neo-islets expressed all the major pancreatic hormones and transcription factors. However, an enduring restoration of glucose-stimulated insulin secretion and euglycemia occurs only when tolerance is also induced by the targeted overexpression of PD-L1 in the neo-islets, which results in inhibition of proliferation and increased apoptosis of infiltrating CD4+ T cells. Further analysis revealed an inhibition of cytokine production from lymphocytes isolated from the liver but not from the spleen of treated mice, indicating that treatment did not result in generalized immunosuppression. This treatment strategy leads to persistence of functional neo-islets that resist autoimmune destruction and consequently an enduring reversal of diabetes in NOD mice. PMID:25332429

A Novel Clinically Relevant Strategy to Abrogate Autoimmunity and Regulate Alloimmunity in NOD Mice

PubMed Central

Vergani, Andrea; D'Addio, Francesca; Jurewicz, Mollie; Petrelli, Alessandra; Watanabe, Toshihiko; Liu, Kaifeng; Law, Kenneth; Schuetz, Christian; Carvello, Michele; Orsenigo, Elena; Deng, Shaoping; Rodig, Scott J.; Ansari, Javeed M.; Staudacher, Carlo; Abdi, Reza; Williams, John; Markmann, James; Atkinson, Mark; Sayegh, Mohamed H.; Fiorina, Paolo

2010-01-01

OBJECTIVE To investigate a new clinically relevant immunoregulatory strategy based on treatment with murine Thymoglobulin mATG Genzyme and CTLA4-Ig in NOD mice to prevent allo- and autoimmune activation using a stringent model of islet transplantation and diabetes reversal. RESEARCH DESIGN AND METHODS Using allogeneic islet transplantation models as well as NOD mice with recent onset type 1 diabetes, we addressed the therapeutic efficacy and immunomodulatory mechanisms associated with a new immunoregulatory protocol based on prolonged low-dose mATG plus CTLA4-Ig. RESULTS BALB/c islets transplanted into hyperglycemic NOD mice under prolonged mATG+CTLA4-Ig treatment showed a pronounced delay in allograft rejection compared with untreated mice (mean survival time: 54 vs. 8 days, P < 0.0001). Immunologic analysis of mice receiving transplants revealed a complete abrogation of autoimmune responses and severe downregulation of alloimmunity in response to treatment. The striking effect on autoimmunity was confirmed by 100% diabetes reversal in newly hyperglycemic NOD mice and 100% indefinite survival of syngeneic islet transplantation (NOD.SCID into NOD mice). CONCLUSIONS The capacity to regulate alloimmunity and to abrogate the autoimmune response in NOD mice in different settings confirmed that prolonged mATG+CTLA4-Ig treatment is a clinically relevant strategy to translate to humans with type 1 diabetes. PMID:20805386

Prevention of Diabetes in NOD Mice by Repeated Exposures to a Contact Allergen Inducing a Sub-Clinical Dermatitis

PubMed Central

Engkilde, Kaare; Buschard, Karsten; Hansen, Axel Kornerup; Menné, Torkil; Johansen, Jeanne Duus

2010-01-01

Background Type 1 diabetes is an autoimmune disease, while allergic contact dermatitis although immune mediated, is considered an exposure driven disease that develops due to epicutanous contact with reactive low-molecular chemicals. The objective of the present study was to experimentally study the effect of contact allergens on the development of diabetes in NOD mice. As the link between contact allergy and diabetes is yet unexplained we also examined the effect of provocation with allergens on Natural Killer T (NKT) cells, since involvement of NKT cells could suggest an innate connection between the two diseases. Method NOD mice 4 weeks of age were exposed, on the ears, to two allergens, p-phenylenediamine and 2,4-dinitrochlorobenzene respectively, to investigate the diabetes development. The mice were followed for a maximum of 32 weeks, and they were either repeatedly exposed to the allergens or only sensitized a week after arrival. The stimulation of NKT cells by the two allergens were additionally studied in C57BL/6 mice. The mice were sensitized and two weeks later provocated with the allergens. The mice were subsequently euthanized at different time points after the provocation. Results It was found that repeated application of p-phenylenediamine reduced the incidence of diabetes compared to application with water (47% vs. 93%, P = 0.004). Moreover it was shown that in C57BL/6 mice both allergens resulted in a slight increment in the quantity of NKT cells in the liver. Application of the allergens at the same time resulted in an increased number of NKT cells in the draining auricular lymph node, and the increase appeared to be somewhat allergen specific as the accumulation was stronger for p-phenylenediamine. Conclusion The study showed that repeated topical application on the ears with a contact allergen could prevent the development of diabetes in NOD mice. The contact allergens gave a non-visible, sub-clinical dermatitis on the application site. The

Troxerutin Attenuates Enhancement of Hepatic Gluconeogenesis by Inhibiting NOD Activation-Mediated Inflammation in High-Fat Diet-Treated Mice.

PubMed

Zhang, Zifeng; Wang, Xin; Zheng, Guihong; Shan, Qun; Lu, Jun; Fan, Shaohua; Sun, Chunhui; Wu, Dongmei; Zhang, Cheng; Su, Weitong; Sui, Junwen; Zheng, Yuanlin

2016-12-25

Recent evidence suggests that troxerutin, a trihydroxyethylated derivative of natural bioflavonoid rutin, exhibits beneficial effects on diabetes-related symptoms. Here we investigated the effects of troxerutin on the enhancement of hepatic gluconeogenesis in high-fat diet (HFD)-treated mice and the mechanisms underlying these effects. Mice were divided into four groups: Control group, HFD group, HFD + Troxerutin group, and Troxerutin group. Troxerutin was treated by daily oral administration at doses of 150 mg/kg/day for 20 weeks. Tauroursodeoxycholic acid (TUDCA) was used to inhibit endoplasmic reticulum stress (ER stress). Our results showed that troxerutin effectively improved obesity and related metabolic parameters, and liver injuries in HFD-treated mouse. Furthermore, troxerutin significantly attenuated enhancement of hepatic gluconeogenesis in HFD-fed mouse. Moreover, troxerutin notably suppressed nuclear factor-κB (NF-κB) p65 transcriptional activation and release of inflammatory cytokines in HFD-treated mouse livers. Mechanismly, troxerutin dramatically decreased Nucleotide oligomerization domain (NOD) expression, as well as interaction between NOD1/2 with interacting protein-2 (RIP2), by abating oxidative stress-induced ER stress in HFD-treated mouse livers, which was confirmed by TUDCA treatment. These improvement effects of troxerutin on hepatic glucose disorders might be mediated by its anti-obesity effect. In conclusion, troxerutin markedly diminished HFD-induced enhancement of hepatic gluconeogenesis via its inhibitory effects on ER stress-mediated NOD activation and consequent inflammation, which might be mediated by its anti-obesity effect.

Troxerutin Attenuates Enhancement of Hepatic Gluconeogenesis by Inhibiting NOD Activation-Mediated Inflammation in High-Fat Diet-Treated Mice

PubMed Central

Zhang, Zifeng; Wang, Xin; Zheng, Guihong; Shan, Qun; Lu, Jun; Fan, Shaohua; Sun, Chunhui; Wu, Dongmei; Zhang, Cheng; Su, Weitong; Sui, Junwen; Zheng, Yuanlin

2016-01-01

Recent evidence suggests that troxerutin, a trihydroxyethylated derivative of natural bioflavonoid rutin, exhibits beneficial effects on diabetes-related symptoms. Here we investigated the effects of troxerutin on the enhancement of hepatic gluconeogenesis in high-fat diet (HFD)-treated mice and the mechanisms underlying these effects. Mice were divided into four groups: Control group, HFD group, HFD + Troxerutin group, and Troxerutin group. Troxerutin was treated by daily oral administration at doses of 150 mg/kg/day for 20 weeks. Tauroursodeoxycholic acid (TUDCA) was used to inhibit endoplasmic reticulum stress (ER stress). Our results showed that troxerutin effectively improved obesity and related metabolic parameters, and liver injuries in HFD-treated mouse. Furthermore, troxerutin significantly attenuated enhancement of hepatic gluconeogenesis in HFD-fed mouse. Moreover, troxerutin notably suppressed nuclear factor-κB (NF-κB) p65 transcriptional activation and release of inflammatory cytokines in HFD-treated mouse livers. Mechanismly, troxerutin dramatically decreased Nucleotide oligomerization domain (NOD) expression, as well as interaction between NOD1/2 with interacting protein-2 (RIP2), by abating oxidative stress-induced ER stress in HFD-treated mouse livers, which was confirmed by TUDCA treatment. These improvement effects of troxerutin on hepatic glucose disorders might be mediated by its anti-obesity effect. In conclusion, troxerutin markedly diminished HFD-induced enhancement of hepatic gluconeogenesis via its inhibitory effects on ER stress-mediated NOD activation and consequent inflammation, which might be mediated by its anti-obesity effect. PMID:28029143

Long-term human immune system reconstitution in non-obese diabetic (NOD)-Rag (-)-γ chain (-) (NRG) mice is similar but not identical to the original stem cell donor.

PubMed

Harris, D T; Badowski, M; Balamurugan, A; Yang, O O

2013-12-01

The murine immune system is not necessarily identical to it human counterpart, which has led to the construction of humanized mice. The current study analysed whether or not a human immune system contained within the non-obese diabetic (NOD)-Rag1(null) -γ chain(null) (NRG) mouse model was an accurate representation of the original stem cell donor and if multiple mice constructed from the same donor were similar to one another. To that end, lightly irradiated NRG mice were injected intrahepatically on day 1 of life with purified cord blood-derived CD34(+) stem and progenitor cells. Multiple mice were constructed from each cord blood donor. Mice were analysed quarterly for changes in the immune system, and followed for periods up to 12 months post-transplant. Mice from the same donor were compared directly with each other as well as with the original donor. Analyses were performed for immune reconstitution, including flow cytometry, T cell receptor (TCR) and B cell receptor (BCR) spectratyping. It was observed that NRG mice could be 'humanized' long-term using cord blood stem cells, and that animals constructed from the same cord blood donor were nearly identical to one another, but quite different from the original stem cell donor immune system. © 2013 British Society for Immunology.

Age-dependent divergent effects of OX40L treatment on the development of diabetes in NOD mice

PubMed Central

Haddad, Christine S.; Bhattacharya, Palash; Alharshawi, Khaled; Marinelarena, Alejandra; Kumar, Prabhakaran; El-Sayed, Osama; Elshabrawy, Hatem A.; Epstein, Alan L.; Prabhakar, Bellur S.

2016-01-01

Earlier, we have shown that GM-CSF derived bone marrow dendritic cells (G-BMDCs) can expand Foxp3+ regulatory T-cells (Tregs) through a TCR-independent, but IL-2 dependent mechanism that required OX40L/OX40 interaction. While some reports have shown suppression of autoimmunity upon treatment with an OX40 agonist, others have shown exacerbation of autoimmune disease instead. To better understand the basis for these differing outcomes, we compared the effects of OX40L treatment in 6-week-old pre-diabetic and 12-week-old near diabetic NOD mice. Upon treatment with OX40L, 6-week-old NOD mice remained normoglycemic and showed a significant increase in Tregs in their spleen and lymph nodes, while 12-week-old NOD mice very rapidly developed hyperglycemia and failed to show Treg increase in spleen or LN. Interestingly, OX40L treatment increased Tregs in the thymus of both age groups. However, it induced Foxp3+CD103+CD38− stable-phenotype Tregs in the thymus and reduced the frequency of autoreactive Teff cells in 6-week-old mice; while it induced Foxp3+CD103−CD38+ labile-phenotype Tregs in the thymus and increased autoreactive CD4+ T cells in the periphery of 12-week-old mice. This increase in autoreactive CD4+ T cells was likely due to either a poor suppressive function or conversion of labile Tregs into Teff cells. Using ex vivo cultures, we found that the reduction in Treg numbers in 12-week-old mice was likely due to IL-2 deficit, and their numbers could be increased upon addition of exogenous IL-2. The observed divergent effects of OX40L treatment were likely due to differences in the ability of 6- and 12-week-old NOD mice to produce IL-2. PMID:27245356

Type 2 diabetes and obesity in adults.

PubMed

Whitmore, Catherine

There are approximately 2.5 million people in the UK with diabetes; 85-95% of whom have type 2 diabetes. Type 2 diabetes mellitus is characterized by insulin resistance and impaired insulin secretion. As approximately 90% of people with type 2 diabetes are overweight or obese, obesity is seen as a significant contributory factor in its development. This article aims to examine some of the physiological mechanisms by which overweight and obesity contribute to the development of type 2 diabetes, and review some of the approaches to managing overweight and obesity in the person with established type 2 diabetes, including dietary management, the use of reduced carbohydrate diets on glycamic control, anti-diabetes and anti-obesity drugs both in use and in development, and bariatric surgery.

Molecular role of TGF-beta, secreted from a new type of CD4+ suppressor T cell, NY4.2, in the prevention of autoimmune IDDM in NOD mice.

PubMed

Han, H S; Jun, H S; Utsugi, T; Yoon, J W

1997-06-01

A new type of CD4+ T cell clone (NY4.2) isolated from pancreatic islet-infiltrated lymphocytes of acutely diabetic non-obese diabetic (NOD) mice prevents the development of insulin-dependent diabetes mellitus (IDDM) in NOD mice, as well as the recurrence of autoimmune diabetes in syngeneic islet-transplanted NOD mice. It has been demonstrated that the cytokine TGF-beta, secreted from the cells of this clone, is the substance which prevents autoimmune IDDM. This investigation was initiated to determine the molecular role TGF-beta plays in the prevention of autoimmune IDDM by determining its effect on IL-2-induced signal transduction in Con A-activated NOD mouse splenocytes and HT-2 cells. First, we determined whether TGF-beta, secreted from NY4.2 T cells, inhibits IL-2-dependent T cell proliferation in HT-2 cells (IL-2-dependent T cell line) and NOD splenocytes. We found that TGF-beta suppresses IL-2-dependent T cell proliferation. Second, we determined whether TGF-beta inhibits the activation of Janus kinases (JAKs), as well as signal transducers and activators of transcription (STAT) proteins, involved in an IL-2-induced signalling pathway that normally leads to the proliferation of T cells. We found that TGF-beta inhibited tyrosine phosphorylation of JAK1, JAK3, STAT3 and STAT5 in Con A blasts from NOD splenocytes and HT-2 cells. Third, we examined whether TGF-beta inhibits the cooperation between STAT proteins and mitogen-activated protein kinase (MAPK), especially extracellular signal-regulated kinase 2 (ERK2). We found that TGF-beta inhibited the association of STAT3 and STAT5 with ERK2 in Con A blasts from NOD splenocytes and HT-2 cells. On the basis of these observations, we conclude that TGF-beta may interfere with signal transduction via inhibition of the IL-2-induced JAK/STAT pathway and inhibition of the association of STAT proteins with ERK2 in T cells from NOD splenocytes, resulting in the inhibition of IL-2-dependent T cell proliferation. TGF

Age-related alterations in IL-1beta, TNF-alpha, and IL-6 concentrations in parotid acinar cells from BALB/c and non-obese diabetic mice.

PubMed

Yamakawa, M; Weinstein, R; Tsuji, T; McBride, J; Wong, D T; Login, G R

2000-08-01

IL-1beta, TNF-alpha, and IL-6 have been implicated in the destruction of parotid gland acinar cells (but not duct cells) in autoimmune sialoadenitis. Here we report the temporal alterations of these cytokines in parotid acinar cells that may lead to this specificity in cell death in the non-obese diabetic (NOD) mouse model for Sjögren's syndrome. Immunohistochemistry on paraffin sections of parotid gland from 5- and 10-week-old BALB/c and NOD mice confirmed the presence of many peri-acinar lymphoid nodules but few T-cells and macrophages between acinar cells. RT-PCR on enzymatically dispersed mouse parotid acinar cells (MPACs) showed no bands for CD3varepsilon, CD20, or F4/80 regardless of mouse strain or age. By ELISA, MPACs from 10-week-old NODs showed a small but highly significant (p<0.003) increase in IL-1beta and a large significant decrease (p<0.008) in IL-6 compared to 5-week-old NODs. Norepinephrine-stimulated amylase release from MPACs was not different regardless of mouse strain or age. These data show that alterations in acinar cell production of IL-1beta and IL-6 in aging NODs precede periductal lymphoid aggregates and acinar cell secretory dysfunction. (J Histochem Cytochem 48:1033-1041,2000)

β-cell-specific IL-2 therapy increases islet Foxp3+Treg and suppresses type 1 diabetes in NOD mice.

PubMed

Johnson, Mark C; Garland, Alaina L; Nicolson, Sarah C; Li, Chengwen; Samulski, R Jude; Wang, Bo; Tisch, Roland

2013-11-01

Interleukin-2 (IL-2) is a critical cytokine for the homeostasis and function of forkhead box p3-expressing regulatory T cells (Foxp3(+)Tregs). Dysregulation of the IL-2-IL-2 receptor axis is associated with aberrant Foxp3(+)Tregs and T cell-mediated autoimmune diseases such as type 1 diabetes. Treatment with recombinant IL-2 has been reported to enhance Foxp3(+)Tregs and suppress different models of autoimmunity. However, efficacy of IL-2 therapy is dependent on achieving sufficient levels of IL-2 to boost tissue-resident Foxp3(+)Tregs while avoiding the potential toxic effects of systemic IL-2. With this in mind, adeno-associated virus (AAV) vector gene delivery was used to localize IL-2 expression to the islets of NOD mice. Injection of a double-stranded AAV vector encoding IL-2 driven by a mouse insulin promoter (dsAAVmIP-IL2) increased Foxp3(+)Tregs in the islets but not the draining pancreatic lymph nodes. Islet Foxp3(+)Tregs in dsAAVmIP-IL2-treated NOD mice exhibited enhanced fitness marked by increased expression of Bcl-2, proliferation, and suppressor function. In contrast, ectopic IL-2 had no significant effect on conventional islet-infiltrating effector T cells. Notably, β-cell-specific IL-2 expression suppressed late preclinical type 1 diabetes in NOD mice. Collectively, these findings demonstrate that β-cell-specific IL-2 expands an islet-resident Foxp3(+)Tregs pool that effectively suppresses ongoing type 1 diabetes long term.

The Inhibitory G Protein α-Subunit, Gαz, Promotes Type 1 Diabetes-Like Pathophysiology in NOD Mice.

PubMed

Fenske, Rachel J; Cadena, Mark T; Harenda, Quincy E; Wienkes, Haley N; Carbajal, Kathryn; Schaid, Michael D; Laundre, Erin; Brill, Allison L; Truchan, Nathan A; Brar, Harpreet; Wisinski, Jaclyn; Cai, Jinjin; Graham, Timothy E; Engin, Feyza; Kimple, Michelle E

2017-06-01

The α-subunit of the heterotrimeric Gz protein, Gαz, promotes β-cell death and inhibits β-cell replication when pancreatic islets are challenged by stressors. Thus, we hypothesized that loss of Gαz protein would preserve functional β-cell mass in the nonobese diabetic (NOD) model, protecting from overt diabetes. We saw that protection from diabetes was robust and durable up to 35 weeks of age in Gαz knockout mice. By 17 weeks of age, Gαz-null NOD mice had significantly higher diabetes-free survival than wild-type littermates. Islets from these mice had reduced markers of proinflammatory immune cell infiltration on both the histological and transcript levels and secreted more insulin in response to glucose. Further analyses of pancreas sections revealed significantly fewer terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive β-cells in Gαz-null islets despite similar immune infiltration in control mice. Islets from Gαz-null mice also exhibited a higher percentage of Ki-67-positive β-cells, a measure of proliferation, even in the presence of immune infiltration. Finally, β-cell-specific Gαz-null mice phenocopy whole-body Gαz-null mice in their protection from developing hyperglycemia after streptozotocin administration, supporting a β-cell-centric role for Gαz in diabetes pathophysiology. We propose that Gαz plays a key role in β-cell signaling that becomes dysfunctional in the type 1 diabetes setting, accelerating the death of β-cells, which promotes further accumulation of immune cells in the pancreatic islets, and inhibiting a restorative proliferative response. Copyright © 2017 Endocrine Society.

Emv30null NOD-scid mice. An improved host for adoptive transfer of autoimmune diabetes and growth of human lymphohematopoietic cells.

PubMed

Serreze, D V; Leiter, E H; Hanson, M S; Christianson, S W; Shultz, L D; Hesselton, R M; Greiner, D L

1995-12-01

When used as hosts in passive transfer experiments, a stock of NOD/Lt mice congenic for the severe combined immunodeficiency (scid) mutation have provided great insight to the contributions of various T-cell populations in the pathogenesis of autoimmune insulin-dependent diabetes mellitus (IDDM). Moreover, NOD-scid mice support higher levels of human lymphohematopoietic cell growth than the C.B-17-scid strain in which the mutation originated. However, the ability to perform long-term lymphohematopoietic repopulation studies in the NOD-scid stock has been limited by the fact that most of these mice develop lethal thymic lymphomas beginning at 20 weeks of age. These thymic lymphomas are characterized by activation and subsequent genomic reintegrations of Emv30, an endogenous murine ecotropic retrovirus unique to the NOD genome. To test the role of this endogenous retrovirus in thymomagenesis, we produced a stock of Emv30null NOD-scid mice by congenic replacement of the proximal end of chromosome 11 with genetic material derived from the closely related NOR/Lt strain. Thymic lymphomas still initiate in Emv30null NOD-scid females, but their rate of progression is significantly retarded since the frequency of tumors weighing between 170 and 910 mg at 25 weeks of age was reduced to 20.8% vs. 76.2% in Emv30% segregants. The thymic lymphomas that did develop in Emv30null NOD-scid mice were not characterized by a compensatory increase in mink cell focus-forming proviral integrations, which initiate thymomagenesis in other susceptible mouse strains. Significantly, the ability of standard NOD T-cells to transfer IDDM to the Emv30null NOD-scid stock was not impaired.(ABSTRACT TRUNCATED AT 250 WORDS)

AAV-mediated pancreatic overexpression of Igf1 counteracts progression to autoimmune diabetes in mice.

PubMed

Mallol, Cristina; Casana, Estefania; Jimenez, Veronica; Casellas, Alba; Haurigot, Virginia; Jambrina, Claudia; Sacristan, Victor; Morró, Meritxell; Agudo, Judith; Vilà, Laia; Bosch, Fatima

2017-07-01

Type 1 diabetes is characterized by autoimmune destruction of β-cells leading to severe insulin deficiency. Although many improvements have been made in recent years, exogenous insulin therapy is still imperfect; new therapeutic approaches, focusing on preserving/expanding β-cell mass and/or blocking the autoimmune process that destroys islets, should be developed. The main objective of this work was to test in non-obese diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, the effects of local expression of Insulin-like growth factor 1 (IGF1), a potent mitogenic and pro-survival factor for β-cells with immunomodulatory properties. Transgenic NOD mice overexpressing IGF1 specifically in β-cells (NOD-IGF1) were generated and phenotyped. In addition, miRT-containing, IGF1-encoding adeno-associated viruses (AAV) of serotype 8 (AAV8-IGF1-dmiRT) were produced and administered to 4- or 11-week-old non-transgenic NOD females through intraductal delivery. Several histological, immunological, and metabolic parameters were measured to monitor disease over a period of 28-30 weeks. In transgenic mice, local IGF1 expression led to long-term suppression of diabetes onset and robust protection of β-cell mass from the autoimmune insult. AAV-mediated pancreatic-specific overexpression of IGF1 in adult animals also dramatically reduced diabetes incidence, both when vectors were delivered before pathology onset or once insulitis was established. Transgenic NOD-IGF1 and AAV8-IGF1-dmiRT-treated NOD animals had much less islet infiltration than controls, preserved β-cell mass, and normal insulinemia. Transgenic and AAV-treated islets showed less expression of antigen-presenting molecules, inflammatory cytokines, and chemokines important for tissue-specific homing of effector T cells, suggesting IGF1 modulated islet autoimmunity in NOD mice. Local expression of Igf1 by AAV-mediated gene transfer counteracts progression to diabetes in NOD mice. This study suggests a

Cannabidiol lowers incidence of diabetes in non-obese diabetic mice.

PubMed

Weiss, L; Zeira, M; Reich, S; Har-Noy, M; Mechoulam, R; Slavin, S; Gallily, R

2006-03-01

Cannabidinoids are components of the Cannabis sativa (marijuana) plant that have been shown capable of suppressing inflammation and various aspects of cell-mediated immunity. Cannabidiol (CBD), a non-psychoactive cannabidinoid has been previously shown by us to suppress cell-mediated autoimmune joint destruction in an animal model of rheumatoid arthritis. We now report that CBD treatment significantly reduces the incidence of diabetes in NOD mice from an incidence of 86% in non-treated control mice to an incidence of 30% in CBD-treated mice. CBD treatment also resulted in the significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-gamma and TNF-alpha. Th1-associated cytokine production of in vitro activated T-cells and peritoneal macrophages was also significantly reduced in CBD-treated mice, whereas production of the Th2-associated cytokines, IL-4 and IL-10, was increased when compared to untreated control mice. Histological examination of the pancreatic islets of CBD-treated mice revealed significantly reduced insulitis. Our results indicate that CBD can inhibit and delay destructive insulitis and inflammatory Th1-associated cytokine production in NOD mice resulting in a decreased incidence of diabetes possibly through an immunomodulatory mechanism shifting the immune response from Th1 to Th2 dominance.

Polyinosine-polycytidylic acid promotes excessive iodine intake induced thyroiditis in non-obese diabetic mice via Toll-like receptor 3 mediated inflammation.

PubMed

Shi, Ya-nan; Liu, Feng-hua; Yu, Xiu-jie; Liu, Ze-bing; Li, Qing-xin; Yuan, Ji-hong; Zang, Xiao-yi; Li, Lan-ying

2013-02-01

Excessive iodine intake and viral infection are recognized as both critical factors associated with autoimmune thyroid diseases. Toll-like receptors (TLRs) have been reported to play an important role in autoimmune and inflammatory disorders. In this study, we aimed to clarify the possible mechanism of TLR3 involved in polyinosine-polycytidylic acid (poly(I:C)) promoting excessive iodine intake induced thyroiditis in non-obese diabetic (NOD) mice. Both NOD and BALB/c mice were randomly assigned to four groups: control group (n = 5), high iodine intake (HI) group (n = 7), poly(I:C) group (n = 7) and combination of excessive iodine and poly(I:C) injection (HIP) group (n = 7). After 8 weeks, mice were weighed and blood samples were collected. All the mice were sacrificed before dissection of spleen and thyroid gland. Then, thyroid histology, thyroid secreted hormone, expression of CD3(+) cells and TLR3 as well as inflammatory mRNA level were evaluated. Both NOD and BALB/c mice from HI and HIP group represented goiter and increasing thyroid relative weight. Thyroid histology evidence indicated that only HIP group of NOD mice showed severe thyroiditis with lymphocytes infiltration in majority of thyroid tissue, severe damage of follicles and general fibrosis. Immunofluorescence staining results displayed a large number of CD3(+) cells in HIP NOD mice. Real-time polymerase chain reaction (PCR) results suggested interferon (IFN)-α increased over 30 folds and IFN-γ expression was doubled compared with control group, but interleukin (IL)-4 remained unchanged in HIP group of NOD mice thyroid. Meanwhile, over one third decrease of blood total thyroxine (TT4) and increased thyroid-stimulating hormone (TSH) was observed in HIP group of NOD mice. Only HIP group of NOD mice represented significantly elevation of TLR3 expression. Poly(I:C) enhanced excessive dietary iodine induced thyroiditis in NOD mice through increasing TLR3 mediated inflammation.

Treatment with Cordyceps sinensis enriches Treg population in peripheral lymph nodes and delays type I diabetes development in NOD mice.

PubMed

Wang, Mei-Fen; Zhu, Qing-Hua; He, Yu-Gong

2013-09-01

Cordyceps sinensis is a widely used Chinese traditional herb with a long history. In China C. sinensis is usually applied in the treatment of respiratory diseases, however, the efficacy of C. sinensis still lacks experimental evidence. Type I diabetes is a multi-factor related autoimmune disease caused by cellular-mediated destruction of insulin-producing pancreatic beta cells in the islets in human. We tested C. sinensis for its ability to work as an immune modulator in NOD mice, an animal model which mimicks the progression of type I diabetes in humans and found that treatment with C. sinensis extract could slow down disease development in NOD mice. Further research also suggested that treatment with C. sinensis extract increased the frequency of Treg cells and IFN-gama producing Th1 cells in peripheral lymph nodes. However, C. sinensis has no effect on the natural Treg cell differentiation in thymus.

Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis.

PubMed

Van Rooyen, Derrick M; Larter, Claire Z; Haigh, W Geoffrey; Yeh, Matthew M; Ioannou, George; Kuver, Rahul; Lee, Sum P; Teoh, Narci C; Farrell, Geoffrey C

2011-10-01

Type 2 diabetes and nonalcoholic steatohepatitis (NASH) are associated with insulin resistance and disordered cholesterol homeostasis. We investigated the basis for hepatic cholesterol accumulation with insulin resistance and its relevance to the pathogenesis of NASH. Alms1 mutant (foz/foz) and wild-type NOD.B10 mice were fed high-fat diets that contained varying percentages of cholesterol; hepatic lipid pools and pathways of cholesterol turnover were determined. Hepatocytes were exposed to insulin concentrations that circulate in diabetic foz/foz mice. Hepatic cholesterol accumulation was attributed to up-regulation of low-density lipoprotein receptor via activation of sterol regulatory element binding protein 2 (SREBP-2), reduced biotransformation to bile acids, and suppression of canalicular pathways for cholesterol and bile acid excretion in bile. Exposing primary hepatocytes to concentrations of insulin that circulate in diabetic Alms1 mice replicated the increases in SREBP-2 and low-density lipoprotein receptor and suppression of bile salt export pump. Removing cholesterol from diet prevented hepatic accumulation of free cholesterol and NASH; increasing dietary cholesterol levels exacerbated hepatic accumulation of free cholesterol, hepatocyte injury or apoptosis, macrophage recruitment, and liver fibrosis. In obese, diabetic mice, hyperinsulinemia alters nuclear transcriptional regulators of cholesterol homeostasis, leading to hepatic accumulation of free cholesterol; the resulting cytotoxicity mediates transition of steatosis to NASH. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Nondepleting anti-CD4 monoclonal antibody prevents diabetes and blocks induction of insulin autoantibodies following insulin peptide B:9-23 immunization in the NOD mouse.

PubMed

Liu, Edwin; Moriyama, Hiroaki; Paronen, Johanna; Abiru, Norio; Miao, Dongmei; Yu, Liping; Taylor, Robert M; Eisenbarth, George S

2003-11-01

Insulin peptide B:9-23 is a major autoantigen in type 1 diabetes that induces insulin autoantibodies and prevents diabetes in the NOD. However, immunization with peptide without adjuvant may be insufficient to reverse disease or induce long-term tolerance. Furthermore, recent experience has demonstrated the potential dangers of disease exacerbation or anaphylaxis with peptide immunotherapy. Combination therapy of B:9-23 with a nondepleting anti-CD4 monoclonal antibody (YTS 177.9) was studied in female NOD mice from 4 through 6 weeks of age. Injections of either B:9-23 in saline, YTS 177.9 antibody, or both peptide and antibody were given to mice. By 52 weeks follow-up, 40% of B:9-23-treated, 100% of YTS177.9-treated, and 70% of B:9-23 and YTS177.9 combination-treated mice remained diabetes-free. IAA, both spontaneous and induced by B:9-23, was almost completely suppressed in mice receiving YTS 177.9. In addition to suppression of IAA expression, anti-B:9-23 peptide antibodies are also suppressed in mice receiving B:9-23 with YTS 177.9, compared to B:9-23 alone. A brief course of the nondepleting anti-CD4 monoclonal antibody (YTS 177.9) in NOD mice confers long-term protection from diabetes and insulitis and profoundly blocks spontaneous and B:9-23 peptide-induced insulin autoantibodies.

Pediatric obesity & type 2 diabetes.

PubMed

Dea, Tara L

2011-01-01

This article focuses on (a) identifying obesity and other risk factors for developing type 2 diabetes, (b) differentiating between pediatric type 1 diabetes and type 2 diabetes, and (c) treating pediatric type 2 diabetes. Obesity has significant implications on a child's health, including an increased risk for insulin resistance and progression to type 2 diabetes. Type 2 diabetes in children, characterized by insulin resistance and relative pancreatic b-cell failure due to the increased demand for insulin production, has now reached epidemic proportions. Longitudinal research on pediatric type 2 diabetes, however, is lacking because this epidemic is relatively new. Treatment of type 2 diabetes in children is focused on lifestyle modification with weight management/increased physical activity, and pharmacological management through oral medication or insulin therapy. Because children with type 2 diabetes are at risk for developing diabetes-related complications earlier in life, they need to be closely monitored for comorbidities.

Childhood obesity affects adult metabolic syndrome and diabetes.

PubMed

Liang, Yajun; Hou, Dongqing; Zhao, Xiaoyuan; Wang, Liang; Hu, Yuehua; Liu, Junting; Cheng, Hong; Yang, Ping; Shan, Xinying; Yan, Yinkun; Cruickshank, J Kennedy; Mi, Jie

2015-09-01

We seek to observe the association between childhood obesity by different measures and adult obesity, metabolic syndrome (MetS), and diabetes. Thousand two hundred and nine subjects from "Beijing Blood Pressure Cohort Study" were followed 22.9 ± 0.5 years in average from childhood to adulthood. We defined childhood obesity using body mass index (BMI) or left subscapular skinfold (LSSF), and adult obesity as BMI ≥ 28 kg/m(2). MetS was defined according to the joint statement of International Diabetes Federation and American Heart Association with modified waist circumference (≥ 90/85 cm for men/women). Diabetes was defined as fasting plasma glucose ≥ 7.0 mmol/L or blood glucose 2 h after oral glucose tolerance test ≥ 11.1 mmol/L or currently using blood glucose-lowering agents. Multiple linear and logistic regression models were used to assess the association. The incidence of adult obesity was 13.4, 60.0, 48.3, and 65.1 % for children without obesity, having obesity by BMI only, by LSSF only, and by both, respectively. Compared to children without obesity, children obese by LSSF only or by both had higher risk of diabetes. After controlling for adult obesity, childhood obesity predicted independently long-term risks of diabetes (odds ratio 2.8, 95 % confidence interval 1.2-6.3) or abdominal obesity (2.7, 1.6-4.7) other than MetS as a whole (1.2, 0.6-2.4). Childhood obesity predicts long-term risk of adult diabetes, and the effect is independent of adult obesity. LSSF is better than BMI in predicting adult diabetes.

Cathepsin L Inhibition Prevents Murine Autoimmune Diabetes via Suppression of CD8+ T Cell Activity

PubMed Central

Yamada, Akiko; Ishimaru, Naozumi; Arakaki, Rieko; Katunuma, Nobuhiko; Hayashi, Yoshio

2010-01-01

Background Type 1 diabetes (T1D) is an autoimmune disease resulting from defects in central and peripheral tolerance and characterized by T cell-mediated destruction of islet β cells. To determine whether specific lysosomal proteases might influence the outcome of a T cell–mediated autoimmune response, we examined the functional significance of cathepsin inhibition on autoimmune T1D-prone non-obese diabetic (NOD) mice. Methods and Findings Here it was found that specific inhibition of cathepsin L affords strong protection from cyclophosphamide (CY)-induced insulitis and diabetes of NOD mice at the advanced stage of CD8+ T cell infiltration via inhibiting granzyme activity. It was discovered that cathepsin L inhibition prevents cytotoxic activity of CD8+ T cells in the pancreatic islets through controlling dipeptidyl peptidase I activity. Moreover, the gene targeting for cathepsin L with application of in vivo siRNA administration successfully prevented CY-induced diabetes of NOD mice. Finally, cathepsin L mRNA expression of peripheral CD8+ T cells from NOD mice developing spontaneous T1D was significantly increased compared with that from control mice. Conclusions Our results identified a novel function of cathepsin L as an enzyme whose activity is essential for the progression of CD8+ T cell-mediated autoimmune diabetes, and inhibition of cathepsin L as a powerful therapeutic strategy for autoimmune diabetes. PMID:20877570

SERPINE 1 Links Obesity and Diabetes: A Pilot Study

PubMed Central

Kaur, Punit; Reis, Michael D.; Couchman, Glen R.; Forjuoh, Samuel N.; Greene, John F.; Asea, Alexzander

2010-01-01

In the past decade there has been a dramatic increase in the number of Americans considered obese. Over this same period, the number of individuals diagnosed with diabetes has increased by over 40%. Interestingly, in a great number of cases individuals considered obese develop diabetes later on. Although a link between obesity and diabetes has been suggested, conclusive scientific evidence is thus far just beginning to emerge. The present pilot study is designed to identify a possible link between obesity and diabetes. The plasma proteome is a desirable biological sample due to their accessibility and representative complexity due, in part, to the wide dynamic range of protein concentrations, which lead to the discovery of new protein markers. Here we present the results for the specific depletion of 14 high-abundant proteins from the plasma samples of obese and diabetic patients. Comparative proteomic profiling of plasma from individuals with either diabetes or obesity and individuals with both obesity and diabetes revealed SERPINE 1 as a possible candidate protein of interest, which might be a link between obesity and diabetes. PMID:21113241

SERPINE 1 Links Obesity and Diabetes: A Pilot Study.

PubMed

Kaur, Punit; Reis, Michael D; Couchman, Glen R; Forjuoh, Samuel N; Greene, John F; Asea, Alexzander

2010-06-01

In the past decade there has been a dramatic increase in the number of Americans considered obese. Over this same period, the number of individuals diagnosed with diabetes has increased by over 40%. Interestingly, in a great number of cases individuals considered obese develop diabetes later on. Although a link between obesity and diabetes has been suggested, conclusive scientific evidence is thus far just beginning to emerge. The present pilot study is designed to identify a possible link between obesity and diabetes. The plasma proteome is a desirable biological sample due to their accessibility and representative complexity due, in part, to the wide dynamic range of protein concentrations, which lead to the discovery of new protein markers. Here we present the results for the specific depletion of 14 high-abundant proteins from the plasma samples of obese and diabetic patients. Comparative proteomic profiling of plasma from individuals with either diabetes or obesity and individuals with both obesity and diabetes revealed SERPINE 1 as a possible candidate protein of interest, which might be a link between obesity and diabetes.

Reevaluation of the major histocompatibility complex genes of the NOD-progenitor CTS/Shi strain.

PubMed

Mathews, C E; Graser, R T; Serreze, D V; Leiter, E H

2000-01-01

The common Kd and/or Db alleles of NOD mice contribute to the development of autoimmune diabetes, but their respective contributions are unresolved. The major histocompatibility complex (MHC) of the CTS/Shi mouse, originally designated as H2ct, shares MHC class II region identity with the H2g7 haplotype of NOD mice. However, CTS mice were reported to express distinct but undefined MHC class I gene products. Because diabetes frequency was reduced 56% in females of a NOD stock congenic for H2ct, this partial resistance may have derived from the MHC class I allelic differences. In the present report, we use a combination of serologic analysis and sequencing of MHC class I cDNAs to establish that NOD/Lt and CTS/Shi share a common H2-Kd allele but differ at the H2-D end of the MHC complex. The H2-D allele of CTS/Shi was identified as the rare H2-Ddx recently described in ALR/Lt, another NOD-related strain. These results in mouse model systems show that multiple MHC genes confer diabetes resistance and suggest that at least one of the protective MHC or MHC-linked genes in CTS mice may be at the H2-D end of the complex.

Gastrointestinal transit in nonobese diabetic mouse: an animal model of human diabetes type 1.

PubMed

El-Salhy, M

2001-01-01

Gastrointestinal transit (GI) in the nonobese diabetic (NOD) mouse, an animal model of human diabetes type 1, was examined in animals with short- (duration 1-5 days) and long-term (duration 28-35 days) diabetes. Blood glucose level, serum insulin concentration, and gut neuroendocrine peptide content were also measured. GI was significantly rapid in NOD mice with long-term diabetes (LTD), but was not correlated with blood glucose level, serum insulin concentration, or pancreatic insulin content. GI was correlated with duodenal secretin content, but not with the content of other neuroendocrine peptides in the different segments investigated. Whereas antral vasoactive intestinal peptide (VIP) content in NOD mice with LTD was significantly higher, colonic VIP was lower in NOD mice with short-term diabetes (STD). In the duodenum, whereas the concentration of secretin in NOD mice with both STD and LTD was lower, the gastrin content was higher. Duodenal somatostatin content in NOD mice with LTD was lower. In colon, the content of galanin in NOD mice with LTD was higher than in controls. The decreased content of secretin may be among the factors that cause rapid GI in NOD mice with LTD. Changes in the antral content of VIP, duodenal somatostatin, and colonic galanin in NOD mice with LTD may cause low intestinal secretion and, together with rapid GI, give rise to diarrhoea, which is a common symptom in diabetes.

Hepatic Free Cholesterol Accumulates in Obese, Diabetic Mice and Causes Non-Alcoholic Steatohepatitis

PubMed Central

Van Rooyen, Derrick M; Larter, Claire Z; Haigh, W Geoffrey; Yeh, Matthew M; Ioannou, George; Kuver, Rahul; Lee, Sum P; Teoh, Narci C; Farrell, Geoffrey C

2011-01-01

Background & Aims Type-2 diabetes and non-alcoholic steatohepatitis (NASH) are associated with insulin resistance and disordered cholesterol homeostasis. We investigated the basis for hepatic cholesterol accumulation with insulin resistance and its relevance to pathogenesis of NASH. Methods Alms1 mutant (foz/foz) and wild-type (WT) NOD.B10 mice were fed high-fat diets that contained varying percentages of cholesterol; hepatic lipid pools and pathways of cholesterol turnover were determined. Hepatocytes were exposed to insulin concentrations that circulate in diabetic foz/foz mice. Results Hepatic cholesterol accumulation was attributed to up-regulation of low density lipoprotein receptor (LDLR) via activation of sterol regulatory element binding protein-2 (SREBP-2), reduced biotransformation to bile acids, and suppression of canalicular pathways for cholesterol and bile acid excretion in bile. Exposing primary hepatocytes to concentrations of insulin that circulate in diabetic Alms1 mice replicated the increases in SREBP-2 and LDLR and suppression of bile salt export pump. Removing cholesterol from diet prevented hepatic accumulation of free cholesterol and NASH; increasing dietary cholesterol exacerbated hepatic accumulation of free cholesterol, hepatocyte injury or apoptosis, macrophage recruitment, and liver fibrosis. Conclusions In obese, diabetic mice, hyperinsulinemia alters nuclear transcriptional regulators of cholesterol homeostasis, leading to hepatic accumulation of free cholesterol; the resulting cytotoxicity mediates transition of steatosis to NASH. PMID:21703998

Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice.

PubMed

Shultz, L D; Schweitzer, P A; Christianson, S W; Gott, B; Schweitzer, I B; Tennent, B; McKenna, S; Mobraaten, L; Rajan, T V; Greiner, D L

1995-01-01

The scid mutation was backcrossed ten generations onto the NOD/Lt strain background, resulting in an immunodeficient stock (NOD/LtSz-scid/scid) with multiple defects in adaptive as well as nonadaptive immunologic function. NOD/LtSz-scid/scid mice lack functional lymphoid cells and show little or no serum Ig with age. Although NOD/(Lt-)+/+ mice develop T cell-mediated autoimmune, insulin-dependent diabetes mellitus, NOD/LtSz-scid/scid mice are both insulitis- and diabetes-free throughout life. However, because of a high incidence of thymic lymphomas, the mean lifespan of this congenic stock is only 8.5 mo under specific pathogen-free conditions. After i.v. injection of human CEM T-lymphoblastoid cells, splenic engraftment of these cells was fourfold greater in NOD/LtSz-scid/scid mice than in C.B17/Sz-scid/scid mice. Although C.B-17Sz-scid/scid mice exhibit robust NK cell activity, this activity is markedly reduced in both NOD/(Lt-)+/+ and NOD/LtSz-scid/scid mice. Presence of a functionally less mature macrophage population in NOD/LtSz-scid/scid vs C.B-17Sz-scid/scid mice is indicated by persistence in the former of the NOD/Lt strain-specific defect in LPS-stimulated IL-1 secretion by marrow-derived macrophages. Although C.B-17Sz-scid/scid and C57BL/6Sz-scid/scid mice have elevated serum hemolytic complement activity compared with their respective +/+ controls, both NOD/(LtSz-)+/+ and NOD/LtSz-scid/scid mice lack this activity. Age-dependent increases in serum Ig levels (> 1 micrograms/ml) were observed in only 2 of 30 NOD/LtSz-scid/scid mice vs 21 of 29 C.B-17/Sz-scid/scid animals. The multiple defects in innate and adaptive immunity unique to the NOD/LtSz-scid/scid mouse provide an excellent in vivo environment for reconstitution with human hematopoietic cells.

Allelic Variation of Ets1 Does Not Contribute to NK and NKT Cell Deficiencies in Type 1 Diabetes Susceptible NOD Mice

PubMed Central

Jordan, Margaret A.; Poulton, Lynn D.; Fletcher, Julie M.; Baxter, Alan G.

2009-01-01

The NOD mouse is a well characterized model of type 1 diabetes that shares several of the characteristics of Ets1-deficient targeted mutant mice, viz: defects in TCR allelic exclusion, susceptibility to a lupus like disease characterized by IgM and IgG autoantibodies and immune complex-mediated glomerulonephritis, and deficiencies of NK and NKT cells. Here, we sought evidence for allelic variation of Ets1 in mice contributing to the NK and NKT cell phenotypes of the NOD strain. ETS1 expression in NK and NKT cells was reduced in NOD mice, compared to C57BL/6 mice. Although NKT cells numbers were significantly correlated with ETS1 expression in both strains, NKT cell numbers were not linked to the Ets1 gene in a first backcross from NOD to C57BL/6 mice. These results indicate that allelic variation of Ets1 did not contribute to variation in NKT cell numbers in these mice. It remains possible that a third factor not linked to the Ets1 locus controls both ETS1 expression and subsequently NK and NKT cell phenotypes. PMID:19806240

CCR7 directs the recruitment of T cells into inflamed pancreatic islets of nonobese diabetic (NOD) mice.

PubMed

Shan, Zhongyan; Xu, Baohui; Mikulowska-Mennis, Anna; Michie, Sara A

2014-05-01

Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease characterized by the destruction of insulin-producing β cells in the pancreatic islets. The migration of T cells from blood vessels into pancreas is critical for the development of islet inflammation and β cell destruction in T1D. To define the roles of C-C chemokine receptor type 7 (CCR7) in recruitment of T cells into islets, we used laser capture microdissection to isolate tissue from inflamed islets of nonobese diabetic (NOD) mice and uninflamed islets of BALB/c and young NOD mice. RT-PCR analyses detected mRNAs for CCR7 and its chemokine ligands CCL19 (ELC; MIP-3β) and CCL21 (SLC) in captures from inflamed, but not from uninflamed, islets. Immunohistology studies revealed that high endothelial venules in inflamed islets co-express CCL21 protein and MAdCAM-1 (an adhesion molecule that recruits lymphocytes into islets). Desensitization of lymphocyte CCR7 blocked about 75 % of T cell migration from the bloodstream into inflamed islets, but had no effect on B cell migration into islets. These results indicate that CCR7 and its ligands are important in the recruitment of T cells into inflamed islets and thus in the pathogenesis of T1D.

Type 1 diabetes susceptibility alleles are associated with distinct alterations in the gut microbiota.

PubMed

Mullaney, Jane A; Stephens, Juliette E; Costello, Mary-Ellen; Fong, Cai; Geeling, Brooke E; Gavin, Patrick G; Wright, Casey M; Spector, Timothy D; Brown, Matthew A; Hamilton-Williams, Emma E

2018-02-17

Dysbiosis of the gut microbiota has been implicated in the pathogenesis of many autoimmune conditions including type 1 diabetes (T1D). It is unknown whether changes in the gut microbiota observed in T1D are due to environmental drivers, genetic risk factors, or both. Here, we have performed an analysis of associations between the gut microbiota and T1D genetic risk using the non-obese diabetic (NOD) mouse model of T1D and the TwinsUK cohort. Through the analysis of five separate colonies of T1D susceptible NOD mice, we identified similarities in NOD microbiome that were independent of animal facility. Introduction of disease protective alleles at the Idd3 and Idd5 loci (IL2, Ctla4, Slc11a1, and Acadl) resulted in significant alterations in the NOD microbiome. Disease-protected strains exhibited a restoration of immune regulatory pathways within the gut which could also be reestablished using IL-2 therapy. Increased T1D disease risk from IL-2 pathway loci in the TwinsUK cohort of human subjects resulted in some similar microbiota changes to those observed in the NOD mouse. These findings demonstrate for the first time that type 1 diabetes-associated genetic variants that restore immune tolerance to islet antigens also result in functional changes in the gut immune system and resultant changes in the microbiota.

Methylation of insulin DNA in response to proinflammatory cytokines during the progression of autoimmune diabetes in NOD mice.

PubMed

Rui, Jinxiu; Deng, Songyan; Lebastchi, Jasmin; Clark, Pamela L; Usmani-Brown, Sahar; Herold, Kevan C

2016-05-01

Type 1 diabetes is caused by the immunological destruction of pancreatic beta cells. Preclinical and clinical data indicate that there are changes in beta cell function at different stages of the disease, but the fate of beta cells has not been closely studied. We studied how immune factors affect the function and epigenetics of beta cells during disease progression and identified possible triggers of these changes. We studied FACS sorted beta cells and infiltrating lymphocytes from NOD mouse and human islets. Gene expression was measured by quantitative real-time RT-PCR (qRT-PCR) and methylation of the insulin genes was investigated by high-throughput and Sanger sequencing. To understand the role of DNA methyltransferases, Dnmt3a was knocked down with small interfering RNA (siRNA). The effects of cytokines on methylation and expression of the insulin gene were studied in humans and mice. During disease progression in NOD mice, there was an inverse relationship between the proportion of infiltrating lymphocytes and the beta cell mass. In beta cells, methylation marks in the Ins1 and Ins2 genes changed over time. Insulin gene expression appears to be most closely regulated by the methylation of Ins1 exon 2 and Ins2 exon 1. Cytokine transcription increased with age in NOD mice, and these cytokines could induce methylation marks in the insulin DNA by inducing methyltransferases. Similar changes were induced by cytokines in human beta cells in vitro. Epigenetic modification of DNA by methylation in response to immunological stressors may be a mechanism that affects insulin gene expression during the progression of type 1 diabetes.

Dynamics of Diabetes and Obesity: Epidemiological Perspective

PubMed Central

Boles, Annette; Kandimalla, Ramesh; Reddy, P. Hemachandra

2017-01-01

The purpose of this review article is to understand the current literature on obesity, diabetes and therapeutic avenues across the world. Diabetes is a chronic lifestyle condition that affects millions of people worldwide and it is a major health concern in our society. Diabetes and obesity are associated with various conditions, including non-modifiable and modifiable risk factors. Early detectable markers are not well established to detect pre-diabetes and as a result, it becomes diabetes. Several published epidemiological studies were assessed and the findings were summarized. Resources from published studies were used to identify criteria used for pre-diabetes, the role of diet in pre-diabetics and potential risks and characteristics associated with pre-diabetes. Preventive strategies are needed to combat diabetes. Individuals diagnosed with pre-diabetes need detailed education, need to fully understand the risk factors and have the ability to manage diabetes. Interventions exist that include chronic disease self-management programs, lifestyle interventions and pharmacological strategies. Obesity plays a large role in causing pre-diabetes and diabetes. Critical analysis of existing epidemiological research data suggests that additional research is needed to determine the efficacy of interventions. PMID:28130199

Serum trace elements in obese women with or without diabetes

PubMed Central

Yerlikaya, F. Hümeyra; Toker, Aysun; Arıbaş, Alpay

2013-01-01

Background & objectives: Relationship of trace elements with obesity and diabetes is complex, alterations in their metabolism can be induced by the diseases and their complications. To study the role of the trace elements in diabetes and obesity, serum trace elements levels (Cr, Se, Fe, Zn, Cu and Mn) were measured in obese women with or without diabetes as well as healthy women. Further, correlation between serum trace elements levels and glucose, insulin, homeostasis model assessment (HOMA-IR), glycated haemoglobin (HbA1c), body mass index (BMI), waist circumferences, waist -to -hip ratio and high-sensitivity C-reactive protein(hsCRP) were also determined in these women. Methods: This study was performed with morbidly obese (BMI >40 kg/m2) women with diabetes (n=41), without diabetes (n=45) and 50 healthly non obese women. Anthropometric measurements were taken and levels of serum Zn, Cr, Fe Cu and Mn were determined. Biochemical parameters included serum glucose, insulin, lipids, haemoglobin, hsCRP and HbA1C. Results: The levels of Zn (P<0.001), Mn (P<0.05), Fe (P<0.05) were significantly lower and the level of Cu (P<0.001) and Cu / Zn ratio (P<0.05) were significantly higher in the diabetic obese women than those of the healthy women. Also, the levels of Zn and Fe were significantly lower and the levels of Cu were significantly higher in the non diabetic obese women than those of the healthy group. Serum Zn levels negatively and serum Cu levels positively correlated with anthropometric values in diabetic and non diabetic obese women. Further, serum Zn, Mn and Cr levels negatively correlated and serum Se levels positively correlated glycaemia control parameters in diabetic obese women. In addition, serum Zn levels negatively correlated with hsCRP in diabetic and nondiabetic obese females. Interpretation & conclusions: Our findings showed significant association between Zn and Fe deficiencies and obesity. Also, obese women with diabetes may be at a greater risk

Dendritic cell subsets in type 1 diabetes: friend or foe?

PubMed

Morel, Penelope A

2013-12-06

Type 1 diabetes (T1D) is a T cell mediated autoimmune disease characterized by immune mediated destruction of the insulin-producing β cells in the islets of Langerhans. Dendritic cells (DC) have been implicated in the pathogenesis of T1D and are also used as immunotherapeutic agents. Plasmacytoid (p)DC have been shown to have both protective and pathogenic effects and a newly described merocytic DC population has been shown to break tolerance in the mouse model of T1D, the non-obese diabetic (NOD) mouse. We have used DC populations to prevent the onset of T1D in NOD mice and clinical trials of DC therapy in T1D diabetes have been initiated. In this review we will critically examine the recent published literature on the role of DC subsets in the induction and regulation of the autoimmune response in T1D.

Characterization of ACE and ACE2 Expression within Different Organs of the NOD Mouse

PubMed Central

Roca-Ho, Heleia; Riera, Marta; Palau, Vanesa; Pascual, Julio; Soler, Maria Jose

2017-01-01

Renin angiotensin system (RAS) is known to play a key role in several diseases such as diabetes, and renal and cardiovascular pathologies. Its blockade has been demonstrated to delay chronic kidney disease progression and cardiovascular damage in diabetic patients. In this sense, since local RAS has been described, the aim of this study is to characterize angiotensin converting enzyme (ACE) and ACE2 activities, as well as protein expression, in several tissues of the non-obese diabetic (NOD) mice model. After 21 or 40 days of diabetes onset, mouse serums and tissues were analyzed for ACE and ACE2 enzyme activities and protein expression. ACE and ACE2 enzyme activities were detected in different tissues. Their expressions vary depending on the studied tissue. Thus, whereas ACE activity was highly expressed in lungs, ACE2 activity was highly expressed in pancreas among the studied tissues. Interestingly, we also observed that diabetes up-regulates ACE mainly in serum, lung, heart, and liver, and ACE2 mainly in serum, liver, and pancreas. In conclusion, we found a marked serum and pulmonary alteration in ACE activity of diabetic mice, suggesting a common regulation. The increase of ACE2 activity within the circulation in diabetic mice may be ascribed to a compensatory mechanism of RAS. PMID:28273875

Characterization of ACE and ACE2 Expression within Different Organs of the NOD Mouse.

PubMed

Roca-Ho, Heleia; Riera, Marta; Palau, Vanesa; Pascual, Julio; Soler, Maria Jose

2017-03-05

Renin angiotensin system (RAS) is known to play a key role in several diseases such as diabetes, and renal and cardiovascular pathologies. Its blockade has been demonstrated to delay chronic kidney disease progression and cardiovascular damage in diabetic patients. In this sense, since local RAS has been described, the aim of this study is to characterize angiotensin converting enzyme (ACE) and ACE2 activities, as well as protein expression, in several tissues of the non-obese diabetic (NOD) mice model. After 21 or 40 days of diabetes onset, mouse serums and tissues were analyzed for ACE and ACE2 enzyme activities and protein expression. ACE and ACE2 enzyme activities were detected in different tissues. Their expressions vary depending on the studied tissue. Thus, whereas ACE activity was highly expressed in lungs, ACE2 activity was highly expressed in pancreas among the studied tissues. Interestingly, we also observed that diabetes up-regulates ACE mainly in serum, lung, heart, and liver, and ACE2 mainly in serum, liver, and pancreas. In conclusion, we found a marked serum and pulmonary alteration in ACE activity of diabetic mice, suggesting a common regulation. The increase of ACE2 activity within the circulation in diabetic mice may be ascribed to a compensatory mechanism of RAS.

Strain dependence of diet-induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype.

PubMed

Farrell, Geoffrey C; Mridha, Auvro R; Yeh, Matthew M; Arsov, Todor; Van Rooyen, Derrick M; Brooling, John; Nguyen, Tori; Heydet, Deborah; Delghingaro-Augusto, Viviane; Nolan, Christopher J; Shackel, Nicholas A; McLennan, Susan V; Teoh, Narci C; Larter, Claire Z

2014-08-01

Obese Alms1 mutant (foz/foz) NOD.B10 mice develop diabetes and fibrotic NASH when fed high-fat(HF) diet. To establish whether diabetes or obesity is more closely associated with NASH fibrosis, we compared diabetic foz/foz C57BL6/J with non-diabetic foz/foz BALB/c mice. We also determined hepatic cytokines, growth factors and related profibrotic pathways. Male and female foz/foz BALB/c and C57BL6/J mice were fed HF or chow for 24 weeks before determining metabolic indices, liver injury, cytokines, growth factors, pathology/fibrosis and matrix deposition pathways. All foz/foz mice were obese. Hepatomegaly, hyperinsulinemia, hyperglycaemia and hypoadiponectinaemia occurred only in foz/foz C57BL6/J mice, whereas foz/foz BALB/c formed more adipose. Serum ALT, steatosis, ballooning, liver inflammation and NAFLD activity score were worse in C57BL6/J mice. In HF-fed mice, fibrosis was severe in foz/foz C57BL6/J, appreciable in WT C57BL6/J, but absent in foz/foz BALB/c mice. Hepatic mRNA expression of TNF-α, IL-12, IL-4, IL-10 was increased (but not IFN-γ, IL-1β, IL-17A), and IL-4:IFN-γ ratio (indicating Th-2 predominance) was higher in HF-fed foz/foz C57BL6/J than BALB/c mice. In livers of HF-fed foz/foz C57BL6/J mice, TGF-β was unaltered but PDGFα and CTGF were increased in association with enhanced α-SMA, CD147and MMP activity. In mice with equivalent genetic/dietary obesity, NASH development is linked to strain differences in hyperinsulinaemia and hyperglycaemia inversely related to lipid partitioning between adipose and liver. Diabetes-mediated CTGF-regulation of MMPs as well as cytokines/growth factors (Th-2 cytokine predominant, PDGFα, not TGF-β) mobilized in the resultant hepatic necroinflammatory change may contribute to strain differences in NASH fibrosis. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A cluster of coregulated genes determines TGF-beta-induced regulatory T-cell (Treg) dysfunction in NOD mice.

PubMed

D'Alise, Anna Morena; Ergun, Ayla; Hill, Jonathan A; Mathis, Diane; Benoist, Christophe

2011-05-24

Foxp3(+) regulatory T cells (Tregs) originate in the thymus, but the Treg phenotype can also be induced in peripheral lymphoid organs or in vitro by stimulation of conventional CD4(+) T cells with IL-2 and TGF-β. There have been divergent reports on the suppressive capacity of these TGF-Treg cells. We find that TGF-Tregs derived from diabetes-prone NOD mice, although expressing normal Foxp3 levels, are uniquely defective in suppressive activity, whereas TGF-Tregs from control strains (B6g7) or ex vivo Tregs from NOD mice all function normally. Most Treg-typical transcripts were shared by NOD or B6g7 TGF-Tregs, except for a small group of differentially expressed genes, including genes relevant for suppressive activity (Lrrc32, Ctla4, and Cd73). Many of these transcripts form a coregulated cluster in a broader analysis of T-cell differentiation. The defect does not map to idd3 or idd5 regions. Whereas Treg cells from NOD mice are normal in spleen and lymph nodes, the NOD defect is observed in locations that have been tied to pathogenesis of diabetes (small intestine lamina propria and pancreatic lymph node). Thus, a genetic defect uniquely affects a specific Treg subpopulation in NOD mice, in a manner consistent with a role in determining diabetes susceptibility.

Optimization of Protocols for Derivation of Mouse Embryonic Stem Cell Lines from Refractory Strains, Including the Non Obese Diabetic Mouse

PubMed Central

Davies, Timothy J.

2012-01-01

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

Prioritizing Environmental Chemicals for Obesity and Diabetes ...

EPA Pesticide Factsheets

Background: Diabetes and obesity are major threats to public health in the US and abroad. Understanding the role chemicals in our environment play in the development of these conditions is an emerging issue in environmental health, although identifying and prioritizing chemicals for testing beyond those already implicated in the literature is a challenge. This review is intended to help researchers generate hypotheses about chemicals potentially contributing to diabetes and obesity-related health outcomes by summarizing relevant findings from the US Environmental Protection Agency (EPA) ToxCast high-throughput screening (HTS) program. Objectives: To develop new hypotheses around environmental chemicals of potential interest for diabetes- or obesity-related outcomes using high throughput screening data. Methods: Identify ToxCast assay targets relevant to several biological processes related to diabetes and obesity (insulin sensitivity in peripheral tissue, pancreatic islet and beta cell function, adipocyte dierentiation, and feeding behavior) and present chemical screening data against those assay targets to identify chemicals of potential interest. Discussion: Results of this screening-level analysis suggest that the spectrum of environmental chemicals to consider in research related to diabetes and obesity is much broader than indicated from research papers and reviews published in the peer-reviewed literature. Testing of hypotheses based on ToxCast data will a

Glyoxalase 1 Modulation in Obesity and Diabetes.

PubMed

Rabbani, Naila; Thornalley, Paul J

2018-01-02

Obesity and type 2 diabetes mellitus are increasing globally. There is also increasing associated complications, such as non-alcoholic fatty liver disease (NAFLD) and vascular complications of diabetes. There is currently no licensed treatment for NAFLD and no recent treatments for diabetic complications. New approaches are required, particularly those addressing mechanism-based risk factors for health decline and disease progression. Recent Advances: Dicarbonyl stress is the abnormal accumulation of reactive dicarbonyl metabolites such as methylglyoxal (MG) leading to cell and tissue dysfunction. It is a potential driver of obesity, diabetes, and related complications that are unaddressed by current treatments. Increased formation of MG is linked to increased glyceroneogenesis and hyperglycemia in obesity and diabetes and also down-regulation of glyoxalase 1 (Glo1)-which provides the main enzymatic detoxification of MG. Glo1 functional genomics studies suggest that increasing Glo1 expression and activity alleviates dicarbonyl stress; slows development of obesity, related insulin resistance; and prevents development of diabetic nephropathy and other microvascular complications of diabetes. A new therapeutic approach constitutes small-molecule inducers of Glo1 expression-Glo1 inducers-exploiting a regulatory antioxidant response element in the GLO1 gene. A prototype Glo1 inducer, trans-resveratrol (tRES)-hesperetin (HESP) combination, in corrected insulin resistance, improved glycemic control and vascular inflammation in healthy overweight and obese subjects in clinical trial. tRES and HESP synergize pharmacologically, and HESP likely overcomes the low bioavailability of tRES by inhibition of intestinal glucuronosyltransferases. Glo1 inducers may now be evaluated in Phase 2 clinical trials for treatment of NAFLD and vascular complications of diabetes. Antioxid. Redox Signal. 00, 000-000.

Systemic alterations in the metabolome of diabetic NOD mice delineate increased oxidative stress accompanied by reduced inflammation and hypertriglyceremia

PubMed Central

Fahrmann, Johannes; Grapov, Dmitry; Yang, Jun; Hammock, Bruce; Fiehn, Oliver; Bell, Graeme I.

2015-01-01

Nonobese diabetic (NOD) mice are a commonly used model of type 1 diabetes (T1D). However, not all animals will develop overt diabetes despite undergoing similar autoimmune insult. In this study, a comprehensive metabolomic approach, consisting of gas chromatography time-of-flight (GC-TOF) mass spectrometry (MS), ultra-high-performance liquid chromatography-accurate mass quadruple time-of-flight (UHPLC-qTOF) MS and targeted UHPLC-tandem mass spectrometry-based methodologies, was used to capture metabolic alterations in the metabolome and lipidome of plasma from NOD mice progressing or not progressing to T1D. Using this multi-platform approach, we identified >1,000 circulating lipids and metabolites in male and female progressor and nonprogressor animals (n = 71). Statistical and multivariate analyses were used to identify age- and sex-independent metabolic markers, which best differentiated metabolic profiles of progressors and nonprogressors. Key T1D-associated perturbations were related with 1) increases in oxidation products glucono-δ-lactone and galactonic acid and reductions in cysteine, methionine and threonic acid, suggesting increased oxidative stress; 2) reductions in circulating polyunsaturated fatty acids and lipid signaling mediators, most notably arachidonic acid (AA) and AA-derived eicosanoids, implying impaired states of systemic inflammation; 3) elevations in circulating triacylglyercides reflective of hypertriglyceridemia; and 4) reductions in major structural lipids, most notably lysophosphatidylcholines and phosphatidylcholines. Taken together, our results highlight the systemic perturbations that accompany a loss of glycemic control and development of overt T1D. PMID:25852003

Quantitative analysis of protein and gene expression in salivary glands of Sjogren's-like disease NOD mice treated by bone marrow soup.

PubMed

Misuno, Kaori; Tran, Simon D; Khalili, Saeed; Huang, Junwei; Liu, Younan; Hu, Shen

2014-01-01

Bone marrow cell extract (termed as BM Soup) has been demonstrated to repair irradiated salivary glands (SGs) and restore saliva secretion in our previous study. In the present study, we aim to investigate if the function of damaged SGs in non-obese diabetic (NOD) mice can be restored by BM Soup treatment and the molecular alterations associated with the treatment. Whole BM cells were lysed and soluble intracellular contents ("BM Soup") were injected I.V. into NOD mice. Tandem mass tagging with 2-D liquid chromatography-mass spectrometry was used to quantify proteins in the submandibular glands (SMGs) between untreated and BM Soup-treated mice. Quantitative PCR was used to identify genes with altered expression in the treated mice. restored salivary flow rates to normal levels and significantly reduced the focus scores of SMGs in NOD mice. More than 1800 proteins in SMG cells were quantified by the proteomic approach. Many SMG proteins involved in inflammation and apoptosis were found to be down-regulated whereas those involved in salivary gland biology and development/regeneration were up-regulated in the BM Soup-treated mice. qPCR analysis also revealed expression changes of growth factors and cytokines in the SMGs of the treated NOD mice. BM Soup treatment is effective to restore the function of damaged SGs in NOD mice. Through gene/protein expression analysis, we have found that BM Soup treatment might effectuate via inhibiting apoptosis, focal adhesion and inflammation whereas promoting development, regeneration and differentiation of the SG cells in NOD mice. These findings provide important insights on the potential mechanisms underlying the BM Soup treatment for functional restoration of damaged SGs in NOD mice. Additional studies are needed to further confirm the identified target genes and their related signaling pathways that are responsible for the BM Soup treatment.

Large Gliadin Peptides Detected in the Pancreas of NOD and Healthy Mice following Oral Administration

PubMed Central

Sidenius, Ulrik; Heegaard, Niels H.

2016-01-01

Gluten promotes type 1 diabetes in nonobese diabetic (NOD) mice and likely also in humans. In NOD mice and in non-diabetes-prone mice, it induces inflammation in the pancreatic lymph nodes, suggesting that gluten can initiate inflammation locally. Further, gliadin fragments stimulate insulin secretion from beta cells directly. We hypothesized that gluten fragments may cross the intestinal barrier to be distributed to organs other than the gut. If present in pancreas, gliadin could interact directly with the immune system and the beta cells to initiate diabetes development. We orally and intravenously administered 33-mer and 19-mer gliadin peptide to NOD, BALB/c, and C57BL/6 mice and found that the peptides readily crossed the intestinal barrier in all strains. Several degradation products were found in the pancreas by mass spectroscopy. Notably, the exocrine pancreas incorporated large amounts of radioactive label shortly after administration of the peptides. The study demonstrates that, even in normal animals, large gliadin fragments can reach the pancreas. If applicable to humans, the increased gut permeability in prediabetes and type 1 diabetes patients could expose beta cells directly to gliadin fragments. Here they could initiate inflammation and induce beta cell stress and thus contribute to the development of type 1 diabetes. PMID:27795959

A cluster of coregulated genes determines TGF-β–induced regulatory T-cell (Treg) dysfunction in NOD mice

PubMed Central

D'Alise, Anna Morena; Ergun, Ayla; Hill, Jonathan A.; Mathis, Diane; Benoist, Christophe

2011-01-01

Foxp3+ regulatory T cells (Tregs) originate in the thymus, but the Treg phenotype can also be induced in peripheral lymphoid organs or in vitro by stimulation of conventional CD4+ T cells with IL-2 and TGF-β. There have been divergent reports on the suppressive capacity of these TGF-Treg cells. We find that TGF-Tregs derived from diabetes-prone NOD mice, although expressing normal Foxp3 levels, are uniquely defective in suppressive activity, whereas TGF-Tregs from control strains (B6g7) or ex vivo Tregs from NOD mice all function normally. Most Treg-typical transcripts were shared by NOD or B6g7 TGF-Tregs, except for a small group of differentially expressed genes, including genes relevant for suppressive activity (Lrrc32, Ctla4, and Cd73). Many of these transcripts form a coregulated cluster in a broader analysis of T-cell differentiation. The defect does not map to idd3 or idd5 regions. Whereas Treg cells from NOD mice are normal in spleen and lymph nodes, the NOD defect is observed in locations that have been tied to pathogenesis of diabetes (small intestine lamina propria and pancreatic lymph node). Thus, a genetic defect uniquely affects a specific Treg subpopulation in NOD mice, in a manner consistent with a role in determining diabetes susceptibility. PMID:21543717

Management of obesity in non- insulin- dependent diabetes mellitus.

PubMed

Cheah, J S

1998-12-01

Obesity is common in non-insulin-dependent diabetes mellitus (NIDDM) patients; in Singapore in a cohort of 314 diabetics, 44.3% were overweight. Management of obesity in diabetics differs from that in non-diabetics in that it is more urgent; weight maintenance is more difficult and hypoglycaemic medication may cause weight changes. However, like in the non-diabetic, management of obesity in the diabetic requires a pragmatic and realistic approach. A team approach is required: the help of a nurse educator, a dietitian, behaviour modification therapist, exercise therapist and others are required. A detailed history, careful physical examination and relevant investigations are required to assess the severity of the diabetic state and to exclude an occasional underlying cause of the obesity in the obese NIDDM patient. Weight loss is urgent in the obese NIDDM patient, especially for those with android obesity. There must be a reduction in energy intake. Weight loss leads to an improvement in glucose tolerance and in insulin sensitivity, as well as to a reduction in lipid levels and to a fall in blood pressure in the hypertensive. Exercise is of limited short-term value measured in terms of weight reduction, except in the younger obese NIDDM patient; but it does allow improvement in overall metabolic control and, long-term, is critical for preferred weight maintenance. The biguanide, Metformin, is the hypoglycaemic drug of choice as it leads to consistent weight reduction. The sulphonylureas may cause weight gain. Insulin should be avoided where possible as it causes further weight gain. Other hypoglycaemic agents include Glucobay (alpha-glucosidase inhibitor) and Troglitazone (insulin sensitizer) which do not alter the weight. Orlistat (lipase inhibitor) is promising as it causes reduction of weight, blood glucose and lipid levels. Anti-obesity drugs (noradrenergic and serotonergic agents) have modest effects on weight reduction in the obese NIDDM patient; a widely

The role of cadmium in obesity and diabetes.

PubMed

Tinkov, Alexey A; Filippini, Tommaso; Ajsuvakova, Olga P; Aaseth, Jan; Gluhcheva, Yordanka G; Ivanova, Juliana M; Bjørklund, Geir; Skalnaya, Margarita G; Gatiatulina, Eugenia R; Popova, Elizaveta V; Nemereshina, Olga N; Vinceti, Marco; Skalny, Anatoly V

2017-12-01

Multiple studies have shown an association between environmental exposure to hazardous chemicals including toxic metals and obesity, diabetes, and metabolic syndrome. At the same time, the existing data on the impact of cadmium exposure on obesity and diabetes are contradictory. Therefore, the aim of the present work was to review the impact of cadmium exposure and status on the risk and potential etiologic mechanisms of obesity and diabetes. In addition, since an effect of cadmium exposure on incidence of diabetes mellitus and insulin resistance was suggested by several epidemiologic studies, we carried out a meta-analysis of all studies assessing risk of prevalence and incidence of diabetes. By comparing the highest versus the lowest cadmium exposure category, we found a high risk of diabetes incidence (odds ratio=1.38, 95% confidence interval 1.12-1.71), which was higher for studies using urine as exposure assessment. On the converse, results of epidemiologic studies linking cadmium exposure and overweight or obesity are far less consistent and even conflicting, also depending on differences in exposure levels and the specific marker of exposure (blood, urine, hair, nails). In turn, laboratory studies demonstrated that cadmium adversely affects adipose tissue physiopathology through several mechanisms, thus contributing to increased insulin resistance and enhancing diabetes. However, intimate biological mechanisms linking Cd exposure with obesity and diabetes are still to be adequately investigated. Copyright © 2017 Elsevier B.V. All rights reserved.

Long Term Effect of Gut Microbiota Transfer on Diabetes Development

PubMed Central

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

2015-01-01

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. PMID:24767831

Epidemiology of Obesity and Diabetes and Their Cardiovascular Complications

PubMed Central

Bhupathiraju, Shilpa N.; Hu, Frank B.

2016-01-01

Obesity and diabetes have reached epidemic proportions in the past few years. In 2011–2012, more than a third of the US population was obese. Although recent trend data indicate that the epidemic has “leveled off”, prevalence of abdominal obesity continues to rise, especially among adults. As seen for obesity, the past few decades have seen a doubling of the diabetes incidence with an increasing number of type 2 diabetes cases being diagnosed in children. Significant racial and ethnic disparities exist in the prevalence and trends of obesity and diabetes. In general, in both adults and children, non-Hispanic blacks and Mexican Americans appear to be at a high risk than their non-Hispanic white counterparts. Secular changes in agricultural policies, diet, food environment, physical activity, and sleep have all contributed to the upward trends in the “diabesity” epidemic. Despite marginal improvements in physical activity and the US diet, the food environment has changed drastically to an “obesogenic” one with increased portion sizes and limited access to healthy food choices especially for disadvantaged populations. Interventions that improve the food environment are critical as both obesity and diabetes raise the risk of cardiovascular disease by nearly two-fold. Among those with type 2 diabetes, significant sex differences occur in the risk of cardiovascular disease such that diabetes completely eliminates or attenuates the advantages of being female. Given the substantial burden of obesity and diabetes, future research efforts should adopt a translational approach to find sustainable and holistic solutions in preventing these costly diseases. PMID:27230638

Erythropoietin and its Carbamylated Derivative Prevent the Development of Experimental Diabetic Autonomic Neuropathy in STZ-Induced Diabetic NOD-SCID Mice

PubMed Central

Schmidt, Robert E.; Green, Karen G.; Feng, Dongyan; Dorsey, Denise A.; Parvin, Curtis A.; Lee, Jin-Moo; Xiao, Qinlgi; Brines, Michael

2008-01-01

Autonomic neuropathy is a significant diabetic complication resulting in increased morbidity and mortality. Studies of autopsied diabetic patients and several rodent models demonstrate that the neuropathologic hallmark of diabetic sympathetic autonomic neuropathy in prevertebral ganglia is the occurrence of synaptic pathology resulting in distinctive dystrophic neurites (“neuritic dystrophy”). Our prior studies show that neuritic dystrophy is reversed by exogenous IGF-I administration without altering the metabolic severity of diabetes, i.e. functioning as a neurotrophic substance. The description of erythropoietin (EPO) synergy with IGF-I function and the recent discovery of EPO’s multifaceted neuroprotective role suggested it might substitute for IGF-I in treatment of diabetic autonomic neuropathy. Our current studies demonstrate EPO receptor (EPO-R) mRNA in a cDNA set prepared from NGF-maintained rat sympathetic neuron cultures which decreased with NGF deprivation, a result which demonstrates clearly that sympathetic neurons express EPO-R, a result confirmed by immunohistochemistry. Treatment of STZ-diabetic NOD-SCID mice have demonstrated a dramatic preventative effect of EPO and carbamylated EPO (CEPO, which is neuroprotective but not hematopoietic) on the development of neuritic dystrophy. Neither EPO nor CEPO had a demonstrable effect on the metabolic severity of diabetes. Our results coupled with reported salutary effects of EPO on postural hypotension in a few clinical studies of EPO-treated anemic diabetic and non-diabetic patients may reflect a primary neurotrophic effect of EPO on the sympathetic autonomic nervous system, rather than a primary hematopoietic effect. These findings may represent a major clinical advance since EPO has been widely and safely used in anemic patients due to a variety of clinical conditions. PMID:17967455

Hepatocytes express functional NOD1 and NOD2 receptors: A role for NOD1 in hepatocyte CC and CXC chemokine production

PubMed Central

Scott, Melanie J.; Chen, Christine; Sun, Qian; Billiar, Timothy R.

2010-01-01

Background & Aims NOD-like receptors are recently described cytosolic pattern recognition receptors. NOD1 and NOD2 are members of this family that recognize bacterial cell wall components, diaminopimelic acid and muramyl dipeptide, respectively. Both NOD1 and NOD2 have been associated with many inflammatory diseases, although their role in liver inflammation and infection has not been well studied. Materials and Methods We investigated the role of NOD receptors in mouse liver by assessing expression and activation of NOD1 and NOD2 in liver and primary isolated hepatocytes from C57BL/6 mice. Results Both NOD1 and NOD2 mRNA and protein were highly expressed in hepatocytes and liver. RIP2, the main signaling partner for NODs, was also expressed. Stimulation of hepatocytes with NOD1 ligand (C12-iEDAP) induced NFκB activation, activation of MAP kinases and expression of chemokines CCL5 (RANTES) and CXCL1 (KC). C12-iEDAP also synergized with interferon (IFN)γ to increase iNOS expression and production of nitric oxide. Despite activating NFκB, NOD1 ligand did not upregulate hepatocyte production of the acute phase proteins lipopolysaccharide binding protein, serum amyloid A, or soluble CD14 in cell culture supernatants, or upregulate mRNA expression of lipopolysaccharide binding protein, serum amyloid A, C-reactive protein, or serum amyloid P. NOD2 ligand (MDP) did not activate hepatocytes when given alone, but did synergize with Toll-like receptor ligands, lipopolysaccharide (LPS), and polyI:C to activate NFκB and MAPK. Conclusions All together these data suggest an important role for hepatocyte NOD1 in attracting leukocytes to the liver during infection and for hepatic NLRs to augment innate immune responses to pathogens. PMID:20615568

Effects of human interleukin-18 and interleukin-12 treatment on human lymphocyte engraftment in NOD-scid mouse

PubMed Central

Senpuku, Hidenobu; Asano, Toshihiko; Matin, Khairul; Salam, M Abdus; Tsuha, Yuzo; Horibata, Shigeo; Shimazu, Yoshihito; Soeno, Yuichi; Aoba, Takaaki; Sata, Tetsutaro; Hanada, Nobuhiro; Honda, Mitsuo

2002-01-01

NOD/LtSz-prkdcscid/prkdcscid (non-obese diabetic-severe combine immunodeficiency; NOD-scid) mice grafted with human peripheral blood lymphoid cells have been used as an in vivo humanized mouse model in various studies. However, cytotoxic human T cells are induced in this model during immune responses, which gives misleading results. To assist in grafting of human lymphocytes without the induction of cytotoxic human T cells, we investigated the effects of T helper type 1 (Th1) and Th2 cytokines on human lymphocyte grafting and migration, as well as the production of immunoglobulin deposited in glomeruli and human immunodeficiency virus-1 (HIV-1) infection using NOD-scid mice. Administration of interleukin-18 (IL-18) and IL-12 enhanced the grafting of human CD4+ and CD8+ T cells in the mice, whereas co-administration prevented grafting due to interferon-γ-dependent apoptosis. Immunoglobulin A (IgA) deposits were observed in mice treated with IL-18 alone, but not in those given phosphate-buffered saline, IL-12 alone, or IL-18 + IL-12. A high rate of HIV infection was also observed in the IL-18-treated group. Together, these results indicate that IL-18 may be effective for the grafting and migration of CD4+ and CD8+ T cells, except for the induction of apoptosis and regulation of class-switching IgA. IL-18-administered NOD-scid mice provide a useful small humanized model for the study of HIV infection and IgA nephropathy. PMID:12383203

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. Copyright © 2015 by The American Association of Immunologists, Inc.

[Association of childhood and adolescents obesity with adult diabetes].

PubMed

Hou, Dongqing; Zhao, Xiaoyuan; Liu, Junting; Chen, Fangfang; Yan, Yinkun; Cheng, Hong; Yang, Ping; Shan, Xinying; Mi, Jie

2016-01-01

To investigate the correlation between obesity in children and diabetes in adults from a cohort study, and further more to explore the necessity of preventing diabetes by controlling obesity in children. In 1987, 3 198 children and adolescents aged 6-18 were recruited from 6 elementary schools and 6 high schools located in 3 districts (Chaoyang, Haidian, and Xicheng) of Beijing using stratified cluster sampling design. The physical examination process included physical development test, blood pressure measurement, and questionnaire investigation. All children were invited to participate in the study, except for those who had history of congenital heart disease, chronic kidney disease, and limb disability. A total of 1,225 adults were enrolled in a prospective follow-up study from March 2010 to July 2012, anthropometric measures and blood sample were obtained. The obesity was defined by the following criteria: for children aged 6, the age-and the gender-specific 95th percentile of BMI from the US Centre for Disease Control and Prevention Growth charts 2000 as the baseline; for children age 7-18, recommendation from Working Group on Obesity in China (WGOC) as the standard; for adults, BMI≥28 kg/m(2) as the diagnosis standard. Diabetes was defined based on fasting plasma glucose(FPG) ≥7.0 mmol/L or 2 hours postprandial blood glucose (2 h PG) ≥11.1 mmol/L or glycosylated hemoglobin (HbA1c) ≥6.5% or current using blood glucose-lowering agents or current using insulin. Logistic regression was used to analyze the association obesity in children with diabetes in adults. The prevalence of diabetes diagnosed by FPG and 2 h PG in adults who were obese children (16.2%, 18/111) was higher than those who were non-obese children (5.6%, 62/1,114)(χ(2)=18.76, P<0.001). The prevalence of diabetes diagnosed by HbA1c in adults who were obese children(18.1%,20/111) was higher than those who were non-obese children (6.9%, 77/1,114) (χ(2)=16.66, P<0.001). With multi

Quantitative Analysis of Protein and Gene Expression in Salivary Glands of Sjogren’s-Like Disease NOD Mice Treated by Bone Marrow Soup

PubMed Central

Misuno, Kaori; Khalili, Saeed; Huang, Junwei; Liu, Younan

2014-01-01

Background Bone marrow cell extract (termed as BM Soup) has been demonstrated to repair irradiated salivary glands (SGs) and restore saliva secretion in our previous study. In the present study, we aim to investigate if the function of damaged SGs in non-obese diabetic (NOD) mice can be restored by BM Soup treatment and the molecular alterations associated with the treatment. Methods Whole BM cells were lysed and soluble intracellular contents (“BM Soup”) were injected I.V. into NOD mice. Tandem mass tagging with 2-D liquid chromatography-mass spectrometry was used to quantify proteins in the submandibular glands (SMGs) between untreated and BM Soup-treated mice. Quantitative PCR was used to identify genes with altered expression in the treated mice. Results BM Soup restored salivary flow rates to normal levels and significantly reduced the focus scores of SMGs in NOD mice. More than 1800 proteins in SMG cells were quantified by the proteomic approach. Many SMG proteins involved in inflammation and apoptosis were found to be down-regulated whereas those involved in salivary gland biology and development/regeneration were up-regulated in the BM Soup-treated mice. qPCR analysis also revealed expression changes of growth factors and cytokines in the SMGs of the treated NOD mice. Conclusion BM Soup treatment is effective to restore the function of damaged SGs in NOD mice. Through gene/protein expression analysis, we have found that BM Soup treatment might effectuate via inhibiting apoptosis, focal adhesion and inflammation whereas promoting development, regeneration and differentiation of the SG cells in NOD mice. These findings provide important insights on the potential mechanisms underlying the BM Soup treatment for functional restoration of damaged SGs in NOD mice. Additional studies are needed to further confirm the identified target genes and their related signaling pathways that are responsible for the BM Soup treatment. PMID:24489858

B-Lymphocytes Expressing an Ig Specificity Recognizing the Pancreatic β-Cell Autoantigen Peripherin Are Potent Contributors to Type 1 Diabetes Development in NOD Mice

PubMed Central

Leeth, Caroline M.; Racine, Jeremy; Chapman, Harold D.; Arpa, Berta; Carrillo, Jorge; Carrascal, Jorge; Wang, Qiming; Ratiu, Jeremy; Egia-Mendikute, Leire; Rosell-Mases, Estela; Stratmann, Thomas

2016-01-01

Although the autoimmune destruction of pancreatic β-cells underlying type 1 diabetes (T1D) development is ultimately mediated by T cells in NOD mice and also likely in humans, B cells play an additional key pathogenic role. It appears that the expression of plasma membrane–bound Ig molecules that efficiently capture β-cell antigens allows autoreactive B cells that bypass normal tolerance induction processes to be the subset of antigen-presenting cells most efficiently activating diabetogenic T cells. NOD mice transgenically expressing Ig molecules recognizing antigens that are (insulin) or are not (hen egg lysozyme [HEL]) expressed by β-cells have proven useful in dissecting the developmental basis of diabetogenic B cells. However, these transgenic Ig specificities were originally selected for their ability to recognize insulin or HEL as foreign, rather than autoantigens. Thus, we generated and characterized NOD mice transgenically expressing an Ig molecule representative of a large proportion of naturally occurring islet-infiltrating B cells in NOD mice recognizing the neuronal antigen peripherin. Transgenic peripherin-autoreactive B cells infiltrate NOD pancreatic islets, acquire an activated proliferative phenotype, and potently support accelerated T1D development. These results support the concept of neuronal autoimmunity as a pathogenic feature of T1D, and targeting such responses could ultimately provide an effective disease intervention approach. PMID:26961115

Management of obesity in NIDDM (non-insulin-dependent diabetes mellitus).

PubMed

Cheah, J S

1998-08-01

Obesity is common in NIDDM; in a cohort of 314 diabetics in Singapore, 44.3% are overweight. Management of obesity in diabetics differs from that in non-diabetics in that it is more urgent; weight maintenance is more difficult and hypoglycaemic medication may cause weight changes. Like in the non-diabetic, management of obesity in diabetic requires a pragmatic and realistic approach. A team approach is required: the help of the nurse educator, the dietitian, behaviour modification therapist, exercise therapist etc are required. A detailed history, careful physical examination and relevant investigations are required to assess the severity of the diabetic state and to exclude an occasional underlying cause of the obesity in the obese NIDDM. Weight loss is urgent in the obese NIDDM, especially those with android obesity. There must be a reduction in caloric intake. Weight loss leads to improvement in the glucose tolerance, insulin sensitivity, reduction in lipid levels and fall in blood pressure in the hypertensive. Exercise is of limited value except in the younger obese NIDDM. Metformin is the hypoglycaemic drug of choice as it leads to consistent weight reduction. The sulphonylureas may cause weight gain. Insulin should be avoided where possible as it causes further weight gain. Other hypoglycaemic agents include Glucobay (alpha-glucosidase inhibitor) and Troglitazone (insulin sensitizer) which do not alter the weight. Orlistat (lipase inhibitor) is promising as it causes reduction of weight, blood-glucose and lipid levels. Anti-obesity drugs (noradrenergic and serotonergic agents) have modest effects on weight reduction in the obese NIDDM; a widely use preparation, Dexfenfluramine (Adifax) has been withdrawn because of side effects. Surgery such as gastric plication is the last resort in treating the morbidly obese NIDDM. The discovery of leptin in 1994 has led to intense research into energy homeostasis in obesity; hopefully this will lead to better treatment of

Prevalence of overweight and obesity among type 2 diabetic patients attending diabetes clinics in northern Tanzania.

PubMed

Damian, Damian J; Kimaro, Kelvin; Mselle, Godwin; Kaaya, Rose; Lyaruu, Isaac

2017-10-26

To determine the prevalence of overweight and obesity among patients with type 2 diabetes who are attending diabetes clinics in northern Tanzania. In total 227 type 2 diabetic patients attending diabetes clinics were enrolled. Majority of patients 193 (85.0%) were overweight (44.9%) or obese (40.1%). Of them, 65 (33.7%) were overweight/obese after diagnosis of type 2 diabetes. The prevalence of overweight/obesity was significantly higher in female participants than the males [92.2% vs. 69.2%; OR = 5.10; 95% CI 2.22-11.05]. Regarding the region of residence, Kilimanjaro (100.0%) and Arusha (89.8%) regions had significantly highest prevalence of overweight/obesity compared to Tanga region (69.2%) [χ 2  = 32.455, P < 0.001].

Stability of Chimerism in Non-Obese Diabetic Mice Achieved By Rapid T Cell Depletion Is Associated With High Levels of Donor Cells Very Early After Transplant.

PubMed

Lin, Jiaxin; Chan, William F N; Boon, Louis; Anderson, Colin C

2018-01-01

Stable mixed hematopoietic chimerism is a robust method for inducing donor-specific tolerance with the potential to prevent rejection of donor islets in recipients with autoimmune type-1 diabetes. However, with reduced intensity conditioning, fully allogeneic chimerism in a tolerance resistant autoimmune-prone non-obese diabetic (NOD) recipient has rarely been successful. In this setting, successful multilineage chimerism has required either partial major histocompatability complex matching, mega doses of bone marrow, or conditioning approaches that are not currently clinically feasible. Irradiation free protocols with moderate bone marrow doses have not generated full tolerance; donor skin grafts were rejected. We tested whether more efficient recipient T cell depletion would generate a more robust tolerance. We show that a combination of donor-specific transfusion-cyclophosphamide and multiple T cell depleting antibodies could induce stable high levels of fully allogeneic chimerism in NOD recipients. Less effective T cell depletion was associated with instability of chimerism. Stable chimeras appeared fully donor-specific tolerant, with clonal deletion of allospecific T cells and acceptance of donor skin grafts, while recovering substantial immunocompetence. The loss of chimerism months after transplant was significantly associated with a lower level of chimerism and donor T cells within the first 2 weeks after transplant. Thus, rapid and robust recipient T cell depletion allows for stable high levels of fully allogeneic chimerism and robust donor-specific tolerance in the stringent NOD model while using a clinically feasible protocol. In addition, these findings open the possibility of identifying recipients whose chimerism will later fail, stratifying patients for early intervention.

Persistent Organic Pollutants as Risk Factors for Obesity and Diabetes.

PubMed

Yang, Chunxue; Kong, Alice Pik Shan; Cai, Zongwei; Chung, Arthur C K

2017-11-02

The rising prevalence of obesity and diabetes cannot be fully explained by known risk factors, such as unhealthy diet, a sedentary lifestyle, and family history. This review summarizes the available studies linking persistent organic pollutants (POPs) to obesity and diabetes and discusses plausible underlying mechanisms. Increasing evidence suggest that POPs may act as obesogens and diabetogens to promote the development of obesity and diabetes and induce metabolic dysfunction. POPs are synthesized chemicals and are used widely in our daily life. These chemicals are resistant to degradation in chemical or biological processes, which enable them to exist in the environment persistently and to be bio-accumulated in animal and human tissue through the food chain. Increasingly, epidemiologic studies suggest a positive association between POPs and risk of developing diabetes. Understanding the relationship of POPs with obesity and diabetes may shed light on preventive strategies for obesity and diabetes.

Hematopoietic stem cells from NOD mice exhibit autonomous behavior and a competitive advantage in allogeneic recipients.

PubMed

Chilton, Paula M; Rezzoug, Francine; Ratajczak, Mariusz Z; Fugier-Vivier, Isabelle; Ratajczak, Janina; Kucia, Magda; Huang, Yiming; Tanner, Michael K; Ildstad, Suzanne T

2005-03-01

Type 1 diabetes is a systemic autoimmune disease that can be cured by transplantation of hematopoietic stem cells (HSCs) from disease-resistant donors. Nonobese diabetic (NOD) mice have a number of features that distinguish them as bone marrow transplant recipients that must be understood prior to the clinical application of chimerism to induce tolerance. In the present studies, we characterized NOD HSCs, comparing their engraftment characteristics to HSCs from disease-resistant strains. Strikingly, NOD HSCs are significantly enhanced in engraftment potential compared with HSCs from disease-resistant donors. Unlike HSCs from disease-resistant strains, they do not require graft-facilitating cells to engraft in allogeneic recipients. Additionally, they exhibit a competitive advantage when coadministered with increasing numbers of syngeneic HSCs, produce significantly more spleen colony-forming units (CFU-Ss) in vivo in allogeneic recipients, and more granulocyte macrophage-colony-forming units (CFU-GMs) in vitro compared with HSCs from disease-resistant controls. NOD HSCs also exhibit significantly enhanced chemotaxis to a stromal cell-derived factor 1 (SDF-1) gradient and adhere significantly better on primary stroma. This enhanced engraftment potential maps to the insulin-dependent diabetes locus 9 (Idd9) locus, and as such the tumor necrosis factor (TNF) receptor family as well as ski/sno genes may be involved in the mechanism underlying the autonomy of NOD HSCs. These findings may have important implications to understand the evolution of autoimmune disease and impact on potential strategies for cure.

Exercise improves cardiac autonomic function in obesity and diabetes.

PubMed

Voulgari, Christina; Pagoni, Stamatina; Vinik, Aaron; Poirier, Paul

2013-05-01

Physical activity is a key element in the prevention and management of obesity and diabetes. Regular physical activity efficiently supports diet-induced weight loss, improves glycemic control, and can prevent or delay type 2 diabetes diagnosis. Furthermore, physical activity positively affects lipid profile, blood pressure, reduces the rate of cardiovascular events and associated mortality, and restores the quality of life in type 2 diabetes. However, recent studies have documented that a high percentage of the cardiovascular benefits of exercise cannot be attributed solely to enhanced cardiovascular risk factor modulation. Obesity in concert with diabetes is characterized by sympathetic overactivity and the progressive loss of cardiac parasympathetic influx. These are manifested via different pathogenetic mechanisms, including hyperinsulinemia, visceral obesity, subclinical inflammation and increased thrombosis. Cardiac autonomic neuropathy is an underestimated risk factor for the increased cardiovascular morbidity and mortality associated with obesity and diabetes. The same is true for the role of physical exercise in the restoration of the heart cardioprotective autonomic modulation in these individuals. This review addresses the interplay of cardiac autonomic function in obesity and diabetes, and focuses on the importance of exercise in improving cardiac autonomic dysfunction. Copyright © 2013 Elsevier Inc. All rights reserved.

Structure-guided design of an invariant natural killer T cell agonist for optimum protection from type 1 diabetes in non-obese diabetic mice

PubMed Central

Blumenfeld, H J; Tohn, R; Haeryfar, S M M; Liu, Y; Savage, P B; Delovitch, T L

2011-01-01

Because invariant natural killer T (iNK T) cells link innate and adaptive immunity, the structure-dependent design of iNK T cell agonists may have therapeutic value as vaccines for many indications, including autoimmune disease. Previously, we showed that treatment of non-obese diabetic (NOD) mice with the iNK T cell activating prototypic glycolipid α-galactosylceramide (α-GalCer) protects them from type 1 diabetes (T1D). However, α-GalCer is a strong agonist that can hyperactivate iNK T cells, elicit several side effects and has shown only limited success in clinical trials. Here, we used a structure-guided design approach to identify an iNK T cell agonist that optimally protects from T1D with minimal side effects. Analyses of the kinetics and function of a panel of synthetic α-GalCer fatty acyl chain derivatives (C8:0-C16:0) were performed in NOD mice. C16:0 elicited the highest protection from insulitis and T1D, which was associated with a higher frequency and survival of iNK T cells and enhanced activity of tolerogenic dendritic cells (DCs) in draining pancreatic lymph nodes (PLN), inability to transactivate NK cells and a more rapid kinetics of induction and recovery of iNK T cells from anergy. We conclude that the length and structure of the acyl chain of α-GalCer regulates the level of protection against T1D in mice, and propose that the extent of this protection depends on the relative capacity of the acyl chain to accommodate an endogenous spacer lipid of appropriate length and structure. Thus, our findings with the α-GalCer C16:0 derivative suggest strongly that it be considered as a lead glycolipid candidate in clinical trials of T1D. PMID:21910729

Antibiotic-associated Manipulation of the Gut Microbiota and Phenotypic Restoration in NOD Mice

PubMed Central

Fahey, James R; Lyons, Bonnie L; Olekszak, Haiyan L; Mourino, Anthony J; Ratiu, Jeremy J; Racine, Jeremy J; Chapman, Harold D; Serreze, David V; Baker, Dina L; Hendrix, N Ken

2017-01-01

Segmented filamentous bacterium (SFB) a gram-positive, anaerobic, and intestinal commensal organism directly influences the development of Th17 helper cells in the small intestine of mice. In NOD mice, SFB colonization interferes with the development of type 1 diabetes (T1D), a T-cell–mediated autoimmune disease, suggesting that SFB may influence Th17 cells to inhibit Th1 populations associated with the anti-β-cell immune response. This effect is a serious concern for investigators who use NOD mice for diabetes research because the expected incidence of disease decreases markedly when they are colonized by SFB. A room housing mice for T1D studies at The Jackson Laboratory was determined by fecal PCR testing to have widespread SFB colonization of multiple NOD strains after a steady decline in the incidence of T1D was noted. Rederivation of all NOD-related mouse strains was not feasible; therefore an alternative treatment using antibiotics to eliminate SFB from colonized mice was undertaken. After antibiotic treatment, soiled bedding from NOD mouse strains housed in SFB-free high-health–status production barrier rooms was used to reintroduce the gastrointestinal microbiota. Over the past 16 mo since treating the mice and disinfecting the mouse room, regular PCR testing has shown that no additional SFB colonization of mice has occurred, and the expected incidence of T1D has been reestablished in the offspring of treated mice. PMID:28830580

Prevalence of diabetes and associated obesity in Pennsylvania adults, 1995-2010.

PubMed

Garcia-Dominic, Oralia; Lengerich, Eugene J; Camacho, Fabian; Gallant, Nancy R; Wray, Linda A; Ahern, Frank; Bogdan, Greg; Weinberg, Gene; Ulbrecht, Jan S

2014-07-03

This study examined trends in the prevalence and sociodemographic distributions of diabetes and the associations of diabetes with obesity over time in adult Pennsylvanians from 1995 through 2010. We used Behavioral Risk Factor Surveillance Survey data collected from 1995 through 2010. Diabetes prevalence was assessed by self-report of physician diagnosis. Obesity was assessed by body mass index computed from self-report of height and weight. State-level data for diabetes and associated obesity prevalence from 1995 through 2010 were collected for each year. Data on sociodemographic factors (age, sex, race, income, education) and 1 known disease risk factor (obesity) were also collected. Logistic regression modeling was used to examine associations between diabetes, sociodemographic factors, and obesity. Diabetes prevalence in Pennsylvania, which increased from 5.6% in 1995 to 10.5% in 2010, followed national trends but exceeded the national prevalence each year by approximately 0.6 percentage points for 12 of the 16 years. The increase in prevalence was not equal across all socioeconomic groups. Obesity became a more dominant risk factor for diabetes during these 16 years. The burden of diabetes and obesity in Pennsylvania is substantial and increasing. Program managers and policy makers in Pennsylvania should consider these trends when allocating limited resources and designing programs for reducing diabetes-related illness. Other states may consider similar studies to monitor the prevalence of diabetes and determine whether disparities are changing and whether programs and resources should also shift.

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

Improvement of type 2 diabetes mellitus in obese and non-obese patients after the duodenal switch operation.

PubMed

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, HbA(1c)-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 HbA(1c)-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.

CD44 gene vaccination for insulin-dependent diabetes mellitus in non-obese diabetic mice.

PubMed

Weiss, Lola; Botero-Anug, Ana Maria; Hand, Carla; Slavin, Shimon; Naor, David

2008-01-01

Standard CD44 and its alternatively spliced variants were found to be associated with the metastatic potential of tumor cells and with cell migration of autoimmune inflammatory cells, including cells involved in experimental insulin-dependent diabetes mellitus. To investigate whether induction of anti-CD44 immune reactivity, through cDNA vaccination, could attenuate IDDM in a transfer model of NOD mice. Our vaccination technique involved the insertion of CD44s or CD44v cDNA into a silicone tube filled with a 2.5 cm long segment of hydroxylated-polyvinyl acetate wound dressing sponge (forming a virtual lymph node) which was implanted under the skin of male NOD recipients reconstituted with diabetogenic spleen cells of female NOD donors. The VLN were implanted 20 days before and 3 days after cell transfer. In contrast to control groups of recipient mice, recipients vaccinated with VLN loaded with CD44v or CD44s cDNAs developed resistance to IDDM almost to the same extent. Our results suggest that the gene vaccination effect was mediated by anti-CD44 antibody rather than by cellular immunity. Histopathological examinations revealed a significant protection of pancreatic islets in the DNA-vaccinated recipients, whereas the islets of control recipients of diabetogenic cells were almost totally destroyed. These findings may open new opportunities for IDDM therapy in the future.

Stressed hearts in children with obesity and diabetes: a cause for concern?

PubMed

Berry, C; Sattar, N

2011-04-01

Obesity in young people is an emerging public health problem, particularly because of its association with type 2 diabetes. Since obesity and diabetes contribute to the development of cardiovascular disease in adults, the question arises as to whether or not these conditions may be associated with cardiovascular abnormalities in children and adolescents. In this issue of Diabetologia, Shah et al. report the results of a cross-sectional study of heart structure and function in 612 adolescents and young adults (aged 10-24 years) subdivided into three groups: (1) those with obesity and type 2 diabetes; (2) those with type 2 diabetes but without obesity; and (3) lean healthy controls. Their results revealed that left ventricular mass (indexed to body surface area) was greater in the obese individuals than in lean controls. Left ventricular systolic function was more dynamic in obese participants and obese participants with type 2 diabetes compared with lean controls, whereas systolic function was comparable in obese patients with or without type 2 diabetes. Furthermore, compared with the healthy lean control participants, diastolic function was impaired in the obese group and further impaired in the obese individuals with diabetes. These results, and those of a few other similar studies, lend support to the notion that obesity and diabetes in children cause subtle abnormalities in cardiovascular structure and function. The present commentary discusses potential mechanisms and possible clinical ramifications for such findings.

Repurposed JAK1/JAK2 Inhibitor Reverses Established Autoimmune Insulitis in NOD Mice.

PubMed

Trivedi, Prerak M; Graham, Kate L; Scott, Nicholas A; Jenkins, Misty R; Majaw, Suktilang; Sutherland, Robyn M; Fynch, Stacey; Lew, Andrew M; Burns, Christopher J; Krishnamurthy, Balasubramanian; Brodnicki, Thomas C; Mannering, Stuart I; Kay, Thomas W; Thomas, Helen E

2017-06-01

Recent advances in immunotherapeutics have not yet changed the routine management of autoimmune type 1 diabetes. There is an opportunity to repurpose therapeutics used to treat other diseases to treat type 1 diabetes, especially when there is evidence for overlapping mechanisms. Janus kinase (JAK) 1/JAK2 inhibitors are in development or clinical use for indications including rheumatoid arthritis. There is good evidence for activation of the JAK1/JAK2 and signal transducer and activator of transcription (STAT) 1 pathway in human type 1 diabetes and in mouse models, especially in β-cells. We tested the hypothesis that using these drugs to block the JAK-STAT pathway would prevent autoimmune diabetes. The JAK1/JAK2 inhibitor AZD1480 blocked the effect of cytokines on mouse and human β-cells by inhibiting MHC class I upregulation. This prevented the direct interaction between CD8 + T cells and β-cells, and reduced immune cell infiltration into islets. NOD mice treated with AZD1480 were protected from autoimmune diabetes, and diabetes was reversed in newly diagnosed NOD mice. This provides mechanistic groundwork for repurposing clinically approved JAK1/JAK2 inhibitors for type 1 diabetes. © 2017 by the American Diabetes Association.

Diabetes-associated dry eye syndrome in a new humanized transgenic model of type 1 diabetes.

PubMed

Imam, Shahnawaz; Elagin, Raya B; Jaume, Juan Carlos

2013-01-01

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. 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. 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. 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.

May diabetes patients have trouble sleeping despite not having obesity?

PubMed

Rizzi, Maurizio; Razionale, Giancarlo; Bamberga, Michele; Barrella, Massimo; Kotzalidis, Georgios D; Certan, Diana; Bevilacqua, Maurizio

2014-06-01

Obstructive sleep apnea (OSA) and periodic limb movements during sleep (PLMs) are sleep-related disorders with a high prevalence in type 2 diabetes. Commonly OSA is considered as a consequence of obesity, but several previous studies have shown the presence of OSA in non-obese diabetic patients. A previous study showed higher PLMs prevalence in patients with type 2 diabetes, compared to age-matched controls. We speculated that both OSA and PLMs may reflect the presence of diabetic autonomic neuropathy. To test this hypothesis, we compared a group of 112 non-obese patients with type 2 diabetes with 66 age-, sex-, and body mass index- matched nondiabetic patients. Both groups have been investigated through a set of tests including the Epworth Sleepiness Scale, polysomnography, and the Orthostatic Grading Scale (OGS), a questionnaire to assess the degree of autonomic dysfunction. Diabetic patients with OSA and PLMs scored higher on the OGS than controls. Our results confirm that both OSA and PLMs are related to dysautonomy and may be unrelated to obesity in type 2 diabetes patients.

Do obese children with diabetic ketoacidosis have type 1 or type 2 diabetes?

PubMed

Low, Joey C; Felner, Eric I; Muir, Andrew B; Brown, Milton; Dorcelet, Margalie; Peng, Limin; Umpierrez, Guillermo E

2012-04-01

Many obese children with unprovoked diabetic ketoacidosis (DKA) display clinical features of type 2 diabetes during follow up. We describe the clinical presentation, autoimmune markers and the long-term course of obese and lean children with DKA. We reviewed the medical records on the initial acute hospitalization and outpatient follow-up care of 21 newly diagnosed obese and 20 lean children with unprovoked DKA at Emory University affiliated children's hospitals between 1/2003 and 12/2006. Obese children with DKA were older and predominantly male, had acanthosis nigricans, and had lower prevalence of autoantibodies to islet cells and glutamic acid decarboxylase than lean children. Half of the obese, but none of the lean children with DKA achieve near-normoglycemia remission and discontinued insulin therapy during follow-up. Time to achieve remission was 2.2±2.3 months. There were no differences on clinical presentation between obese children who achieved near-normoglycemia remission versus those who did not. The addition of metformin to insulin therapy shortly after resolution of DKA resulted in lower hemoglobin A1c (HbA1c) levels, higher rates of near-normoglycemia remission, and lower frequency of DKA recurrence. Near-normoglycemia remission, however, was of short duration and the majority of obese patients required reinstitution of insulin treatment within 15 months of follow-up. In contrast to lean children with DKA, many obese children with unprovoked DKA display clinical and immunologic features of type 2 diabetes during follow-up. The addition of metformin to insulin therapy shortly after resolution of DKA improves glycemic control, facilitates achieving near-normoglycemia remission and prevents DKA recurrence in obese children with DKA. Copyright © 2011 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

Racial/Ethnic Residential Segregation, Obesity, and Diabetes Mellitus.

PubMed

Kershaw, Kiarri N; Pender, Ashley E

2016-11-01

Persistent racial/ethnic disparities in obesity and type 2 diabetes mellitus seen in the US are likely due to a combination of social, biological, and environmental factors. A growing number of studies have examined the role of racial/ethnic residential segregation with respect to these outcomes because this macro-level process is believed to be a fundamental cause of many of the factors that contribute to these disparities. This review provides an overview of findings from studies of racial/ethnic residential segregation with obesity and diabetes published between 2013 and 2015. Findings for obesity varied by geographic scale of the segregation measure, gender, ethnicity, and racial identity (among Hispanics/Latinos). Recent studies found no association between racial/ethnic residential segregation and diabetes prevalence, but higher segregation of Blacks was related to higher diabetes mortality. Implications of these recent studies are discussed as well as promising areas of future research.

Prevalence of Diabetes and Associated Obesity in Pennsylvania Adults, 1995–2010

PubMed Central

Lengerich, Eugene J.; Camacho, Fabian; Gallant, Nancy R.; Wray, Linda A.; Ahern, Frank; Bogdan, Greg; Weinberg, Gene; Ulbrecht, Jan S.

2014-01-01

Introduction This study examined trends in the prevalence and sociodemographic distributions of diabetes and the associations of diabetes with obesity over time in adult Pennsylvanians from 1995 through 2010. Methods We used Behavioral Risk Factor Surveillance Survey data collected from 1995 through 2010. Diabetes prevalence was assessed by self-report of physician diagnosis. Obesity was assessed by body mass index computed from self-report of height and weight. State-level data for diabetes and associated obesity prevalence from 1995 through 2010 were collected for each year. Data on sociodemographic factors (age, sex, race, income, education) and 1 known disease risk factor (obesity) were also collected. Logistic regression modeling was used to examine associations between diabetes, sociodemographic factors, and obesity. Results Diabetes prevalence in Pennsylvania, which increased from 5.6% in 1995 to 10.5% in 2010, followed national trends but exceeded the national prevalence each year by approximately 0.6 percentage points for 12 of the 16 years. The increase in prevalence was not equal across all socioeconomic groups. Obesity became a more dominant risk factor for diabetes during these 16 years. Conclusion The burden of diabetes and obesity in Pennsylvania is substantial and increasing. Program managers and policy makers in Pennsylvania should consider these trends when allocating limited resources and designing programs for reducing diabetes-related illness. Other states may consider similar studies to monitor the prevalence of diabetes and determine whether disparities are changing and whether programs and resources should also shift. PMID:24995653

High-fat, carbohydrate-free diet markedly aggravates obesity but prevents beta-cell loss and diabetes in the obese, diabetes-susceptible db/db strain.

PubMed

Mirhashemi, Farshad; Kluth, Oliver; Scherneck, Stephan; Vogel, Heike; Kluge, Reinhart; Schurmann, Annette; Joost, Hans-Georg; Neschen, Susanne

2008-01-01

We have previously reported that a high-fat, carbohydrate-free diet prevents diabetes and beta-cell destruction in the New Zealand Obese (NZO) mouse strain. Here we investigated the effect of diets with and without carbohydrates on obesity and development of beta-cell failure in a second mouse model of type 2 diabetes, the db/db mouse. When kept on a carbohydrate-containing standard (SD; with (w/w) 5.1, 58.3, and 17.6% fat, carbohydrates and protein, respectively) or high-fat diet (HFD; 14.6, 46.7 and 17.1%), db/db mice developed severe diabetes (blood glucose >20 mmol/l, weight loss, polydipsia and polyurea) associated with a selective loss of pancreatic beta-cells, reduced GLUT2 expression in the remaining beta-cells, and reduced plasma insulin levels. In contrast, db/db mice kept on a high-fat, carbohydrate-free diet (CFD; with 30.2 and 26.4% (w/w) fat or protein) did not develop diabetes and exhibited near-normal, hyperplastic islets in spite of a morbid obesity (fat content >60%) associated with hyperinsulinaemia. These data indicate that in genetically different mouse models of obesity-associated diabetes, obesity and dietary fat are not sufficient, and dietary carbohydrates are required, for beta-cell destruction.

Brd2 gene disruption causes ‘metabolically healthy’ obesity: Epigenetic and chromatin-based mechanisms that uncouple obesity from Type 2 diabetes

PubMed Central

Wang, Fangnian; Deeney, Jude T.; Denis, Gerald V.

2014-01-01

Disturbed body energy balance can lead to obesity and obesity-driven diseases such as Type 2 diabetes, which have reached an epidemic level. Evidence indicates that obesity induced inflammation is a major cause of insulin resistance and Type 2 diabetes. Environmental factors, such as nutrients, affect body energy balance through epigenetic or chromatin-based mechanisms. As a bromodomain and external domain family transcription regulator, Brd2 regulates expression of many genes through interpretation of chromatin codes, and participates in the regulation of body energy balance and immune function. In the severely obese state, Brd2 knockdown in mice prevented obesity-induced inflammatory responses, protected animals from Type 2 diabetes, and thus uncoupled obesity from diabetes. Brd2 provides an important model for investigation of the function of transcription regulators and the development of obesity and diabetes; it also provides a possible target to treat obesity and diabetes through modulation of the function of a chromatin code reader. PMID:23374712

Anti-obesity and pro-diabetic effects of hemochromatosis.

PubMed

Abbas, Mousa Al; Abraham, Deveraprabu; Kushner, James P; McClain, Donald A

2014-10-01

Levels of tissue iron contribute to determining diabetes risk, but little is known about the effects of higher iron levels on weight, and on the interaction of weight and iron overload on diabetes risk. Therefore, the effect of iron on body mass index and diabetes in individuals with iron overload from hereditary hemochromatosis (HH), compared to non-HH siblings and historical controls was examined. Chart reviews were performed on a cohort of adults (age ≥40, N = 101) with the common C282Y/C282Y HFE genotype, compared to wild type siblings (N = 32) and comparable NHANES cohorts, with respect to body mass index and diabetes status. Males with HH have lower body mass index (BMI) than control siblings. Females had a trend toward decreased BMI that was not significant, possibly related to decreased degrees of iron overload. In both males and females, increased rates of diabetes were seen, especially in the overweight or obese. High tissue iron levels may be both pro- and anti-diabetic. The prevalence of obesity and diabetes in HH is likely dependent upon the degree of iron overload, caloric intake, and other genetic and environmental factors, contributing to the observed heterogeneity in the frequency of disease-related morbidities in HH. Copyright © 2014 The Obesity Society.

Gastric bypass surgery reveals independency of obesity and diabetes melitus type 2.

PubMed

Fenger, Mogens; Hansen, Dorte Lindqvist; Worm, Dorte; Hvolris, Lisbeth; Kristiansen, Viggo B; Carlsson, Elin Rebecka; Madsbad, Sten

2016-11-09

Roux-en-Y gastric bypass surgery is widely applied to ameliorate morbid obesity, including diabetes in people with type 2 diabetes. The latter vanish a few days after surgery for many, but not in all patients before any weight reduction has occurred. The explanation for this change in metabolic status is poorly understood, but the observation may suggest that the fate obesity and diabetes is only partly linked after surgery. The trajectories of weight reduction measured as reduced body mass index (BMI) in 741obese subjects with and without diabetes were evaluated. Evaluation was performed on three groups: 1) subjects that were non-diabetic before and after surgery; 2) subjects that were diabetics before surgery but non-diabetics after surgery; and 3) subjects that were diabetics before surgery and remained diabetics after surgery. The diabetic state was established at HbA1c above 48 mmol/mol. The trajectories differ significantly between groups and any sub-populations of groups, the latter identified by the distance between individual trajectories using a k-means procedure. The results suggest that different domains in the enormous genetic network governing basic metabolism are perturbed in obesity and diabetes, and in fact some of the patients are affected by two distinct diseases: obesity and diabetes mellitus type 2. Although RYGB "normalized" many glycaemic parameters in some of the diabetic subjects apparently converting to a non-diabetics state, other diabetic subjects stay diabetic in the context of the new gut anatomy after surgery. Thus, the obesity part of the glycaemic derangement may have been ameliorated, but some defects of the diabetic state had not.

α-Motoneurons maintain biophysical heterogeneity in obesity and diabetes in Zucker rats.

PubMed

MacDonell, Christopher W; Chopek, Jeremy W; Gardiner, Kalan R; Gardiner, Phillip F

2017-10-01

Small-diameter sensory dysfunction resulting from diabetes has received much attention in the literature, whereas the impact of diabetes on α-motoneurons (MN) has not. In addition, the chance of developing insulin resistance and diabetes is increased in obesity. No study has examined the impact of obesity or diabetes on the biophysical properties of MN. Lean Zucker rats and Zucker diabetic fatty (ZDF) rats were separated into lean, obese (ZDF fed standard chow), and diabetic (ZDF fed high-fat diet that led to diabetes) groups. Glass micropipettes recorded hindlimb MN properties from identified flexor and extensor MN. MN were separated within their groups on the basis of input conductance, which created high- and low-input conductance subpopulations for each. A significant shorter (20%) afterhyperpolarization half-decay (AHP 1/2 ) was found in low-conductance MN for the diabetic group only, whereas AHP½ tended to be shorter in the obese group (19%). Significant positive correlations were found among rheobase and input conductance for both lean and obese animals. No differences were found between the groups for afterhyperpolarization amplitude (AHP amp ), input conductance, rheobase, or any of the rhythmic firing properties (frequency-current slope and spike-frequency adaptation index). MN properties continue to be heterogeneous in obese and diabetic animals. Obesity does not seem to influence lumbar MN. Despite the resistance of MN to the impact of diabetes, the reduced AHP 1/2 decay and the tendency for a reduction in AHP amp may be the first sign of change to MN function. NEW & NOTEWORTHY Knowledge about the impact of obesity and diabetes on the biophysical properties of motoneurons is lacking. We found that diabetes reduces the duration of the afterhyperpolarization and that motoneuron function is unchanged by obesity. A reduced afterhyperpolarization may impact discharge characteristics and may be the first sign of change to motoneuron function. Copyright �

Pathogenesis of NOD Diabetes is Initiated by Reactivity to the Insulin B Chain 9–23 Epitope and Involves Functional Epitope Spreading1

PubMed Central

Prasad, Suchitra; Kohm, Adam P.; McMahon, Jeffrey S.; Luo, Xunrong; Miller, Stephen D.

2012-01-01

Type 1 diabetes (T1D) is mediated by destruction of pancreatic β cells by CD4 and CD8 T cells specific for epitopes on numerous diabetogenic autoantigens resulting in loss of glucose homeostasis. Employing antigen-specific tolerance induced by i.v. administration of syngeneic splenocytes ECDI cross-linked to various diabetogenic antigens/epitopes (Ag-SP), we show that epitope spreading plays a functional role in the pathogenesis of T1D in NOD mice. Specifically, Ag-SP coupled with intact insulin, Ins B9–23 or Ins B15–23, but not GAD65509–528, GAD65524–543 or IGRP206–214, protected 4–6 week-old NOD mice from the eventual development of clinical disease; infiltration of immune cells to the pancreatic islets; and blocked the induction of DTH responses in a Treg-dependent, antigen-specific manner. However, tolerance induction in 19–21 week-old NOD mice was effectively accomplished only by Ins-SP, suggesting Ins B9–23 is a dominant initiating epitope, but autoimmune responses to insulin epitope(s) distinct from Ins B9–23 emerge during disease progression. PMID:22647732

The JAK/STAT pathway in obesity and diabetes.

PubMed

Gurzov, Esteban N; Stanley, William J; Pappas, Evan G; Thomas, Helen E; Gough, Daniel J

2016-08-01

Diabetes mellitus are complex, multi-organ metabolic pathologies characterized by hyperglycemia. Emerging evidence shows that the highly conserved and potent JAK/STAT signaling pathway is required for normal homeostasis, and, when dysregulated, contributes to the development of obesity and diabetes. In this review, we analyze the role of JAK/STAT activation in the brain, liver, muscle, fat and pancreas, and how this affects the course of the disease. We also consider the therapeutic implications of targeting the JAK/STAT pathway in treatment of obesity and diabetes. © 2016 Federation of European Biochemical Societies.

Incident Type 2 Diabetes Risk is Influenced by Obesity and Diabetes in Social Contacts: a Social Network Analysis.

PubMed

Raghavan, Sridharan; Pachucki, Mark C; Chang, Yuchiao; Porneala, Bianca; Fox, Caroline S; Dupuis, Josée; Meigs, James B

2016-10-01

Obesity and diabetes family history are the two strongest risk factors for type 2 diabetes (T2D). Prior work shows that an individual's obesity risk is associated with obesity in social contacts, but whether T2D risk follows similar patterns is unknown. We aimed to estimate the relationship between obesity or diabetes in an individual's social contacts and his/her T2D risk. We hypothesized that obesity and diabetes in social contacts would increase an individual's T2D risk. This was a retrospective analysis of the community-based Framingham Offspring Study (FOS). FOS participants with T2D status, height and weight, and at least one social contact were eligible for this study (n = 4797 at Exam 1). Participants' interpersonal ties, cardiometabolic and demographic variables were available at eight exams from 1971 to 2008, and a T2D additive polygenic risk score was measured at the fifth exam. Primary exposures were T2D (fasting glucose ≥ 7 mmol/L or taking diabetes medications) and obesity status (BMI ≥ 30 kg/m(2)) of social contacts at a prior exam. Primary outcome was incident T2D in participants. Incident T2D was associated with having a social contact with diabetes (OR 1.32, p = 0.004) or with obesity (OR 1.21, p = 0.004). In stratified analyses, incident T2D was associated with diabetes in siblings (OR 1.64, p = 0.001) and obesity in spouses (OR 1.54, p = 0.0004). The associations between diabetes and obesity in social contacts and an individual's incident diabetes risk were stronger in individuals with a high diabetes genetic risk score. T2D and obesity in social contacts, particularly siblings and spouses, were associated with an individual's risk of incident diabetes even after accounting for parental T2D history. Assessing risk factors in an individual's siblings and spouses can inform T2D risk; furthermore, social network based lifestyle interventions involving spouses and siblings might be a novel T2D prevention approach.

[Carbohydrate metabolism disorders among obese children and adolescents. Diabetes mellitus type 2].

PubMed

Sergeyev, E; Wagner, I; Neef, M; Adler, M; Körner, A; Kiess, W

2013-04-01

As obesity has become more prevalent, the incidence of type 2 diabetes mellitus in children and adolescents has also increased. Obesity during adolescence leads to an increased risk for disease and premature death during adulthood, independent of obesity during adulthood. Obesity is the major risk factor impacting insulin sensitivity. Subjects with insulin resistance are at risk for progression to diabetes. Type 2 diabetes mellitus in obese children and adolescents is frequently asymptomatic. It is essential to identify children at high risk who need aggressive lifestyle modification focused on weight reduction and increased physical activity. Early detection and therapy of obese children and adolescents with type 2 diabetes may reduce the risk of cardiometabolic consequences and other long-term complications in adulthood.

The Gene Expression Profile of CD11c+CD8α− Dendritic Cells in the Pre-Diabetic Pancreas of the NOD Mouse

PubMed Central

Beumer, Wouter; Welzen-Coppens, Jojanneke M. C.; van Helden-Meeuwsen, Cornelia G.; Gibney, Sinead M.; Drexhage, Hemmo A.; Versnel, Marjan A.

2014-01-01

Two major dendritic cell (DC) subsets have been described in the pancreas of mice: The CD11c+CD8α− DCs (strong CD4+ T cell proliferation inducers) and the CD8α+CD103+ DCs (T cell apoptosis inducers). Here we analyzed the larger subset of CD11c+CD8α− DCs isolated from the pancreas of pre-diabetic NOD mice for genome-wide gene expression (validated by Q-PCR) to elucidate abnormalities in underlying gene expression networks. CD11c+CD8α− DCs were isolated from 5 week old NOD and control C57BL/6 pancreas. The steady state pancreatic NOD CD11c+CD8α− DCs showed a reduced expression of several gene networks important for the prime functions of these cells, i.e. for cell renewal, immune tolerance induction, migration and for the provision of growth factors including those for beta cell regeneration. A functional in vivo BrdU incorporation test showed the reduced proliferation of steady state pancreatic DC. The reduced expression of tolerance induction genes (CD200R, CCR5 and CD24) was supported on the protein level by flow cytometry. Also previously published functional tests on maturation, immune stimulation and migration confirm the molecular deficits of NOD steady state DC. Despite these deficiencies NOD pancreas CD11c+CD8α− DCs showed a hyperreactivity to LPS, which resulted in an enhanced pro-inflammatory state characterized by a gene profile of an enhanced expression of a number of classical inflammatory cytokines. The enhanced up-regulation of inflammatory genes was supported by the in vitro cytokine production profile of the DCs. In conclusion, our data show that NOD pancreatic CD11c+CD8α− DCs show various deficiencies in steady state, while hyperreactive when encountering a danger signal such as LPS. PMID:25166904

Diabetes among non-obese Filipino Americans: Findings from a large population-based study.

PubMed

Fuller-Thomson, Esme; Roy, Adity; Chan, Keith Tsz-Kit; Kobayashi, Karen M

2017-04-20

Filipino Americans form the second-largest Asian American and Pacific Islanders subgroup. Growing evidence suggests that Filipino Americans have higher rates of diabetes than non-Hispanic whites. The key objectives of this study are 1) to determine the prevalence of diabetes in non-obese Filipino Americans compared to non-obese non-Hispanic whites, and 2) to identify risk factors for diabetes in non-obese Filipino men and women. Secondary analysis of population-based data from combined waves (2007, 2009 and 2011) of the adult California Health Interview Survey (CHIS). The study sample was restricted to non-obese Filipino Americans (n = 1629) and non-Hispanic whites (n = 72 072). Non-obese Filipino Americans had more than twice the odds of diabetes compared to non-Hispanic whites, even after correcting for several known risk factors (OR = 2.80, p < 0.001). For non-obese Filipino men, older age, poverty, cigarette smoking, and being overweight are associated with increased odds for diabetes, while older age was the only factor associated with diabetes among Filipina women. Diabetes prevention approaches need to be targeted towards non-obese Filipino Americans, due to their high risk of diabetes.

Trends in diabetes and obesity in Samoa over 35 years, 1978-2013.

PubMed

Lin, S; Naseri, T; Linhart, C; Morrell, S; Taylor, R; McGarvey, S T; Magliano, D J; Zimmet, P

2017-05-01

Population surveys of Type 2 diabetes mellitus and obesity conducted in Samoa over three decades have used varying methodologies and definitions. This study standardizes measures, and trends of Type 2 diabetes mellitus and obesity for 1978-2013 are projected to 2020 for adults aged 25-64 years. Unit records from eight surveys (n = 12 516) were adjusted to the previous census for Division of residence, sex and age to improve national representativeness. Type 2 diabetes mellitus is defined as a fasting plasma glucose ≥ 7.0 mmol/l and/or on medication. Obesity is defined as BMI ≥ 30 kg/m 2 . Random effects meta-regression was employed to assess time trends following logit transformation. Poisson regression from strata was used to assess the effects of mean BMI changes on Type 2 diabetes mellitus period trends. Over 1978-2013, Type 2 diabetes mellitus prevalence increased from 1.2% to 19.6% in men (2.3% per 5 years), and from 2.2% to 19.5% in women (2.2% per 5 years). Obesity prevalence increased from 27.7% to 53.1% in men (3.6% per 5 years) and from 44.4% to 76.7% (4.5% per 5 years) in women. Type 2 diabetes mellitus and obesity prevalences increased in all age groups. From period trends, Type 2 diabetes mellitus prevalence in 2020 is projected to be 26% in men and women. Projected obesity prevalence is projected to be 59% in men and 81% in women. Type 2 diabetes mellitus period trends attributable to BMI increase are estimated as 31% (men) and 16% (women), after adjusting for age. This is the first study to produce trends of Type 2 diabetes mellitus and obesity in Samoa based on standardized data from population surveys. Type 2 diabetes mellitus is equally prevalent in both sexes, and obesity is widespread. Type 2 diabetes mellitus prevalence in Samoa is likely to continue to increase in the near future. © 2016 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

[Epigenetics of childhood obesity and diabetes].

PubMed

Valladares-Salgado, Adán; Suárez-Sánchez, Fernando; Burguete-García, Ana I; Cruz, Miguel

2014-01-01

Obesity and type 2 diabetes mellitus (T2DM) result from sedentary lifestyle, high-carbohydrate diets and genetic predisposition. Epigenetics is a form of genetic regulation in specialized cells that does not involve changes in the deoxyribonucleic acid (DNA) sequence, but it can be inherited to one or more generations through mitosis or meiosis. Children whose mothers develop gestational diabetes are more likely to become obese and diabetic in adult life. DNA methylation is a major mechanism in the regulation of transcription and gene expression of several genes. High levels of glucose and insulin during pregnancy modify the risk of developing T2DM, suggesting that the expression pattern is modified due to cell memory in a specific tissue. If T2DM is linked to adaptation in utero, the obvious primary prevention is to protect the fetal development. Future epidemiological studies need to employ more accurate indicators or markers of development to show the relationship between a specific disease and the exposure to environmental factors. The mechanisms by which malnutrition, and intrauterine growth retardation produce changes in the metabolism of glucose and insuline are worth to explore in order to control obesity and T2DM.

[Overweight, obesity and lipids abnormalities in adolescents with type 1 diabetes].

PubMed

Wysocka-Mincewicz, Marta; Kołodziejczyk, Honorata; Wierzbicka, Elżbieta; Szalecki, Mieczysław

2016-02-18

Overweight children are growing problem as in the pediatric, as well in the diabetic population. The aim of the study was to research the percentage of overweight and obesity in a group of adolescents with type 1 diabetes, and to analyzethe lipid parameters, as well risk factors of these abnormalities. The study group consist of 60 type 1 diabetic adolescents (including 32 girls, 53.3%), aged above 12 years (mean age for girls 14.6+/-0,3years, boys 15.6+/-0.4 years) with diabetes duration (girls 5.7+-0.6 years, boys 4.4+/-0.8 years). Statistical analysis was performed using Statistica v 9.0 and SPSS v20. The study revealed that boys with type 1 diabetes are significantly higher than healthy population, with weight, waist circumference and BMI comparable to the healthy counterparts. However, diabetic girls are more likely to be overweight and have bigger waist circumference, and higher BMI than the healthy population. Overweight were 12 adolescents (20%) using BMI ≥1SD criterion, and 10 (16%) using waist circumference as obesity parameter. Logistic regression revealed that the most important factors for obesity and abdominal obesity are female gender (OR=2.43 and OR=4.56for obesity and abdominal, respectively), diabetes duration above 5 years (respectively OR=1.96 and OR=3.27) and poor metabolic control (respectively OR=1.74 and OR=2.89). The most important risk factor for obesity in adolescents with type 1 diabetes is female gender. Lipids profile is closely dependent on metabolic control and mass excess. Diabetes duration, metabolic control and lipids profile are significant risk factors for overweight and abdominal obesity. © Polish Society for Pediatric Endocrinology and Diabetology.

Prevention of obesity and diabetes in childbearing women.

PubMed

Trout, Kimberly K; Ellis, Kathryn K; Bratschie, Alexandra

2013-01-01

Obesity and diabetes have become pandemic in the United States, with more than one-third of the US population obese and 8.3% of the population affected by diabetes. Efforts to prevent type 2 diabetes focus primarily on healthy eating and physical activity. In particular, women from at-risk racial and ethnic groups and those who have experienced gestational diabetes are at high risk for developing type 2 diabetes. Achieving a healthy weight prior to conception, staying within weight gain guidelines during pregnancy, and losing accumulated pregnancy weight postpartum are key prevention factors. Maintaining a healthy weight in the long-term is a challenge. Behavioral psychology and coaching techniques are presented in this article that can be useful in sustaining behaviors that promote a healthy weight. © 2013 by the American College of Nurse-Midwives.

Downregulation of cathepsin G reduces the activation of CD4+ T cells in murine autoimmune diabetes.

PubMed

Zou, Fang; Lai, Xiaoyang; Li, Jing; Lei, Shuihong; Hu, Lei

2017-01-01

Type 1 diabetes mellitus (T1DM) is an autoimmune disease due to progressive injury of islet cells mediated by T lymphocytes (T cells). Our previous studies have shown that only cathepsin G (CatG), not other proteases, is involved in the antigen presentation of proinsulin, and if the presentation is inhibited, the activation of CD4+ T cells induced by proinsulin is alleviated in T1DM patients, and CatG-specific inhibitor reduces the activation of CD4+ cells induced by proinsulin in T1DM patients. Therefore, we hypothesize that CatG may play an important role in the activation of CD4+ T cells in T1DM. To this end, mouse studies were conducted to demonstrate that CatG impacts the activation of CD4+ T cells in non-obese diabetic (NOD) mice. CatG gene expression and the activation of CD4+ T cells were examined in NOD mice. The effect of CatG inhibitor was investigated in NOD mice on the activation of CD4+ T cells, islet β cell function, islet inflammation and β-cell apoptosis. Furthermore, NOD mice were injected with CatG siRNA in early stage to observe the effect of CatG knockdown on the activation status of CD4+ T cells and the progression of diabetes. During the pathogenesis of diabetes, the expression level of CatG in NOD mice gradually increased and the CD4+ T cells were gradually activated, resulting in more TH1 cells and less TH2 and Treg cells. Treatment with CatG-specific inhibitor reduced the blood glucose level, improved the function of islet β cells and reduced the activation of CD4+ T cells. Early application of CatG siRNA improved the function of islet β cells, reduced islet inflammation and β cell apoptosis, and lowered the activation level of CD4+ T cells, thus slowing down the progression of diabetes.

Downregulation of cathepsin G reduces the activation of CD4+ T cells in murine autoimmune diabetes

PubMed Central

Zou, Fang; Lai, Xiaoyang; Li, Jing; Lei, Shuihong; Hu, Lei

2017-01-01

Type 1 diabetes mellitus (T1DM) is an autoimmune disease due to progressive injury of islet cells mediated by T lymphocytes (T cells). Our previous studies have shown that only cathepsin G (CatG), not other proteases, is involved in the antigen presentation of proinsulin, and if the presentation is inhibited, the activation of CD4+ T cells induced by proinsulin is alleviated in T1DM patients, and CatG-specific inhibitor reduces the activation of CD4+ cells induced by proinsulin in T1DM patients. Therefore, we hypothesize that CatG may play an important role in the activation of CD4+ T cells in T1DM. To this end, mouse studies were conducted to demonstrate that CatG impacts the activation of CD4+ T cells in non-obese diabetic (NOD) mice. CatG gene expression and the activation of CD4+ T cells were examined in NOD mice. The effect of CatG inhibitor was investigated in NOD mice on the activation of CD4+ T cells, islet β cell function, islet inflammation and β-cell apoptosis. Furthermore, NOD mice were injected with CatG siRNA in early stage to observe the effect of CatG knockdown on the activation status of CD4+ T cells and the progression of diabetes. During the pathogenesis of diabetes, the expression level of CatG in NOD mice gradually increased and the CD4+ T cells were gradually activated, resulting in more TH1 cells and less TH2 and Treg cells. Treatment with CatG-specific inhibitor reduced the blood glucose level, improved the function of islet β cells and reduced the activation of CD4+ T cells. Early application of CatG siRNA improved the function of islet β cells, reduced islet inflammation and β cell apoptosis, and lowered the activation level of CD4+ T cells, thus slowing down the progression of diabetes. PMID:29218110

Effects of obesity surgery on non-insulin-dependent diabetes mellitus.

PubMed

Greenway, Scott E; Greenway, Frank L; Klein, Stanley

2002-10-01

Most individuals who have non-insulin-dependent diabetes mellitus are obese. The obese population has proved a frustrating entity regarding weight loss and diabetes control. Results of medical weight loss programs, medications, and behavior therapy have proved disappointing. Bariatric surgery is the most effective method of diabetes management and cure in the morbidly obese population. Surgical procedures to cause malabsorption provide a more dramatic effect on diabetes owing to the imparted bypass of the hormonally active foregut. Pertinent journal articles spanning the last 40 years, as well as textbooks. Bariatric surgical procedures have proven a much more successful method of weight loss and diabetes control in the obese population than conservative methods. These surgical procedures have proven safe with reported mortality rates of 0% to 1.5%. Bariatric operations may be divided based on the method of weight loss and effect on diabetes. The first category is restrictive and includes vertical banded gastroplasty and adjustable silicone gastric banding. These operations improve diabetes by decreasing food intake and body weight with a slowing of gastric emptying. The second category not only contains restrictive components but also elements of malabsorption. This category includes the Roux-en-Y gastric bypass and biliary-pancreatic diversion, which bypass the foregut. Although all of the surgical procedures for obesity offer improved weight loss and diabetes control compared with conservative methods, the Roux-en-Y gastric bypass and biliary-pancreatic diversion offer superior weight loss and resolution of diabetes. The more dramatic effect seen in the surgical procedures to cause malabsorption is likely secondary to the bypass of the foregut resulting in increased weight loss and elevation of the enteroglucagon level.

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

Type 2 diabetes, but not obesity, prevalence is positively associated with ambient temperature.

PubMed

Speakman, John R; Heidari-Bakavoli, Sahar

2016-08-01

Cold exposure stimulates energy expenditure and glucose disposal. If these factors play a significant role in whole body energy balance, and glucose homeostasis, it is predicted that both obesity and type 2 diabetes prevalence would be lower where it is colder. Previous studies have noted connections between ambient temperature and obesity, but the direction of the effect is confused. No previous studies have explored the link of type 2 diabetes to ambient temperature. We used county level data for obesity and diabetes prevalence across the mainland USA and matched this to county level ambient temperature data. Average ambient temperature explained 5.7% of the spatial variation in obesity and 29.6% of the spatial variation in type 2 diabetes prevalence. Correcting the type 2 diabetes data for the effect of obesity reduced the explained variation to 26.8%. Even when correcting for obesity, poverty and race, ambient temperature explained 12.4% of the variation in the prevalence of type 2 diabetes, and this significant effect remained when latitude was entered into the model as a predictor. When obesity prevalence was corrected for poverty and race the significant effect of temperature disappeared. Enhancing energy expenditure by cold exposure will likely not impact obesity significantly, but may be useful to combat type 2 diabetes.

Laser capture microdissection tailored to type 1 diabetes mellitus research.

PubMed

Szulawski, Robert; Nakazawa, Masato; McCall, Kelly D; James, Calvin B L; Schwartz, Frank L

2016-01-01

RNA isolation from pancreatic islets poses unique challenges. Here, we present a reproducible means of obtaining high-quality RNA from juvenile rodent islets in sufficient quantities for use in ex vivo expression studies. Tissue was extracted from female non-obese diabetic (NOD) toll-like receptor 3 (TLR3)(+/+) and (TLR3)(-/-) mice in the pre-diabetic stage. Samples were frozen in liquid nitrogen, sectioned, fixed in a highly alcoholic solution, and stained with an alcoholic cresyl violet (CV) solution. Rehydration of the fixed sections was minimized. Islets were identified visually and isolated with the Leica LMD6000 laser capture microdissection (LCM) system to yield samples highly enriched in islet RNA. Real time qPCR was performed on the islet cDNA using probes for CXC chemokine ligand 10 (CXCL10), an inflammatory marker that plays a critical role in the pathogenesis of type 1 diabetes mellitus (TIDM). This method represents an improvement over currently described LCM techniques for rodent pancreatic islets and makes feasible expression studies using small amounts of starting tissue without the need for RNA pre-amplification. This has immediate implications for ongoing TIDM studies using the NOD mouse.

FREQUENCY OF ABDOMINAL OBESITY AND ITS ASSOCIATION WITH DIABETES MELLITUS AMONG PEOPLE OF PESHAWAR.

PubMed

Khan, Attaullah; Faheem, Muhammad; Shah, Syed Tahir; Hadi, Abdul; Rafiullah; Ahmad, Salman; Gul, Adnan Mahmood; Shah, Sayyad Farhat Abbas; Jan, Hikmatullah; Hafizullah, Mohammad

2015-01-01

Increased body weight is a major risk factor for the metabolic syndrome which is a cluster of coronary heart disease risk factors, like: hypertension, diabetes mellitus and dyslipidaemia. This study was conducted to determine the frequency of abdominal obesity and diabetes mellitus in the population of Peshawar and association between them. This was a cross sectional study, performed by the Cardiology Department, Lady Reading Hospital Peshawar, in the population of Peshawar. All participants were interviewed in detail regarding known risk factors for coronary artery disease. Waist circumference (≥102 cm in male and ≥88 cm in females) was used as the surrogate marker for abdominal obesity in already diagnosed patients of type-2 diabetes mellitus. A total of 2548 individuals were included, 71.1% were male. Mean age was 37.94±12.59 years. Mean waist circumference was 90.25±13.45cm in males and 90.52±12.52cm in females. Diabetes was present in 4.4% of the participants and abdominal obesity in 56.6% Among the male, abdominal obesity was present in 39.4% and diabetes in 2.9%. Out of 39.4% males with abdominal obesity, 2% were diabetic. Out of 38.6% males with no abdominal obesity, 0.9% was diabetic. Amongst the total 559 (21.1%) female subjects, 17.2% were having abdominal obesity and 1.4% was diabetics. Among 123 (4.8%) females with no abdominal obesity, 0.1% was diabetic. A positive association was established between abdominal obesity and diabetes mellitus with a significant p-valve (<0.05). Abdominal obesity is more common in the local population of Peshawar and associated with type-2 diabetes mellitus.

Muramyl Dipeptide-Based Postbiotics Mitigate Obesity-Induced Insulin Resistance via IRF4.

PubMed

Cavallari, Joseph F; Fullerton, Morgan D; Duggan, Brittany M; Foley, Kevin P; Denou, Emmanuel; Smith, Brennan K; Desjardins, Eric M; Henriksbo, Brandyn D; Kim, Kalvin J; Tuinema, Brian R; Stearns, Jennifer C; Prescott, David; Rosenstiel, Philip; Coombes, Brian K; Steinberg, Gregory R; Schertzer, Jonathan D

2017-05-02

Intestinal dysbiosis contributes to obesity and insulin resistance, but intervening with antibiotics, prebiotics, or probiotics can be limited by specificity or sustained changes in microbial composition. Postbiotics include bacterial components such as lipopolysaccharides, which have been shown to promote insulin resistance during metabolic endotoxemia. We found that bacterial cell wall-derived muramyl dipeptide (MDP) is an insulin-sensitizing postbiotic that requires NOD2. Injecting MDP lowered adipose inflammation and reduced glucose intolerance in obese mice without causing weight loss or altering the composition of the microbiome. MDP reduced hepatic insulin resistance during obesity and low-level endotoxemia. NOD1-activating muropeptides worsened glucose tolerance. IRF4 distinguished opposing glycemic responses to different types of peptidoglycan and was required for MDP/NOD2-induced insulin sensitization and lower metabolic tissue inflammation during obesity and endotoxemia. IRF4 was dispensable for exacerbated glucose intolerance via NOD1. Mifamurtide, an MDP-based drug with orphan drug status, was an insulin sensitizer at clinically relevant doses in obese mice. Copyright © 2017 Elsevier Inc. All rights reserved.

Pharmacotherapy for obesity in individuals with type 2 diabetes.

PubMed

Chukir, Tariq; Shukla, Alpana P; Saunders, Katherine H; Aronne, Louis J

2018-02-01

Type 2 diabetes (T2DM) is associated with significant morbidity and mortality. Obesity is one of the main risk factors for T2DM and its management requires a multidisciplinary approach, which may include pharmacotherapy. Areas covered: In this paper, data on efficacy, tolerability and safety of FDA-approved pharmacotherapies for obesity (orlistat, phentermine/topiramate extended-release, lorcaserin, bupropion sustained release/naltrexone sustained release and liraglutide) are reviewed, focusing on individuals with type 2 diabetes. Expert opinion: Obesity is the major pathophysiologic driver of T2DM; conversely 5-10% weight loss leads to significant improvement in glycemic control, lipids and blood pressure. Weight loss maintenance is difficult with lifestyle interventions alone and may require adjunctive therapies. There is good evidence for the efficacy and tolerability of approved anti-obesity pharmacotherapies in individuals with T2DM, with current cardiovascular safety data being most favorable for liraglutide, orlistat and lorcaserin. Given the link between obesity and T2DM, a weight-centric therapeutic approach including use of weight reducing anti-diabetic therapies, and anti-obesity pharmacotherapies is both intuitive and rational to improve glycemic and other metabolic outcomes in patients with T2DM.

Childhood obesity and type 2 diabetes in India.

PubMed

Praveen, Pradeep A; Tandon, Nikhil

2016-04-01

India is witnessing an increase in the burden of childhood obesity, especially among the upper socioeconomic strata and in urban areas. Emerging literature suggests a link between childhood obesity and the diabetes epidemic in India. Asian-Indian children and adolescents are increasingly susceptible to a high percentage of body fat and abdominal adiposity. Further, they are exposed to an obesogenic environment, created by rapid urbanization and nutrition transition in India. Obese children have a higher risk of developing abnormalities that are recognized as precursors to diabetes, such as subclinical inflammation, insulin resistance and metabolic syndrome, which often track to adulthood. A review of the literature suggests the need for more longitudinal studies to improve understanding of the long-term consequences of childhood obesity in India. A life-course approach with a combination of population- and risk-based strategies is warranted, to prevent childhood obesity and curtail its consequences in adulthood.

Anti-Diabetic Activity and Metabolic Changes Induced by Andrographis paniculata Plant Extract in Obese Diabetic Rats.

PubMed

Akhtar, Muhammad Tayyab; Bin Mohd Sarib, Mohamad Syakir; Ismail, Intan Safinar; Abas, Faridah; Ismail, Amin; Lajis, Nordin Hj; Shaari, Khozirah

2016-08-09

Andrographis paniculata is an annual herb and widely cultivated in Southeast Asian countries for its medicinal use. In recent investigations, A. paniculata was found to be effective against Type 1 diabetes mellitus (Type 1 DM). Here, we used a non-genetic out-bred Sprague-Dawley rat model to test the antidiabetic activity of A. paniculata against Type 2 diabetes mellitus (Type 2 DM). Proton Nuclear Magnetic Resonance (¹H-NMR) spectroscopy in combination with multivariate data analyses was used to evaluate the A. paniculata and metformin induced metabolic effects on the obese and obese-diabetic (obdb) rat models. Compared to the normal rats, high levels of creatinine, lactate, and allantoin were found in the urine of obese rats, whereas, obese-diabetic rats were marked by high glucose, choline and taurine levels, and low lactate, formate, creatinine, citrate, 2-oxoglutarate, succinate, dimethylamine, acetoacetate, acetate, allantoin and hippurate levels. Treatment of A. paniculata leaf water extract was found to be quite effective in restoring the disturbed metabolic profile of obdb rats back towards normal conditions. Thisstudy shows the anti-diabetic potential of A. paniculata plant extract and strengthens the idea of using this plant against the diabetes. Further classical genetic methods and state of the art molecular techniques could provide insights into the molecular mechanisms involved in the pathogenesis of diabetes mellitus and anti-diabetic effects of A. paniculata water extract.

Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality

PubMed Central

LeRoith, Derek

2015-01-01

Obesity and type 2 diabetes are becoming increasingly prevalent worldwide, and both are associated with an increased incidence and mortality from many cancers. The metabolic abnormalities associated with type 2 diabetes develop many years before the onset of diabetes and, therefore, may be contributing to cancer risk before individuals are aware that they are at risk. Multiple factors potentially contribute to the progression of cancer in obesity and type 2 diabetes, including hyperinsulinemia and insulin-like growth factor I, hyperglycemia, dyslipidemia, adipokines and cytokines, and the gut microbiome. These metabolic changes may contribute directly or indirectly to cancer progression. Intentional weight loss may protect against cancer development, and therapies for diabetes may prove to be effective adjuvant agents in reducing cancer progression. In this review we discuss the current epidemiology, basic science, and clinical data that link obesity, diabetes, and cancer and how treating obesity and type 2 diabetes could also reduce cancer risk and improve outcomes. PMID:26084689

Obesity and metabolic surgery in type 1 diabetes mellitus.

PubMed

Raab, Heike; Weiner, R A; Frenken, M; Rett, K; Weiner, S

2013-03-01

Obesity surgery is an effective method for treating obesity and diabetes mellitus type 2. This type of diabetes can be completely resolved in 78.1% of diabetic patients and can be improved or resolved in 86.6% of diabetic patients. But little is known about bariatric surgery in type 1 diabetes mellitus. We report of 6 female obese patients with diabetes mellitus type 1 who had bariatric surgery. Two of them underwent Roux-en Y gastric bypass (RNYGB), one of them had sleeve gastrectomy and the remaining three had biliopancreatic diversion with duodenal-switch (BPD-DS). Our results showed a remarkable weight reduction as well as an improvement in their blood glucose control and the insulin requirement in the followup years after surgery. Pre-surgery the BMI of our 6 patients ranged between 37.3-46.0 kg/m2 and improved to 25.8-29.0 kg/m2 one year after surgery. HbA1c decreased from 6.7-9.8% pre-surgery to 5.7-8.5% after one year post-surgery. The total amount of daily insulin requirement was reduced from 62-150 IU/day pre-surgery to 15- 54 IU/day after one year. The results are impressive and show an improvement in insulin sensitivity following obesity surgery. However, an optimal blood glucose control still remains very important in the therapy of diabetes mellitus type 1 to avoid long-term-complications. Copyright © AULA MEDICA EDICIONES 2013. Published by AULA MEDICA. All rights reserved.

Obesity Paradox: Comparison of Heart Failure Patients With and Without Comorbid Diabetes.

PubMed

Lee, Kyoung Suk; Moser, Debra K; Lennie, Terry A; Pelter, Michele M; Nesbitt, Thomas; Southard, Jeffrey A; Dracup, Kathleen

2017-03-01

Diabetes is a common comorbid condition in patients with heart failure and is strongly associated with poor outcomes. Patients with heart failure who have diabetes are more likely to be obese than are those without diabetes. Obesity is positively associated with survival in patients with heart failure, but how comorbid diabetes influences the relationship between obesity and favorable prognosis is unclear. To explore whether the relationship between body mass index and survival differs between patients with heart failure who do or do not have diabetes. The sample consisted of 560 ambulatory patients with heart failure (mean age, 66 years; mean body mass index, 32; diabetes, 41%). The association between body mass index and all-cause mortality was examined by using multivariate Cox proportional hazards regression after adjustments for covariates. In patients without diabetes, higher body mass index was associated with a lower risk for all-cause mortality after adjustments for covariates (hazard ratio, 0.952; 95% CI, 0.909-0.998). In patients with diabetes, body mass index was not predictive of all-cause death after adjustments for covariates. Obesity was a survival benefit in heart failure patients without comorbid diabetes but not in those with comorbid diabetes. The mechanisms underlying the difference in the relationship between obesity and survival due to the presence of diabetes in patients with heart failure need to be elucidated. ©2017 American Association of Critical-Care Nurses.

Adrenoceptor Polymorphisms in Hypertension and Diabetes with obesity-update in 2014.

PubMed

Masuo, K

2014-08-12

Hypertension, diabetes mellitus (especially type 2 diabetes mellitus) and metabolic syndrome associated with obesity are rapidly growing public health problems. Sympathetic nerve activation is well documented in hypertension, diabetes mellitus, and obesity, hypertension and diabetes are determined by genetic background and environmental factors. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of sympathetic nervous system in obesity have been mainly mediated via the β2 and β3-adrenergic receptors in humans. Further, β2-adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. Genetic polymorphisms of the -adrenoceptor gene have been shown to alter the function of several adrenoceptor subtype and thus to modify the response to catecholamine. Among β2-adrenoceptor polymorphisms, Arg16Gly, Gln27Glu, and Thr164Ile are considered the most functionally important. β2-adrenoceptor genes have been studied in relation to hypertension. Genetic variations in the β3-adrenoceptor, such as the Try64Arg variant, are also associated with both obesity and hypertension. This review is an update of several versions published of the relationships between adrenoceptor polymorphisms and hypertension, diabetes and obesiy based on the my own review on the relationship with obesity in 2011 in "Journal of Obesity" [1], and another of my own reviews on the relationships with hypertension in 2010 in "International journal of Hypertension" [2], with 37 articles provided by the "PubMed" with the keywords of "adrenoceptor polymorphisms, obesity, hypertension and diabetes" searched on December 2013. However, the relationships of the polymorphisms of β2- and β3-adrenoceptor genes with sympathetic nervous system activity, hypertension and metabolic syndrome have been still discordant, it might be

Development of the Nonobese Diabetic Mouse and Contribution of Animal Models for Understanding Type 1 Diabetes.

PubMed

Mullen, Yoko

2017-04-01

In 1974, the discovery of a mouse and a rat that spontaneously developed hyperglycemia led to the development of 2 autoimmune diabetes models: nonobese diabetic (NOD) mouse and Bio-Breeding rat. These models have contributed to our understanding of autoimmune diabetes, provided tools to dissect autoimmune islet damage, and facilitated development of early detection, prevention, and treatment of type 1 diabetes. The genetic characterization, monoclonal antibodies, and congenic strains have made NOD mice especially useful.Although the establishment of the inbred NOD mouse strain was documented by Makino et al (Jikken Dobutsu. 1980;29:1-13), this review will focus on the not-as-well-known history leading to the discovery of a glycosuric female mouse by Yoshihiro Tochino. This discovery was spearheaded by years of effort by Japanese scientists from different disciplines and dedicated animal care personnel and by the support of the Shionogi Pharmaceutical Company, Osaka, Japan. The history is based on the early literature, mostly written in Japanese, and personal communications especially with Dr Tochino, who was involved in diabetes animal model development and who contributed to the release of NOD mice to the international scientific community. This article also reviews the scientific contributions made by the Bio-Breeding rat to autoimmune diabetes.

A proteomic approach to obesity and type 2 diabetes

PubMed Central

López-Villar, Elena; Martos-Moreno, Gabriel Á; Chowen, Julie A; Okada, Shigeru; Kopchick, John J; Argente, Jesús

2015-01-01

The incidence of obesity and type diabetes 2 has increased dramatically resulting in an increased interest in its biomedical relevance. However, the mechanisms that trigger the development of diabetes type 2 in obese patients remain largely unknown. Scientific, clinical and pharmaceutical communities are dedicating vast resources to unravel this issue by applying different omics tools. During the last decade, the advances in proteomic approaches and the Human Proteome Organization have opened and are opening a new door that may be helpful in the identification of patients at risk and to improve current therapies. Here, we briefly review some of the advances in our understanding of type 2 diabetes that have occurred through the application of proteomics. We also review, in detail, the current improvements in proteomic methodologies and new strategies that could be employed to further advance our understanding of this pathology. By applying these new proteomic advances, novel therapeutic and/or diagnostic protein targets will be discovered in the obesity/Type 2 diabetes area. PMID:25960181

Trends in obesity and diabetes prevalence in a Chilean urban population: 1993-2001.

PubMed

Cuevas, Ada; Molina, Alfredo; Rigotti, Attilio; Miquel, Juan Francisco; Marshall, Guillermo; Reyes, Soledad; Nervi, Flavio

2008-09-01

In recent years, the Chilean population has suffered significant lifestyle changes associated with the rapid socioeconomic development of the country. These changes can induce a significant increase in the prevalence of some chronic diseases, such as obesity, dyslipidemia, and diabetes mellitus. We aimed to assess diabetes mellitus, obesity, and hypercholesterolemia trends in a Chilean urban population followed between 1993 and 2001. A total of 1584 adults, living in Santiago, the capital of Chile, were randomly enrolled in a cross-sectional epidemiologic study in 1993. The same population was re-evaluated in 2001, recruiting 964 individuals from the original sample. Prevalences of diabetes mellitus, obesity, and hypercholesterolemia were determined according to standard criteria. We tested the significance of the differences between the observed prevalence of diabetes mellitus, obesity, and hypercholesterolemia in the 964 subjects evaluated in 2001 compared with the expected prevalence according to population aging based in data from 1993. In 1993, 3.8% of the sample population had diabetes mellitus, 21.8% had obesity, and 37.3 % exhibited hypercholesterolemia. In 2001, the observed prevalence of diabetes mellitus, obesity, and hypercholesterolemia was 10.1%, 32%, and 58%, respectively. The latter percentages were significantly higher than the expected prevalence according to the aging of the population (6.5% for diabetes mellitus, 27.7% for obesity, and 47.7 for hypercholesteromia). Our findings indicate that Chilean population has suffered an accelerated increase in the prevalence of diabetes mellitus, obesity, and hypercholesterolemia, due to the ongoing epidemiological transition that will lead to an enormous public health burden in the near future.

Models and mechanisms for hippocampal dysfunction in obesity and diabetes

PubMed Central

Stranahan, Alexis M.

2015-01-01

Clinical studies suggest that obesity and type 2 (insulin resistant) diabetes impair the structural integrity of medial temporal lobe regions involved in memory and confer greater vulnerability to neurological insults. While eliminating obesity and its endocrine comorbidities would be the most straightforward way to minimize cognitive risk, structural barriers to physical activity and the widespread availability of calorically dense, highly palatable foods will likely necessitate additional strategies to maintain brain health over the lifespan. Research in rodents has identified numerous correlates of hippocampal functional impairment in obesity and diabetes, with several studies demonstrating causality in subsequent mechanistic studies. This review highlights recent work on pathways and cell-cell interactions underlying the synaptic consequences of obesity, diabetes, or in models with both pathological conditions. Although the mechanisms vary across different animal models, immune activation has emerged as a shared feature of obesity and diabetes, with synergistic exacerbation of neuroinflammation in model systems with both conditions. This Review discusses these findings with reference to the benefits of incorporating existing models from the fields of obesity and metabolic disease. Many transgenic lines with basal metabolic alterations or differential susceptibility to diet-induced obesity have yet to be characterized with respect to their cognitive and synaptic phenotype. Adopting these models, and building on the extensive knowledge base used to generate them, is a promising avenue for understanding interactions between peripheral disease states and neurodegenerative disorders. PMID:25934036

Epidemiological bases and molecular mechanisms linking obesity, diabetes, and cancer.

PubMed

Gutiérrez-Salmerón, María; Chocarro-Calvo, Ana; García-Martínez, José Manuel; de la Vieja, Antonio; García-Jiménez, Custodia

2017-02-01

The association between diabetes and cancer was hypothesized almost one century ago. Today, a vast number of epidemiological studies support that obese and diabetic populations are more likely to experience tissue-specific cancers, but the underlying molecular mechanisms remain unknown. Obesity, diabetes, and cancer share many hormonal, immune, and metabolic changes that may account for the relationship between diabetes and cancer. In addition, antidiabetic treatments may have an impact on the occurrence and course of some cancers. Moreover, some anticancer treatments may induce diabetes. These observations aroused a great controversy because of the ethical implications and the associated commercial interests. We report an epidemiological update from a mechanistic perspective that suggests the existence of many common and differential individual mechanisms linking obesity and type 1 and 2 diabetes mellitus to certain cancers. The challenge today is to identify the molecular links responsible for this association. Classification of cancers by their molecular signatures may facilitate future mechanistic and epidemiological studies. Copyright © 2016 SEEN. Publicado por Elsevier España, S.L.U. All rights reserved.

Some pharmacological effects of cinnamon and ginger herbs in obese diabetic rats

PubMed Central

Shalaby, Mostafa Abbas; Saifan, Hamed Yahya

2014-01-01

Aims: The present study was designed to assess some pharmacological effects of cinnamon (CAE) and ginger (GAE) aqueous extracts in obese diabetic rats, and to elucidate the potential mechanisms. Materials and Methods: Forty-two Sprague-Dawley rats were randomized into 6 equal groups. Group 1 was a negative control and the other groups were rendered obese by feeding rats on high-fat diet for 4 weeks. The obese rats were subcutaneously injected with alloxan for 5*days to induce diabetes. Group 2 was a positive control, and Groups 3, 4, 5 and 6 were orally given CAE in doses 200 and 400 mg/kg and GAE in the same doses, respectively for 6 weeks. Blood samples were collected for serum biochemical analyses. Kidneys were dissected out to assay activity of tissue antioxidant enzymes: Superoxide dismutase, glutathione peroxidase and catalase. Results: CAE and GAE significantly reduced body weight and body fat mass; normalized serum levels of liver enzymes; improved lipid profile; decreased blood glucose and leptin and increased insulin serum levels in obese diabetic rats. Both extracts also increased activity of kidney antioxidant enzymes. Conclusion: CAE and GAE exhibit anti-obesity, hepatoprotective, hypolipidemic, antidiabetic and anti-oxidant effects in obese diabetic rats. These results confirm the previous reports on both extracts. The potential mechanisms underlying these effects are fully discussed and clarified. Our results affirm the traditional use of cinnamon and ginger for treating patients suffering from obesity and diabetes. The obese diabetic rat model used in this study is a novel animal model used in pharmacology researches. PMID:26401364

Trends of obesity prevalence among Spanish adults with diabetes, 1987-2012.

PubMed

Basterra-Gortari, Francisco Javier; Bes-Rastrollo, Maira; Ruiz-Canela, Miguel; Gea, Alfredo; Sayón-Orea, Carmen; Martínez-González, Miguel Ángel

2018-04-24

Our aim was to examine the secular trends in obesity prevalence among Spanish adults with diabetes. Data were collected from 8 waves (from 1987 to 2012) of the National Health Surveys (NHS). NHS are cross-sectional studies conducted in representative samples of the Spanish adult population. Data of 7378 adults (≥16 years) who reported having been diagnosed of diabetes were analyzed. Previously validated self-reported weight and height were used to estimate body mass index (BMI). Obesity was defined as a BMI of 30kg/m 2 or greater. Age-adjusted obesity prevalence for each wave was calculated by the direct standardization method. From 1987 to 2012 age-adjusted prevalence of obesity among persons with diabetes increased from 18.2% (95% confidence interval [CI]: 14.2-22.2%) to 39.8% (95% CI: 36.8-42.8%). Age-adjusted prevalence of obesity in males with diabetes increased from 13.2% (95% CI: 7.3-19.1%) to 38.0% (95% CI: 33.8-42.1%) and in females from 23.0% (95% CI: 17.6-28.4%) to 42.3% (95% CI: 38.0-46.6%). Between 1987 and 2012 the prevalence of obesity markedly increased in Spain among adults with diabetes. Copyright © 2018 Elsevier España, S.L.U. All rights reserved.

Beyond gut microbiota: understanding obesity and type 2 diabetes.

PubMed

Lau, Eva; Carvalho, Davide; Pina-Vaz, Cidália; Barbosa, José-Adelino; Freitas, Paula

2015-01-01

Obesity and type 2 diabetes are metabolic diseases that have reached epidemic proportions worldwide. Although their etiology is complex, both result from interplay between behaviour, environment and genetic factors. Within ambient determinants, human overall gut bacteria have been identified as a crucial mediator of obesity and its consequences. Gut microbiota plays a crucial role in gastro-intestinal mucosa permeability and regulates the fermentation and absorption of dietary polyssacharides, which may explain its importance in the regulation of fat accumulation and the resultant development of obesity-related diseases. The main objective of this review is to address the pathogenic association between gut microbiota and obesity and to explore related innovative therapeutic targets. New insights into the role of the small bowel and gut microbiota in diabetes and obesity may make possible the development of integrated strategies to prevent and treat these metabolic disorders.

Prevalence of disability in Australian elderly: Impact of trends in obesity and diabetes.

PubMed

Wong, Evelyn; Woodward, Mark; Stevenson, Christopher; Backholer, Kathryn; Sarink, Danja; Peeters, Anna

2016-01-01

We aimed to estimate the impact of past and future changes in obesity and diabetes prevalence in mid-life on disability prevalence for adult Australians. We analysed data from the Australian Diabetes, Obesity and Lifestyle study (AusDiab) including participants aged 45-64years, disability-free at baseline (1999/2000) with disability information at follow-up (2011/12) (n=2107). We used coefficients from multinomial logistic regression to predict 10-year probabilities of disability and death from baseline predictors (age, sex, obesity, smoking, diabetes and hypertension). We estimated the prevalence of disability attributable to past (1980) and expected future (2025) changes in obesity and diabetes prevalence using the life table approach. We estimated that the prevalence of disability for those aged between 55 and 74years would have been 1697 cases per 100,000 persons less in 2010 (10.3% less) if the rates of obesity and diabetes observed in 2000 had been as low as the levels observed in 1980. However, if instead the prevalence of obesity and diabetes had been as high as the levels expected in 2025, then the prevalence of disability would have been an additional 2173 per 100,000 persons (an additional 13.2%). We demonstrate, for the first time, a substantial potential impact of obesity and diabetes trends on disability amongst those aged 55-74years. In Australian adults by 2025 we estimate that around 26% of disability cases would have been avoidable if there had been no change in obesity and diabetes prevalence since 1980. A similar impact is likely around the world in developed countries. Copyright © 2015 Elsevier Inc. All rights reserved.

[Effects of diabetes and obesity on the higher brain functions in rodents].

PubMed

Asato, Megumi; Ikeda, Hiroko; Kamei, Junzo

2012-11-01

Metabolic disorders, such as diabetes and obesity, have been indicated to disturb the function of the central nervous system (CNS) as well as several peripheral organs. Clinically, it is well recognized that the prevalence of anxiety and depression is higher in diabetic and obesity patients than in the general population. We have recently indicated that streptozotocin-induced diabetic and diet-induced obesity mice have enhanced fear memory and higher anxiety-like behavior in several tests such as the conditioned fear, tail-suspension, hole-board and elevated open-platform tests. The changes in fear memory and anxiety-like behavior of diabetic and obese mice are due to the dysfunction of central glutamatergic and monoaminergic systems, which is mediated by the changes of intracellular signaling. These results suggest that metabolic disorders strongly affect the function of the CNS and disturb the higher brain functions. These dysfunctions of the CNS in diabetes and obesity are involved in the increased prevalence of anxiety disorders and depression. Normalization of these dysfunctions in the CNS will be a new attractive target to treat the metabolic disorders and their complications.

Maternal overweight and obesity and risk of pre-eclampsia in women with type 1 diabetes or type 2 diabetes.

PubMed

Persson, Martina; Cnattingius, Sven; Wikström, Anna-Karin; Johansson, Stefan

2016-10-01

Women with type 1 or type 2 diabetes are at increased risk of pre-eclampsia. Overweight and obesity are associated with an increased risk of pre-eclampsia in women without diabetes. The aim of the study was to investigate the impact of maternal overweight and obesity on the risk of pre-eclampsia in women with type 1 diabetes or type 2 diabetes. In a population-based cohort study including singleton births in Sweden, we estimated the risk of pre-eclampsia among women with type 1 diabetes (n = 7062) and type 2 diabetes (n = 886), and investigated whether maternal overweight (BMI 25-29.9 kg/m(2)) and obesity (BMI ≥30.0 kg/m(2)) modified the risk. Logistic regression analyses were used to estimate crude and adjusted ORs with 95% CIs, using women without diabetes as the reference group (n = 1,509,525). Compared with women without diabetes, the adjusted ORs for pre-eclampsia in women with type 1 and type 2 diabetes were 5.74 (95% CI 5.31, 6.20) and 2.11 (95% CI 1.65, 2.70), respectively. The corresponding risks of pre-eclampsia combined with preterm birth were even higher. Risks of pre-eclampsia increased with maternal overweight (BMI 25-29.9 kg/m(2)) and obesity (BMI ≥30.0 kg/m(2)), foremost in women without diabetes, to a lesser extent in women with type 1 diabetes but not in women with type 2 diabetes. Maternal overweight and obesity increased risks of pre-eclampsia in women with type 1 diabetes but not in women with type 2 diabetes. Even so, considering associations between maternal BMI and overall maternal and offspring risk, all women (with and without diabetes) should aim for a normal weight before pregnancy.

Monocyte Chemoattractant Protein 1 (MCP-1) in Obesity and Diabetes

PubMed Central

Panee, Jun

2012-01-01

Monocyte chemoattractant protein-1 (MCP-1) is the first discovered and most extensively studied CC chemokine, and the amount of studies on its role in the etiologies of obesity- and diabetes-related diseases have increased exponentially during the past 2 decades. This review attempted to provide a panoramic perspective of the history, regulatory mechanisms, functions, and therapeutic strategies of this chemokine. The highlights of this review include the roles of MCP-1 in the development of obesity, diabetes, cardiovascular diseases, insulitis, diabetic nephropathy, and diabetic retinopathy. Therapies that specifically or non-specifically inhibit MCP-1 overproduction have been summarized. PMID:22766373

Empowerment in the Treatment of Diabetes and Obesity.

PubMed

Łuczyński, Włodzimierz; Głowińska-Olszewska, Barbara; Bossowski, Artur

2016-01-01

As the available therapies for diabetes and obesity are not effective enough, diabetologists and educators search for new methods to collaborate with patients in order to support their health behaviors. The aim of this review is to discuss perspectives for the development of new empowerment-type therapies in the treatment of diabetes/obesity. Empowerment is a process whereby patients gain the necessary knowledge to influence their own behavior to improve the quality of their lives. It is carried out in five stages: (1) identify the problem, (2) explain the feelings and meanings, (3) build a plan, (4) act, and (5) experience and assess the execution. Although many years have passed since the advent and popularization of the concept of empowerment, the area remains controversial, mainly with regard to the methodology of therapy. Some previous studies have confirmed the positive effect of empowerment on body weight, metabolic control, and quality of life of patients with type 2 diabetes; however, few studies have been conducted in patients with type 1 diabetes. There is still a need to confirm the effectiveness of empowerment in accordance with Evidence Based Medicine by performing long-term observational studies in a large group of patients. In future, empowerment may become part of the standard of care for patients with diabetes and/or obesity.

Empowerment in the Treatment of Diabetes and Obesity

PubMed Central

2016-01-01

As the available therapies for diabetes and obesity are not effective enough, diabetologists and educators search for new methods to collaborate with patients in order to support their health behaviors. The aim of this review is to discuss perspectives for the development of new empowerment-type therapies in the treatment of diabetes/obesity. Empowerment is a process whereby patients gain the necessary knowledge to influence their own behavior to improve the quality of their lives. It is carried out in five stages: (1) identify the problem, (2) explain the feelings and meanings, (3) build a plan, (4) act, and (5) experience and assess the execution. Although many years have passed since the advent and popularization of the concept of empowerment, the area remains controversial, mainly with regard to the methodology of therapy. Some previous studies have confirmed the positive effect of empowerment on body weight, metabolic control, and quality of life of patients with type 2 diabetes; however, few studies have been conducted in patients with type 1 diabetes. There is still a need to confirm the effectiveness of empowerment in accordance with Evidence Based Medicine by performing long-term observational studies in a large group of patients. In future, empowerment may become part of the standard of care for patients with diabetes and/or obesity. PMID:28090541

How Effective Are Antioxidant Supplements in Obesity and Diabetes?

PubMed Central

Abdali, Daniyal; Samson, Sue E.; Grover, Ashok Kumar

2015-01-01

Obesity is a central health issue due to its epidemic prevalence and its association with type 2 diabetes and other comorbidities. Obesity is not just being overweight. It is a metabolic disorder due to the accumulation of excess dietary calories into visceral fat and the release of high concentrations of free fatty acids into various organs. It represents a state of chronic oxidative stress and low-grade inflammation whose intermediary molecules may include leptin, adiponectin and cytokines. It may progress to hyperglycemia, leading to type 2 diabetes. Whether or not dietary antioxidant supplements are useful in the management of obesity and type 2 diabetes is discussed in this review. Only the benefits for obesity and diabetes are examined here. Other health benefits of antioxidants are not considered. There are difficulties in comparing studies in this field because they differ in the time frame, participants' ethnicity, administration of antioxidant supplements, and even in how obesity was measured. However, the literature presents reasonable evidence for marginal benefits of supplementation with zinc, lipoic acid, carnitine, cinnamon, green tea, and possibly vitamin C plus E, although the evidence is much weaker for omega-3 polyunsaturated fatty acids, coenzyme Q10, green coffee, resveratrol, or lycopene. Overall, antioxidant supplements are not a panacea to compensate for a fast-food and video-game way of living, but antioxidant-rich foods are recommended as part of the lifestyle. Such antioxidant foods are commonly available. PMID:25791371

Abdominal obesity validates the association between elevated alanine aminotransferase and newly diagnosed diabetes mellitus.

PubMed

Yueh, Chen-Yu; Yang, Yao-Hsu; Sung, Yi-Ting; Lee, Li-Wen

2014-01-01

To examine how elevated alanine aminotransferase (ALT) could be associated with newly diagnosed diabetes mellitus. We conducted a cross-sectional analysis on a mass health examination. The odds ratios (ORs) for diabetes mellitus and newly diagnosed diabetes mellitus were compared between people with and without abdominal obesity, together with and without elevated ALT levels. 5499 people were included in this study. Two hundred fifty two (4.6%) fulfilled the diagnosis of diabetes mellitus with 178 (3.2%) undiagnosed before. Metabolic syndrome was vigorously associated with diabetes mellitus and newly diagnosed diabetes mellitus (12.4% vs. 1.4% and 9.0% vs. 0.9%), but elevated ALT alone was not. However, coexisting with obesity, elevated ALTs were robustly associated with diabetes mellitus and newly diagnosed diabetes mellitus. For the incidence of newly diagnosed diabetes mellitus, in comparison to non-obese people with normal ALT (1.7%, OR = 1), obese people especially with elevated ALT levels had significantly higher ORs (obese with ALT ≤ 40 U/L: 4.7%, OR 1.73, 95% CI 1.08-2.77, P 0.023; ALT 41-80 U/L: 6.8%, OR 2.06, 95% CI 1.20-3.55, P 0.009; ALT 81-120 U/L: 8.8%, OR 3.07, 95% CI 1.38-6.84, P 0.006; ALT > 120 U/L: 18.2%, OR 7.44, 95% CI 3.04-18.18, P < 0.001). Abdominal obesity validates the association between elevated alanine aminotransferase and diabetes mellitus and newly diagnosed diabetes mellitus. People with abdominal obesity, especially with coexisting elevated ALT levels should be screened for undiagnosed diabetes mellitus.

Restoration of the type I IFN–IL-1 balance through targeted blockade of PTGER4 inhibits autoimmunity in NOD mice

PubMed Central

Rahman, M. Jubayer; Quiel, Juan A.; Liu, Yi; Bhargava, Vipul; Zhao, Yongge; Hotta-Iwamura, Chie; Lau-Kilby, Annie W.; Malloy, Allison M.W.; Thoner, Timothy W.; Tarbell, Kristin V.

2018-01-01

Type I IFN (IFN-I) dysregulation contributes to type 1 diabetes (T1D) development, and although increased IFN-I signals are pathogenic at the initiation of autoimmune diabetes, IFN-I dysregulation at later pathogenic stages more relevant for therapeutic intervention is not well understood. We discovered that 5 key antigen-presenting cell subsets from adult prediabetic NOD mice have reduced responsiveness to IFN-I that is dominated by a decrease in the tonic-sensitive subset of IFN-I response genes. Blockade of IFNAR1 in prediabetic NOD mice accelerated diabetes and increased Th1 responses. Therefore, IFN-I responses shift from pathogenic to protective as autoimmunity progresses, consistent with chronic IFN-I exposure. In contrast, IL-1–associated inflammatory pathways were elevated in prediabetic mice. These changes correlated with human T1D onset-associated gene expression. Prostaglandin E2 (PGE2) and prostaglandin receptor 4 (PTGER4), a receptor for PGE2 that mediates both inflammatory and regulatory eicosanoid signaling, were higher in NOD mice and drive innate immune dysregulation. Treating prediabetic NOD mice with a PTGER4 antagonist restored IFNAR signaling, decreased IL-1 signaling, and decreased infiltration of leukocytes into the islets. Therefore, innate cytokine alterations contribute to both T1D-associated inflammation and autoimmune pathogenesis. Modulating innate immune balance via signals such as PTGER4 may contribute to treatments for autoimmunity. PMID:29415894

Restoration of the type I IFN-IL-1 balance through targeted blockade of PTGER4 inhibits autoimmunity in NOD mice.

PubMed

Rahman, M Jubayer; Rodrigues, Kameron B; Quiel, Juan A; Liu, Yi; Bhargava, Vipul; Zhao, Yongge; Hotta-Iwamura, Chie; Shih, Han-Yu; Lau-Kilby, Annie W; Malloy, Allison Mw; Thoner, Timothy W; Tarbell, Kristin V

2018-02-08

Type I IFN (IFN-I) dysregulation contributes to type 1 diabetes (T1D) development, and although increased IFN-I signals are pathogenic at the initiation of autoimmune diabetes, IFN-I dysregulation at later pathogenic stages more relevant for therapeutic intervention is not well understood. We discovered that 5 key antigen-presenting cell subsets from adult prediabetic NOD mice have reduced responsiveness to IFN-I that is dominated by a decrease in the tonic-sensitive subset of IFN-I response genes. Blockade of IFNAR1 in prediabetic NOD mice accelerated diabetes and increased Th1 responses. Therefore, IFN-I responses shift from pathogenic to protective as autoimmunity progresses, consistent with chronic IFN-I exposure. In contrast, IL-1-associated inflammatory pathways were elevated in prediabetic mice. These changes correlated with human T1D onset-associated gene expression. Prostaglandin E2 (PGE2) and prostaglandin receptor 4 (PTGER4), a receptor for PGE2 that mediates both inflammatory and regulatory eicosanoid signaling, were higher in NOD mice and drive innate immune dysregulation. Treating prediabetic NOD mice with a PTGER4 antagonist restored IFNAR signaling, decreased IL-1 signaling, and decreased infiltration of leukocytes into the islets. Therefore, innate cytokine alterations contribute to both T1D-associated inflammation and autoimmune pathogenesis. Modulating innate immune balance via signals such as PTGER4 may contribute to treatments for autoimmunity.

Excess health care costs of obesity in adults with diabetes mellitus: a claims data analysis.

PubMed

von Lengerke, T; Hagenmeyer, E-G; Gothe, H; Schiffhorst, G; Happich, M; Häussler, B

2010-08-01

Body weight management is a key factor in diabetes mellitus. However, both behavioral and pharmacological innovations to manage obesity may imply additional costs. In order to provide further insights into the role of obesity in diabetes-associated resource consumption, this study aims to estimate incremental costs of concomitant obesity in German adult patients (≥ 18 years) with different types of diabetes. Adopting a third-party payer perspective, claims data from a German statutory sickness fund (N=1,094,496) were analyzed for costs of annual drug prescriptions and out- and inpatient care in adult beneficiaries with diabetes in 2004. Using diagnostic information, 37,570 beneficiaries with diabetes were identified. Concomitant obesity was assessed by ICD-10-codes (E66) in the claims data. Adjusting for sex, age, and micro- and macro-vascular complications, one generalized gamma regression model with the log link was performed for type 2 diabetes patients (N=24,562), type 1 diabetes patients (N=5,663), and an unclassified group (N=7,345), respectively. Overall, 33% of the patients with diabetes were identified as obese (type 2 diabetes: 34%, type 1 diabetes: 20%, unclassified: 38%). Affirming descriptive analyses, the generalized gamma regression models revealed that obesity is associated with significant increments in health care costs regardless of type of diabetes (type 2 diabetes: € 454, type 1 diabetes: € 812, unclassified: € 532). The interaction of obesity and macro-vascular complications was numerically stronger in type 1 than in type 2 diabetes but reached statistical significance only in type 2 diabetes (and the unclassified group). Moreover, concurrent macro- and micro-vascular complications were associated with higher incremental costs in all groups. Concomitant obesity is independently associated with incremental health care costs in adult patients with type 2 diabetes and, even more so, type 1 diabetes. Results are discussed with

Mortality as a function of obesity and diabetes mellitus.

PubMed

Pettitt, D J; Lisse, J R; Knowler, W C; Bennett, P H

1982-03-01

Mortality according to body mass index (weight/height2) was studied in 2197 Pima Indians aged 15-74 years, as part of the longitudinal study of diabetes begun in 1965 in the Gila River Indian Community of Arizona. The Pima Indians are a population with a high prevalence of obesity, and they have the highest known incidence of type II (non-insulin dependent) diabetes mellitus. Among males, mortality was greatest in those with a body mass index of at least 40 kg/m2, but obesity had little effect on mortality at body mass indices below 40 kg/m2. Age-specific death rates in women were not consistently related to obesity, although mortality in subjects with diabetes was higher than in those without. In men, diabetes had little effect on mortality. In this study, as in several other mortality studies, the lowest mortality rates were experienced by people with body weights well above those recommended as "desirable" by the Society of Actuaries in 1959. Thus, the applicability of the "desirable" weight standards in common use is questioned.

Association of lipocalin-2 level, glycemic status and obesity in type 2 diabetes mellitus.

PubMed

Elkhidir, Areej E; Eltaher, Halima B; Mohamed, Abdelrahim O

2017-07-14

Management of type 2 diabetes mellitus aims to maintain a normal glycemic status, which if not, it may lead to acute and/or chronic diabetic complications. Earlier studies found Lipocalin-2 elevated in complications associated with type 2 diabetes mellitus such as ischemic heart disease. These lipocalin-2 changes had been linked to obesity and uncontrolled diabetes. So, it could be useful to understand the effect of glycemic control and obesity on lipocalin-2. This was a case control study. Fifty-seven patients with type 2 diabetes and 30 non-diabetic controls participated after getting a written consent. Weight (kg), height (m) and waist circumference (cm) were measured then the body mass index (kg/m 2 ) was determined. Blood samples were collected after an overnight fasting. HbA1c, lipid profile and serum creatinine were measured using enzymatic methods. Lipocalin-2 was measured using sandwich ELISA. Lipocalin-2 was found significantly higher in patients with type 2 diabetes (P = 0.001). However, it had no significant correlation with any of the studied variables. Females had elevated BMI compared to males in the patients group (P < 0.001). HbA1c, serum creatinine, LDL and total cholesterol were elevated in patients with diabetes (P < 0.02). HDL was lower in the patients (P = 0.002). Significant elevation in HbA1c was found in male patients (P = 0.028) compared to female patients. Patients were further classified into controlled, uncontrolled diabetics, obese and non-obese. There was a significant elevation in waist circumference in uncontrolled diabetics compared to controlled ones. Lipocalin-2 had no significant changes between controlled and uncontrolled diabetics nor non-obese and obese patients. Patients with type 2 diabetes mellitus have elevated level of serum lipocalin-2. There was no significant association found between lipocalin-2 and glycemic control nor obesity.

Effect of Diabetes and Obesity on Disparities in Prostate Cancer Outcomes

DTIC Science & Technology

2016-10-01

AWARD NUMBER: W81XWH-14-1-0503 TITLE: Effect of Diabetes and Obesity on Disparities in Prostate Cancer Outcomes PRINCIPAL INVESTIGATOR: Bettina F...Effect of Diabetes and Obesity on Disparities in Prostate Cancer Outcomes 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0503 5c. PROGRAM ELEMENT...prostate cancer related death by identifying potential modifiable factors. 15. SUBJECT TERMS Prostate cancer, disparities, VHA and VACCR data, obesity

Bariatric surgery: an IDF statement for obese Type 2 diabetes

PubMed Central

Dixon, J B; Zimmet, P; Alberti, K G; Rubino, F

2011-01-01

The International Diabetes Federation Taskforce on Epidemiology and Prevention of Diabetes convened a consensus working group of diabetologists, endocrinologists, surgeons and public health experts to review the appropriate role of surgery and other gastrointestinal interventions in the treatment and prevention of Type 2 diabetes. The specific goals were: to develop practical recommendations for clinicians on patient selection; to identify barriers to surgical access and suggest interventions for health policy changes that ensure equitable access to surgery when indicated; and to identify priorities for research. Bariatric surgery can significantly improve glycaemic control in severely obese patients with Type 2 diabetes. It is an effective, safe and cost-effective therapy for obese Type 2 diabetes. Surgery can be considered an appropriate treatment for people with Type 2 diabetes and obesity not achieving recommended treatment targets with medical therapies, especially in the presence of other major co-morbidities. The procedures must be performed within accepted guidelines and require appropriate multidisciplinary assessment for the procedure, comprehensive patient education and ongoing care, as well as safe and standardized surgical procedures. National guidelines for bariatric surgery need to be developed for people with Type 2 diabetes and a BMI of 35 kg/m2 or more. PMID:21480973

Obesity, Diabetes, and Birth Outcomes Among American Indians and Alaska Natives.

PubMed

Anderson, Kermyt G; Spicer, Paul; Peercy, Michael T

2016-12-01

Objectives To examine the relationships between prepregnancy diabetes mellitus (DM), gestational diabetes mellitus (GDM), and prepregnancy body mass index, with several adverse birth outcomes: preterm delivery (PTB), low birthweight (LBW), and macrosomia, comparing American Indians and Alaska Natives (AI/AN) with other race/ethnic groups. Methods The sample includes 5,193,386 singleton US first births from 2009-2013. Logistic regression is used to calculate adjusted odds ratios controlling for calendar year, maternal age, education, marital status, Kotelchuck prenatal care index, and child's sex. Results AI/AN have higher rates of diabetes than all other groups, and higher rates of overweight and obesity than whites or Hispanics. Neither overweight nor obesity predict PTB for AI/AN, in contrast to other groups, while diabetes predicts increased odds of PTB for all groups. Being overweight predicts reduced odds of LBW for all groups, but obesity is not predictive of LBW for AI/AN. Diabetes status also does not predict LBW for AI/AN; for other groups, LBW is more likely for women with DM or GDM. Overweight, obesity, DM, and GDM all predict higher odds of macrosomia for all race/ethnic groups. Conclusions for Practice Controlling diabetes in pregnancy, as well as prepregnancy weight gain, may help decrease preterm birth and macrosomia among AI/AN.

Relationship of abdominal obesity with cardiovascular disease, diabetes and hyperlipidaemia in Spain.

PubMed

Casanueva, Felipe F; Moreno, Basilio; Rodríguez-Azeredo, Rosario; Massien, Christine; Conthe, Pedro; Formiguera, Xavier; Barrios, Vivencio; Balkau, Beberly

2010-07-01

To evaluate the relevance of obesity and abdominal obesity in the prevalence of cardiovascular disease (CVD), diabetes mellitus, hyperlipidaemia and hypertension in primary care patients and to ascertain whether waist circumference (WC) measurement should be included in routine clinical practice in addition to body mass index (BMI). As part of the IDEA study, primary care physicians from Spain recruited patients aged 18-80 years. WC and BMI and the presence of CVD, diabetes mellitus, hyperlipidaemia and hypertension were recorded. Finally, 17 980 were analysed. An age-related increase in adiposity was observed. Overall 33% were obese by BMI, and 51% of subjects presented abdominal obesity by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII) (WC > 102 cm for men and > 88 cm for women). Although there was a correlation between BMI and WC, they presented different distribution patterns. Women, but not men, with a high level of education, professional activity and smoking were associated with a lower WC. Abdominal obesity was significantly associated with CVD. Some subjects with abdominal obesity but lean by BMI, showed an increased prevalence of CVD and diabetes. Furthermore, abdominal obesity was strongly associated with dyslipidaemia and hypertension. Half of the primary care patients studied showed abdominal obesity as measured by WC, whereas one-third was obese by BMI. Abdominal obesity was strongly associated with CVD and diabetes, even in patients lean by BMI. WC should be included in the routine clinical practice in addition to BMI.

Ubiquitin Regulates Caspase Recruitment Domain-mediated Signaling by Nucleotide-binding Oligomerization Domain-containing Proteins NOD1 and NOD2*

PubMed Central

Ver Heul, Aaron M.; Fowler, C. Andrew; Ramaswamy, S.; Piper, Robert C.

2013-01-01

NOD1 and NOD2 (nucleotide-binding oligomerization domain-containing proteins) are intracellular pattern recognition receptors that activate inflammation and autophagy. These pathways rely on the caspase recruitment domains (CARDs) within the receptors, which serve as protein interaction platforms that coordinately regulate immune signaling. We show that NOD1 CARD binds ubiquitin (Ub), in addition to directly binding its downstream targets receptor-interacting protein kinase 2 (RIP2) and autophagy-related protein 16-1 (ATG16L1). NMR spectroscopy and structure-guided mutagenesis identified a small hydrophobic surface of NOD1 CARD that binds Ub. In vitro, Ub competes with RIP2 for association with NOD1 CARD. In vivo, we found that the ligand-stimulated activity of NOD1 with a mutant CARD lacking Ub binding but retaining ATG16L1 and RIP2 binding is increased relative to wild-type NOD1. Likewise, point mutations in the tandem NOD2 CARDs at positions analogous to the surface residues defining the Ub interface on NOD1 resulted in loss of Ub binding and increased ligand-stimulated NOD2 signaling. These data suggest that Ub binding provides a negative feedback loop upon NOD-dependent activation of RIP2. PMID:23300079

Anti-Obesity and Pro-Diabetic Effects of Hemochromatosis

PubMed Central

Abbas, Mousa Al; Abraham, Deveraprabu; Kushner, James P.; McClain, Donald A.

2014-01-01

Objective Levels of tissue iron contribute to determining diabetes risk, but little is known about the effects of higher iron levels on weight, nor on the interaction of weight and iron overload on diabetes risk. We therefore examined the effect of iron on body mass index and diabetes in individuals with iron overload from hereditary hemochromatosis (HH), compared to non-HH siblings and historical controls. Methods Chart reviews were performed on a cohort of adults (age ≥40, N=101) with the common C282Y/C282Y HFE genotype, compared to wild type siblings (N=32) and comparable NHANES cohorts, with respect to body mass index and diabetes status. Results Males with HH have lower body mass index (BMI) than control siblings. Females had a trend toward decreased BMI that was not significant, possibly related to decreased degrees of iron overload. In both males and females, increased rates of diabetes were seen, especially in the overweight or obese. Conclusions High tissue iron levels may be both pro- and anti-diabetic. The prevalence of obesity and diabetes in HH is likely dependent upon the degree of iron overload, caloric intake, and other genetic and environmental factors, contributing to the observed heterogeneity in the frequency of disease-related morbidities in HH. PMID:25044717

Epigenetics: spotlight on type 2 diabetes and obesity.

PubMed

Desiderio, A; Spinelli, R; Ciccarelli, M; Nigro, C; Miele, C; Beguinot, F; Raciti, G A

2016-10-01

Type 2 diabetes (T2D) and obesity are the major public health problems. Substantial efforts have been made to define loci and variants contributing to the individual risk of these disorders. However, the overall risk explained by genetic variation is very modest. Epigenetics is one of the fastest growing research areas in biomedicine as changes in the epigenome are involved in many biological processes, impact on the risk for several complex diseases including diabetes and may explain susceptibility. In this review, we focus on the role of DNA methylation in contributing to the risk of T2D and obesity.

[Cross-sectional association between diabetes and obesity among the elderly of different genders in Yantai City].

PubMed

Mi, Wei; Wang, Nan; Lian, Wu; Yi, Weijie; Shi, Tala; Han, Wenting

2016-01-01

To explore the cross-sectional association between the incidence of diabetes and obesity among the elderly of different genders, which intends to provide the scientific basis for undertaking glycemia interventions in the early stage to be conducive to the old folks' health status in Yantai City. A total of 986 old people (≥ 60 years old) were recruited from 4 districts in Laishan District Yantai City, Penglai City, Qixia City, Haiyang City by stratified cluster of random sampling and surveyed using questionnaires, while the physical examinations and blood glucose tests were conducted. The logistic regression model was used to analyze the cross-sectional association between the incidence of diabetes and obesity among the elderly of different genders in Yantai City. The rates of obesity and abdominal obesity were 10.04% and 60.85% among the old people in Yantai, respectively. The morbidity rate of diabetes was 10.85%. The influencing factors such as age, cultural standard, monthly income, past job category, smoking, drinking were adjusted, the fat old people had 3.121 times as much chance of suffering from obesity as the normal weight ones (OR = 3.121, 95% CI 1.978 - 5.119). And there was a gender difference between diabetes and obesity. The cross-sectional association between the incidence of diabetes and masculine obesity was of statistical significance alone (OR = 3.924, 95% CI 1.561 - 7.174). The elderly with the abdominal obesity 2.398 times as likely to suffer from diabetes as the elderly with the non-abdominal obesity (OR = 2.398, 95% CI 2.123 - 4.412). There was a gender difference between diabetes and abdominal obesity. The cross-sectional association between the incidence of diabetes and masculine abdominal obesity was of statistical significance alone (OR = 2.917, 95% CI 1.249 - 4.019). There are gender difference in the relationship between obesity, abdominal obesity and diabetes in the elderly in Yantai. BMI and waist circumference can be used as the

Bone turnover biomarkers in obese postmenopausal Saudi women with type-II diabetes mellitus.

PubMed

Alselami, Nada M; Noureldeen, Amani F H; Al-Ghamdi, Maryam A; Khan, Jalaluddin A; Moselhy, Said S

2015-03-01

There is a high prevalence of diabetes mellitus type-2 (T2DM) and osteoporosis are problems worldwide. In this study, we evaluated the correlation between T2DM and bone turnover in diabetic obese postmenopausal Saudi women. The present study included total of 65 T2-DM obese postmenopausal Saudi women, (36 uncontrolled, 29 controlled). The following serum biochemical parameters were evaluated [fasting blood glucose (FBG), total calcium (Ca), phosphorus (Pi), parathyroid hormone (PTH), 1,25-(OH)2 Vitamin D3, osteocalcin (OC), procollagen (PICP) and cathepsin k (Cath K)]. Serum OC levels were significantly decreased in diabetic obese postmenopausal group compared to their respective healthy group (P < 0.004). PICP and Cath K were significantly elevated in diabetic postmenopausal group compared to the healthy group (P < 0.024 & 0.001). A significant elevation in 1,25(OH)2 Vitamin D3, Ca and Pi levels in diabetic obese postmenopausal patients group compared to the healthy group. However, a non-significant changes was observed in serum PTH level between different groups. In this study, the changes in the biochemical parameters and bone turnover markers in obese women are strong risk factors for diabetes development that may contribute to osteopenia and osteoporosis. The study showed the strong effect of T2DM on biochemical markers of bone turnover in obese postmenopausal Saudi women.

A proteomic approach to obesity and type 2 diabetes.

PubMed

López-Villar, Elena; Martos-Moreno, Gabriel Á; Chowen, Julie A; Okada, Shigeru; Kopchick, John J; Argente, Jesús

2015-07-01

The incidence of obesity and type diabetes 2 has increased dramatically resulting in an increased interest in its biomedical relevance. However, the mechanisms that trigger the development of diabetes type 2 in obese patients remain largely unknown. Scientific, clinical and pharmaceutical communities are dedicating vast resources to unravel this issue by applying different omics tools. During the last decade, the advances in proteomic approaches and the Human Proteome Organization have opened and are opening a new door that may be helpful in the identification of patients at risk and to improve current therapies. Here, we briefly review some of the advances in our understanding of type 2 diabetes that have occurred through the application of proteomics. We also review, in detail, the current improvements in proteomic methodologies and new strategies that could be employed to further advance our understanding of this pathology. By applying these new proteomic advances, novel therapeutic and/or diagnostic protein targets will be discovered in the obesity/Type 2 diabetes area. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Do diabetes and obesity affect the metabolic response to exercise?

PubMed

Plomgaard, Peter; Weigert, Cora

2017-07-01

Exercise is recommended as therapeutic intervention for people at risk to develop type 2 diabetes to prevent or treat the disease. Recent studies on the influence of obesity and type 2 diabetes on the outcome of exercise programs are discussed. Poor glycemic control before an intervention can be a risk factor of reduced therapeutic benefit from exercise. But the acute metabolic response to exercise and the transcriptional profile of the working muscle is similar in healthy controls and type 2 diabetic patients, including but not limited to intact activation of skeletal muscle AMP-activated kinase signaling, glucose uptake and expression of peroxisome proliferator-activated receptor gamma coactivator 1α. The increase in plasma acylcarnitines during exercise is not influenced by type 2 diabetes or obesity. The hepatic response to exercise is dependent on the glucagon/insulin ratio and the exercise-induced increase in hepatokines such as fibroblast growth factor 21 and follistatin is impaired in type 2 diabetes and obesity, but consequences for the benefit from exercise are unknown yet. Severe metabolic dysregulation can reduce the benefit from exercise, but the intact response of key metabolic regulators in exercising skeletal muscle of diabetic patients demonstrates the effectiveness of exercise programs to treat the disease.

Effects of obesity and diabetes on rate of bone density loss.

PubMed

Leslie, W D; Morin, S N; Majumdar, S R; Lix, L M

2018-01-01

In this large registry-based study, women with diabetes had marginally greater bone mineral density (BMD) loss at the femoral neck but not at other measurement sites, whereas obesity was not associated with greater BMD loss. Our data do not support the hypothesis that rapid BMD loss explains the increased fracture risk associated with type 2 diabetes and obesity observed in prior studies. Type 2 diabetes and obesity are associated with higher bone mineral density (BMD) which may be less protective against fracture than previously assumed. Inconsistent data suggest that rapid BMD loss may be a contributing factor. We examined the rate of BMD loss in women with diabetes and/or obesity in a population-based BMD registry for Manitoba, Canada. We identified 4960 women aged ≥ 40 years undergoing baseline and follow-up BMD assessments (mean interval 4.3 years) without confounding medication use or large weight fluctuation. We calculated annualized rate of BMD change for the lumbar spine, total hip, and femoral neck in relation to diagnosed diabetes and body mass index (BMI) category. Baseline age-adjusted BMD was greater in women with diabetes and for increasing BMI category (all P < 0.001). In women with diabetes, unadjusted BMD loss was less at the lumbar spine (P = 0.017), non-significantly greater at the femoral neck (P = 0.085), and similar at the total hip (P = 0.488). When adjusted for age and BMI, diabetes was associated with slightly greater femoral neck BMD loss (- 0.0018 g/cm 2 /year, P = 0.012) but not at the lumbar spine or total hip. There was a strong linear effect of increasing BMI on attenuated BMI loss at the lumbar spine with negligible effects on hip BMD. Diabetes was associated with slightly greater BMD loss at the femoral neck but not at other measurement sites. BMD loss at the lumbar spine was reduced in overweight and obese women but BMI did not significantly affect hip BMD loss.

Association of gestational diabetes and breastfeeding on obesity prevalence in predominately Hispanic low-income youth.

PubMed

Shearrer, G E; Whaley, S E; Miller, S J; House, B T; Held, T; Davis, J N

2015-06-01

The goal of this study was to examine if breastfeeding duration by gestational diabetes mellitus status impacted the prevalence of obesity in offspring. Data were obtained from a 2011 phone survey with caregivers of low-income children (2-4 years) participating in the Women, Infants and Children programme in Los Angeles County. The final sample included 2295 children, 84% Hispanic and 48% female. Chi-square and binary logistic regression were used to assess gestational diabetes status and breastfeeding duration on the prevalence of obesity, with the following a priori covariates: child's ethnicity, birth weight, age in months and sex. Breastfeeding and gestational diabetes were significantly associated with obesity prevalence (P < 0.01). Using gestational diabetes mellitus and no breastfeeding as the referent category, gestational diabetes mellitus offspring who were breastfed ≥12 months had a 72% decrease in obesity prevalence (adjusted odds ratio = 0.28, confidence interval 0.89-0.03, P = 0.05). These findings suggest that > 12 months of breastfeeding duration in the gestational diabetes mellitus group and any duration of breastfeeding in the non-gestational diabetes mellitus mothers is needed to reduce obesity levels in a primarily Hispanic population. © 2014 The Authors. Pediatric Obesity © 2014 World Obesity.

Anti-Obesity and Anti-Diabetic Effects of Acacia Polyphenol in Obese Diabetic KKAy Mice Fed High-Fat Diet

PubMed Central

Ikarashi, Nobutomo; Toda, Takahiro; Okaniwa, Takehiro; Ito, Kiyomi; Ochiai, Wataru; Sugiyama, Kiyoshi

2011-01-01

Acacia polyphenol (AP) extracted from the bark of the black wattle tree (Acacia meansii) is rich in unique catechin-like flavan-3-ols, such as robinetinidol and fisetinidol. The present study investigated the anti-obesity/anti-diabetic effects of AP using obese diabetic KKAy mice. KKAy mice received either normal diet, high-fat diet or high-fat diet with additional AP for 7 weeks. After the end of administration, body weight, plasma glucose and insulin were measured. Furthermore, mRNA and protein expression of obesity/diabetic suppression-related genes were measured in skeletal muscle, liver and white adipose tissue. As a result, compared to the high-fat diet group, increases in body weight, plasma glucose and insulin were significantly suppressed for AP groups. Furthermore, compared to the high-fat diet group, mRNA expression of energy expenditure-related genes (PPARα, PPARδ, CPT1, ACO and UCP3) was significantly higher for AP groups in skeletal muscle. Protein expressions of CPT1, ACO and UCP3 for AP groups were also significantly higher when compared to the high-fat diet group. Moreover, AP lowered the expression of fat acid synthesis-related genes (SREBP-1c, ACC and FAS) in the liver. AP also increased mRNA expression of adiponectin and decreased expression of TNF-α in white adipose tissue. In conclusion, the anti-obesity actions of AP are considered attributable to increased expression of energy expenditure-related genes in skeletal muscle, and decreased fatty acid synthesis and fat intake in the liver. These results suggest that AP is expected to be a useful plant extract for alleviating metabolic syndrome. PMID:21799697

Resistin increases the expression of NOD2 in mouse monocytes.

PubMed

Ren, Yi; Wan, Taomei; Zuo, Zhicai; Cui, Hengmin; Peng, Xi; Fang, Jing; Deng, Junliang; Hu, Yanchun; Yu, Shuming; Shen, Liuhong; Ma, Xiaoping; Wang, Ya; Ren, Zhihua

2017-05-01

Previous studies have indicated that resistin, a type of adipokine, contributes to the development of insulin resistance and type 2 diabetes mellitus, and mediates inflammatory reactions. However, a specific receptor for resistin has not yet been identified. In this study, the relationship between resistin and nucleotide-binding oligomerization domain-like receptors, as well as resistin signal transduction, was examined through transfection, quantitative polymerase chain reaction, western blot analysis and ELISA. The mRNA expression of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a key immune receptor related to insulin resistance, was significantly increased by resistin treatment at concentrations of 100, 150 and 200 ng/ml (P<0.05, P<0.01 and P<0.01, respectively). The mRNA expression of downstream signaling molecules in the NOD2 signaling pathway, receptor-interacting serine/threonine-protein kinase 2 (RIP2; P<0.01 at 6, 12 and 24 h) and inhibitor of NF-κB kinase subunit beta (P<0.01 at 3, 6, 12 and 24 h) were significantly increased by resistin treatment compared with the control. The mRNA expression of key proinflammatory cytokines, tumor necrosis factor α, IL (interleukin)-6 and IL-1β, were also significantly increased by resistin treatment compared with the control (P<0.01). NOD2 knockdown by small interfering RNA (siRNA) significantly decreased the expression of NOD2 and RIP2 (P<0.01), and there was no significant increase in the levels of cytokines, as compared with treatment with control siRNA. These findings indicate that the inflammatory reaction induced by resistin involves the NOD2-nuclear factor (NF)-κB signaling pathway. The inhibition of NF-κB significantly decreased the secretion of key inflammatory cytokines (P<0.01), suggesting that NF-κB signaling mechanisms are essential to the resistin-induced inflammatory response.

[Prevalence of fibromyalgia in diabetes mellitus and obesity].

PubMed

Patucchi, Emanuele; Fatati, Giuseppe; Puxeddu, Adolfo; Coaccioli, Stefano

2003-04-01

To determine the prevalence of fibromyalgia in diabetes mellitus and obesity, 121 consecutive patients have been observed: 27 with obesity (6 males and 21 females; mean age 57 years, range 20-57; mean body mass index [BMI] 34); 88 with type 2 diabetes mellitus (T2DM; 40 males and 48 females; mean age 63 years, range 44-78; mean BMI 28.8; mean glycated haemoglobin [HbA1c] in the last year 8.3%); 6 with type 1 diabetes mellitus (T1DM; 2 males and 4 females; mean age 52 years, range 26-76; mean BMI 24.5; mean HbA1c < 7%). An original questionnaire has been proposed (answer yes/not) as follows: 1) chronic (more than 3 months) and diffuse musculoskeletal pain; 2) sleep disturbances; 3) generalized fatigue; 4) paresthesias at the extremities; 5) swollen impression at hands and feet; 6) symptoms referred to irritable bowel syndrome; 7) headache; 8) symptoms change related with environmental climatic variations and/or exercise. A chronic and diffuse musculoskeletal pain has been reported by 62% of patients as well as in 9% of patients 11/18 positive tender points have been documented. In the patients with a BMI less that 26 the diagnosis of fibromyalgia was negative. Our data seem to reveal the presence of a significant clinical association between obesity, diabetes mellitus and fibromyalgia.

Obese individuals with type 2 diabetes demonstrate decreased activation of the salience-related insula and increased activation of the emotion/salience-related amygdala to visual food cues compared to non-obese individuals with diabetes: a preliminary study.

PubMed

Farr, Olivia M; Mantzoros, Christos S

2018-06-08

A better understanding of the underlying pathophysiology of obesity and its comorbidities is needed to develop more effective therapeutics. Although several studies have observed differences in CNS activation/deactivation patterns between obese and lean individuals when viewing food cues, few studies have examined whether the same holds true among diabetics. We examined cross-sectionally, using functional magnetic resonance imaging (fMRI), differences in brain activation to food cues between obese (n=6) vs. non-obese (n=5) individuals with type 2 diabetes. Obese individuals with type 2 diabetes demonstrate less activation of the salience- and reward-related insula while fasting and increased activation of the amygdala to highly desirable foods after a meal. Our findings in type 2 diabetes suggest a persistence of differences between obese versus non-obese individuals. Future, larger studies should confirm this differential activation between lean and obese individuals with and without type 2 diabetes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adachi, Yusuke; Yoshikawa, Yutaka; Yoshida, Jiro

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, followingmore » 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.« less

Dynapenic Obesity and Prevalence of Type 2 Diabetes in Middle-Aged Japanese Men

PubMed Central

Kawakami, Ryoko; Sawada, Susumu S.; Lee, I-Min; Matsushita, Munehiro; Gando, Yuko; Okamoto, Takashi; Tsukamoto, Koji; Higuchi, Mitsuru; Miyachi, Motohiko; Blair, Steven N.

2015-01-01

Background The independent and combined associations of muscle strength and obesity on the prevalence of type 2 diabetes in Japanese men remain unclear. Methods Hand grip strength was cross-sectionally evaluated between 2011 and 2013 to assess muscle strength in 5039 male workers aged 40 to 64 years. Weight and height were measured, and overweight/obesity was defined as a body mass index ≥25 kg/m2. The prevalence of type 2 diabetes, defined as fasting plasma glucose ≥126 mg/dL and/or hemoglobin A1c ≥6.5% and/or self-reported physician-diagnosed diabetes, was evaluated. Odds ratios (OR) and 95% confidence intervals (95% CI) for the prevalence of type 2 diabetes were obtained using a logistic regression model. Results In total, 611 participants had type 2 diabetes, and 1763 participants were overweight/obese. After adjustment for covariates, we found an inverse association between muscle strength and the prevalence of type 2 diabetes (P for trend <0.01). In addition, when the analyses were stratified by obesity status, the multivariable-adjusted OR per 2-standard-deviation increase in muscle strength was 0.64 (95% CI, 0.49–0.83) in the overweight/obese group, compared to a weaker relationship in the normal-weight group (OR 0.79 per 2-standard-deviation increase; 95% CI, 0.60–1.06). Conclusions Dynapenia, an age-related decrease in muscle strength, is associated with increased prevalence of type 2 diabetes, and this relationship is stronger in overweight/obese middle-aged Japanese men than in normal-weight men. PMID:26256772

Identifying counties vulnerable to diabetes from obesity prevalence in the United States: a spatiotemporal analysis.

PubMed

Li, Xiao; Staudt, Amanda; Chien, Lung-Chang

2016-11-21

Clinical and epidemiological research has reported a strong association between diabetes and obesity. However, whether increased diabetes prevalence is more likely to appear in areas with increased obesity prevalence has not been thoroughly investigated in the United States (US). The Bayesian structured additive regression model was applied to identify whether counties with higher obesity prevalence are more likely clustered in specific regions in 48 contiguous US states. Prevalence data adopted the small area estimate from the Behavioral Risk Factor Surveillance System. Confounding variables like socioeconomic status adopted data were from the American Community Survey. This study reveals that an increased percentage of relative risk of diabetes was more likely to appear in Southeast, Northeast, Central and South regions. Of counties vulnerable to diabetes, 36.8% had low obesity prevalence, and most of them were located in the Southeast, Central, and South regions. The geographic distribution of counties vulnerable to diabetes expanded to the Southwest, West and Northern regions when obesity prevalence increased. This study also discloses that 7.4% of counties had the largest average in predicted diabetes prevalence compared to the other counties. Their average diabetes prevalence escalated from 8.7% in 2004 to 11.2% in 2011. This study not only identifies counties vulnerable to diabetes due to obesity, but also distinguishes counties in terms of different levels of vulnerability to diabetes. The findings can provide the possibility of establishing targeted surveillance systems to raise awareness of diabetes in those counties.

Gestational diabetes predicts the risk of childhood overweight and abdominal circumference independent of maternal obesity.

PubMed

Nehring, I; Chmitorz, A; Reulen, H; von Kries, R; Ensenauer, R

2013-12-01

Gestational diabetes mellitus is believed to be a risk factor for childhood overweight/obesity. We aimed to assess whether this association is either a reflection or independent of confounding by maternal BMI. Data from 7355 mother-child dyads of the German Perinatal Prevention of Obesity cohort with full anthropometric information on mothers and children, gestational diabetes and confounding factors were obtained at school entry health examination. We calculated crude and adjusted logistic regression models for the association of gestational diabetes and childhood overweight/obesity and abdominal adiposity defined by age- and sex-specific percentiles for BMI and waist circumference. Among all children (mean age 5.8 years), 8.1% were overweight, 2.6% were obese and 15.5% had abdominal adiposity. The prevalence of overweight (obesity) was 21% (8.2%) in children of mothers with gestational diabetes and 10.4% (2.4%) in children of healthy mothers. Analyses with adjustment for maternal BMI and other potential confounders yielded an odds ratio of 1.81 (95% CI 1.23-2.65) and 2.80 (95% CI 1.58-4.99) for the impact of gestational diabetes on childhood overweight and obesity, respectively. Similar results were obtained for the risk of childhood abdominal adiposity (odds ratio 1.64, 95% CI 1.16-2.33) by maternal gestational diabetes. The postulated increased risk of overweight and abdominal adiposity in offspring of mothers with gestational diabetes cannot be explained by maternal BMI alone and may be stronger for childhood obesity than for overweight. © 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.

Prevalence of obesity and diabetes in patients with schizophrenia.

PubMed

Annamalai, Aniyizhai; Kosir, Urska; Tek, Cenk

2017-08-15

To compare the prevalence of diabetes in patients with schizophrenia treated at a community mental health center with controls in the same metropolitan area and to examine the effect of antipsychotic exposure on diabetes prevalence in schizophrenia patients. The study was a comprehensive chart review of psychiatric notes of patients with schizophrenia and schizoaffective disorder treated at a psychosis program in a community mental health center. Data collected included psychiatric diagnoses, diabetes mellitus diagnosis, medications, allergies, primary care status, height, weight, body mass index (BMI), substance use and mental status exam. Local population data was downloaded from the Centers for Disease Control Behavioral Risk Factor Surveillance System. Statistical methods used were χ 2 test, Student's t test, general linear model procedure and binary logistic regression analysis. The study sample included 326 patients with schizophrenia and 1899 subjects in the population control group. Demographic data showed control group was on average 7.6 years older ( P = 0.000), more Caucasians (78.7% vs 38.3%, P = 0.000), and lower percentage of males (40.7% vs 58.3%, P = 0.000). Patients with schizophrenia had a higher average BMI than the subjects in the population control (32.11, SD = 7.72 vs 27.62, SD = 5.93, P = 0.000). Patients with schizophrenia had a significantly higher percentage of obesity (58.5% vs 27%, P = 0.000) than the population group. The patients with schizophrenia also had a much higher rate of diabetes compared to population control (23.9% vs 12.2%, P = 0.000). After controlling for age sex, and race, having schizophrenia was still associated with increased risk for both obesity (OR = 3.25, P = 0.000) and diabetes (OR = 2.42, P = 0.000). The increased risk for diabetes remained even after controlling for obesity (OR = 1.82, P = 0.001). There was no difference in the distribution of antipsychotic dosage, second generation antipsychotic use or

Incremental Treatment Costs Attributable to Overweight and Obesity in Patients with Diabetes: Quantile Regression Approach.

PubMed

Lee, Seung-Mi; Choi, In-Sun; Han, Euna; Suh, David; Shin, Eun-Kyung; Je, Seyunghe; Lee, Sung Su; Suh, Dong-Churl

2018-01-01

This study aimed to estimate treatment costs attributable to overweight and obesity in patients with diabetes who were less than 65 years of age in the United States. This study used data from the Medical Expenditure Panel Survey from 2001 to 2013. Patients with diabetes were identified by using the International Classification of Diseases, Ninth Revision, Clinical Modification code (250), clinical classification codes (049 and 050), or self-reported physician diagnoses. Total treatment costs attributable to overweight and obesity were calculated as the differences in the adjusted costs compared with individuals with diabetes and normal weight. Adjusted costs were estimated by using generalized linear models or unconditional quantile regression models. The mean annual treatment costs attributable to obesity were $1,852 higher than those attributable to normal weight, while costs attributable to overweight were $133 higher. The unconditional quantile regression results indicated that the impact of obesity on total treatment costs gradually became more significant as treatment costs approached the upper quantile. Among patients with diabetes who were less than 65 years of age, patients with diabetes and obesity have significantly higher treatment costs than patients with diabetes and normal weight. The economic burden of diabetes to society will continue to increase unless more proactive preventive measures are taken to effectively treat patients with overweight or obesity. © 2017 The Obesity Society.

Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes.

PubMed

Mariño, Eliana; Richards, James L; McLeod, Keiran H; Stanley, Dragana; Yap, Yu Anne; Knight, Jacinta; McKenzie, Craig; Kranich, Jan; Oliveira, Ana Carolina; Rossello, Fernando J; Krishnamurthy, Balasubramanian; Nefzger, Christian M; Macia, Laurence; Thorburn, Alison; Baxter, Alan G; Morahan, Grant; Wong, Lee H; Polo, Jose M; Moore, Robert J; Lockett, Trevor J; Clarke, Julie M; Topping, David L; Harrison, Leonard C; Mackay, Charles R

2017-05-01

Gut dysbiosis might underlie the pathogenesis of type 1 diabetes. In mice of the non-obese diabetic (NOD) strain, we found that key features of disease correlated inversely with blood and fecal concentrations of the microbial metabolites acetate and butyrate. We therefore fed NOD mice specialized diets designed to release large amounts of acetate or butyrate after bacterial fermentation in the colon. Each diet provided a high degree of protection from diabetes, even when administered after breakdown of immunotolerance. Feeding mice a combined acetate- and butyrate-yielding diet provided complete protection, which suggested that acetate and butyrate might operate through distinct mechanisms. Acetate markedly decreased the frequency of autoreactive T cells in lymphoid tissues, through effects on B cells and their ability to expand populations of autoreactive T cells. A diet containing butyrate boosted the number and function of regulatory T cells, whereas acetate- and butyrate-yielding diets enhanced gut integrity and decreased serum concentration of diabetogenic cytokines such as IL-21. Medicinal foods or metabolites might represent an effective and natural approach for countering the numerous immunological defects that contribute to T cell-dependent autoimmune diseases.

The nodC, nodG, and glgX genes of Rhizobium tropici strain PRF 81.

PubMed

Oliveira, Luciana Ruano; Marcelino, Francismar Corrêa; Barcellos, Fernando Gomes; Rodrigues, Elisete Pains; Megías, Manuel; Hungria, Mariangela

2010-08-01

Rhizobium tropici is a diazotrophic microsymbiont of common bean (Phaseolus vulgaris L.) that encompasses important but still poorly studied tropical strains, and a recent significant contribution to the knowledge of the species was the publication of a genomic draft of strain PRF 81, which revealed several novel genes [Pinto et al. Funct Int Gen 9:263-270, 2009]. In this study, we investigated the transcription of nodC, nodG, and glgX genes, located in the nod operon of PRF 81 strain, by reverse-transcription quantitative PCR. All three genes showed low levels of transcription when the cells were grown until exponential growth phase in the presence of common-bean-seed exudates or of the root nod-gene inducer naringenin. However, when cells at the exponential phase of growth were incubated with seed exudates, transcription occurred after only 5 min, and nodC, nodG, and glgX were transcribed 121.97-, 14.86-, and 50.29-fold more than the control, respectively, followed by a rapid decrease in gene transcription. Much lower levels of transcription were observed in the presence of naringenin; furthermore, maximum transcription required 8 h of incubation for all three genes. In light of these results, the mechanisms of induction of the nodulation genes by flavonoids are discussed.

Management of obesity in patients with type 2 diabetes mellitus in primary care.

PubMed

Mohammad, Shoaib; Ahmad, Jamal

2016-01-01

Obesity and being overweight is the most powerful risk factor accounting for 80-90% of patients with type 2 diabetes mellitus (T2DM). The epidemic of obesity is driving the diabetes epidemic to alarming levels and primary care is becoming an important setting for obesity management in T2DM in India. Yet many primary care providers feel ill-equipped or inadequately supported to address obesity in patients with diabetes. This article reviews the most recent and strongest evidence-based strategies that may aid physicians in management of obesity in patients with T2DM in primary care. A systematic literature search of MEDLINE using the search terms Obesity, Obesity in T2DM, weight loss and Primary Care was conducted. The American Diabetes Association, National Institute for Health, National Institute of Health and Excellence (NICE), Scottish Intercollegiate Guidelines Network (SIGN) and World Health Organization websites were also searched. Most studies in this area are observational in design with few randomized controlled trials (RCTs). Articles and studies involving meta-analysis or RCTs were preferred over other types. Effective weight management treatment in T2DM patient can be implemented in the primary care setting. Evidence based individualized lifestyle and pharmacologic measures supported by behavioral intervention and counseling with appropriate and informed surgical referrals has the potential to improve the success of weight management within primary care. Copyright © 2016 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Anti-Obesity Effects of Onion Extract in Zucker Diabetic Fatty Rats

PubMed Central

Yoshinari, Orie; Shiojima, Yoshiaki; Igarashi, Kiharu

2012-01-01

Anti-obesity effects of onion extract were determined in obesity and diabetes-prone Zucker diabetic fatty rats by measuring the efficacy of markers concerned with diabetes and obesity. Body and adipose tissue weights in 5% of onion extract-fed group were found to be significantly lower than the control group without onion extract. Fasting blood glucose and HOMA-IR levels were also improved, although the serum insulin and leptin levels did not show any remarkable difference. Serum triglyceride and free fatty acid levels in both the 3% and 5%-fed group were found to be reduced compared to the control group. Additionally the feeding of the onion extract increased the glucose tolerance. These results suggest that dietary onion extract is beneficial for improving diabetes by decreasing lipid levels. We also examined differentiation ability of rat white preadipocyte cells using the onion extract and its sulfur-containing components. Cycloalliin, S-methyl-L-cysteine, S-propyl-L-cysteine sulfoxide, dimethyl trisulfide, especially S-methyl-L-cysteine sulfoxide were reported to be effective in inhibiting formation of oil drop in the cells, suggesting that these compounds may be involved in the anti-obesity effect of the onion extract. PMID:23201769

The investigation of the some body parameters of obese and (obese+diabetes) patients with using bioelectrical impedance analysis techniques

NASA Astrophysics Data System (ADS)

Yerlikaya, Emrah; Karageçili, Hasan; Aydin, Ruken Zeynep

2016-04-01

Obesity is a key risk for the development of hyperglycemia, hypertension, hyperlipidemia, insulin resistance and is totally referred to as the metabolic disorders. Diabetes mellitus, a metabolic disorder, is related with hyperglycemia, altered metabolism of lipids, carbohydrates and proteins. The minimum defining characteristic feature to identify diabetes mellitus is chronic and substantiated elevation of circulating glucose concentration. In this study, it is aimed to determine the body composition analyze of obese and (obese+diabetes) patients.We studied the datas taken from three independent groups with the body composition analyzer instrument. The body composition analyzer calculates body parameters, such as body fat ratio, body fat mass, fat free mass, estimated muscle mass, and base metabolic rate on the basis of data obtained by Dual Energy X-ray Absorptiometry using Bioelectrical Impedance Analysis. All patients and healthy subjects applied to Siirt University Medico and their datas were taken. The Statistical Package for Social Sciences version 21 was used for descriptive data analysis. When we compared and analyzed three groups datas, we found statistically significant difference between obese, (obese+diabetes) and control groups values. Anova test and tukey test are used to analyze the difference between groups and to do multiple comparisons. T test is also used to analyze the difference between genders. We observed the statistically significant difference in age and mineral amount p<0.00 between (diabetes+obese) and obese groups. Besides, when these patient groups and control group were analyzed, there were significant difference between most parameters. In terms of education level among the illiterate and university graduates; fat mass kg, fat percentage, internal lubrication, body mass index, water percentage, protein mass percentage, mineral percentage p<0.05, significant statistically difference were observed. This difference especially may result

Low serum amylase and obesity, diabetes and metabolic syndrome: A novel interpretation

PubMed Central

Nakajima, Kei

2016-01-01

For the last decade, low serum amylase (hypoamylasemia) has been reported in certain common cardiometabolic conditions such as obesity, diabetes (regardless of type), and metabolic syndrome, all of which appear to have a common etiology of insufficient insulin action due to insulin resistance and/or diminished insulin secretion. Some clinical studies have shown that salivary amylase may be preferentially decreased in obese individuals, whereas others have revealed that pancreatic amylase may be preferentially decreased in diabetic subjects with insulin dependence. Despite this accumulated evidence, the clinical relevance of serum, salivary, and pancreatic amylase and the underlying mechanisms have not been fully elucidated. In recent years, copy number variations (CNVs) in the salivary amylase gene (AMY1), which range more broadly than the pancreatic amylase gene (AMY2A and AMY2B), have been shown to be well correlated with salivary and serum amylase levels. In addition, low CNV of AMY1, indicating low salivary amylase, was associated with insulin resistance, obesity, low taste perception/satiety, and postprandial hyperglycemia through impaired insulin secretion at early cephalic phase. In most populations, insulin-dependent diabetes is less prevalent (minor contribution) compared with insulin-independent diabetes, and obesity is highly prevalent compared with low body weight. Therefore, obesity as a condition that elicits cardiometabolic diseases relating to insulin resistance (major contribution) may be a common determinant for low serum amylase in a general population. In this review, the novel interpretation of low serum, salivary, and pancreas amylase is discussed in terms of major contributions of obesity, diabetes, and metabolic syndrome. PMID:27022442

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Gu-Jiun; Sytwu, Huey-Kang; Yu, Jyh-Cherng

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 inmore » 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.« less

Timing and duration of obesity in relation to diabetes: findings from an ethnically diverse, nationally representative sample.

PubMed

The, Natalie S; Richardson, Andrea S; Gordon-Larsen, Penny

2013-04-01

The influence on diabetes of the timing and duration of obesity across the high-risk period of adolescence to young adulthood has not been investigated in a population-based, ethnically diverse sample. A cohort of 10,481 individuals aged 12-21 years enrolled in the U.S. National Longitudinal Study of Adolescent Health (1996) was followed over two visits during young adulthood (18-27 years, 2001-2002; 24-33 years, 2007-2009). Separate logistic regression models were used to examine the associations of diabetes (A1C ≥6.5% or diagnosis by a health care provider) in young adulthood with 1) obesity timing (never obese, onset <16 years, onset 16 to <18 years, onset ≥18 years) and 2) obesity duration over time (never obese, incident obesity, fluctuating obesity, and persistent obesity), testing differences by sex and race/ethnicity. Among 24- to 33-year-old participants, 4.4% had diabetes (approximately half were undiagnosed), with a higher prevalence in blacks and Hispanics than whites. In multivariable analyses, women who became obese before age 16 were more likely to have diabetes than women who became obese at or after age 18 (odds ratio 2.77 [95% CI 1.39-5.52]), even after accounting for current BMI, waist circumference, and age at menarche. Persistent (vs. adult onset) obesity was associated with increased likelihood of diabetes in men (2.27 [1.41-3.64]) and women (2.08 [1.34-3.24]). Diabetes risk is particularly high in individuals who were obese as adolescents relative to those with adult-onset obesity, thus highlighting the need for diabetes prevention efforts to address pediatric obesity.

Socioeconomic status: The missing link between obesity and diabetes mellitus?

PubMed

Volaco, Alexei; Cavalcanti, Ana Maria; Filho, Roberto Pecoits; Précoma, Dalton Bertolim

2017-06-21

Currently, there is an epidemic expansion of the obesity rates worldwide. The increasing number of obese individuals associated with the aging of population leads to increasing number of individuals with type 2 diabetes mellitus (T2DM) at the same rate. The traditional factors that link obesity to T2DM are related to genetics, hypercaloric diet, sedentary lifestyle, and stress. Individuals from lower socioeconomic status (SES) have restricted autonomy and opportunities that could lead to more stress and consequently increase in stress hormones, such as cortisol, catecholamines, glucagon, and growth hormone, which might ultimately change fat deposition, increasing visceral fat and increasing the risk of T2DM mellitus development. We conducted a review of the literature on the effects of low SES and the risk of developing type 2 diabetes mellitus in obese persons. 191 studies were found. The obesity of lower SES individuals is more central than that for individuals from higher socioeconomic position. It is also proposed that the quality of food seems to be lower, with more intake of fat and simple carbohydrates and less of fruits, vegetables and whole wheat bread, in the more disadvantaged social classes. The lower income neighborhoods, without exercise facilities and unsafety are also associated with higher indices of physical inactivity. Cross sectional and prospective studies confirm the relationship between lower socioeconomic status and obesity and diabetes. The lower SES is associated to metabolic implications that are linked to insulin resistance and possibly may also interfere with the ability of beta cell to secrete insulin and change the gut microbiota, increasing even more the future risk of developing diabetes. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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. Copyright 2006 Wiley-Liss, Inc.

High-Throughput Sequencing of Islet-Infiltrating Memory CD4+ T Cells Reveals a Similar Pattern of TCR Vβ Usage in Prediabetic and Diabetic NOD Mice

PubMed Central

Marrero, Idania; Hamm, David E.; Davies, Joanna D.

2013-01-01

Autoreactive memory CD4+ T cells play a critical role in the development of type 1 diabetes, but it is not yet known how the clonotypic composition and TCRβ repertoire of the memory CD4+ T cell compartment changes during the transition from prediabetes to diabetes. In this study, we used high-throughput sequencing to analyze the TCRβ repertoire of sorted islet-infiltrating memory CD4+CD44high T cells in 10-week-old prediabetic and recently diabetic NOD mice. We show that most clonotypes of islet-infiltrating CD4+CD44high T cells were rare, but high-frequency clonotypes were significantly more common in diabetic than in prediabetic mice. Moreover, although the CD4+CD44high TCRβ repertoires were highly diverse at both stages of disease development, dominant use of TRBV1 (Vβ2), TRBV13-3 (Vβ8.1), and TRBV19 (Vβ6) was evident in both prediabetic and diabetic mice. Our findings strongly suggest that therapeutic targeting of cells specifically expressing the dominant TCRβ might reduce pancreatic infiltration in prediabetic mice and attenuate the progression to diabetes. PMID:24146886

Expression of the central obesity and Type 2 Diabetes mellitus genes is associated with insulin resistance in young obese children.

PubMed

Skoczen, S; Wojcik, M; Fijorek, K; Siedlar, M; Starzyk, J B

2015-04-01

The assessment of the health consequences associated with obesity in young children is challenging. The aims of this study were: (1) to compare insulin resistance indices derived from OGTT in obese patients and healthy control (2) to analyze central obesity and Type 2 Diabetes genes expression in obese children, with special attention to the youngest group (< 10 years old). The study included 49 children with obesity (median age 13.5 years old), and 25 healthy peers. Biochemical blood tests and expression of 11 central obesity and 33 Type 2 Diabetes genes was assessed. A significant difference in insulin resistance between obese and non-obese adolescents was observed in all studied indices (mean values of the insulin levels: 24.9 vs. 9.71 mIU/L in T0, 128 vs. 54.7 mIU/L in T60 and 98.7 vs. 41.1 mIU/L in T120 respectively; AUC: 217 vs. 77.2 ng/ml*h, mean values of B% (state beta cell function), S% (insulin sensitivity), and IR were 255 (±97) vs. 135 (±37.8), 46.6 (±37.3) vs. 84.2 (±29.6) and 3 (±1.55) vs. 1.36 (±0,56); HIS, WBIS and ISIBel median 3.89, 44.7, 0.73 vs. 8.57, 110, 2.25. All comparisons differed significantly p<0.001). Moreover, insulin sensitivity was significantly better in the older obese group (>10 years old): median AUC 239 vs. 104 ng/ml*h, and HIS, WBIS and ISIBel 3.57, 38, 0.67 vs. 6.23, 75.6, 1.87 respectively in the obese older compared to the obese younger subgroup, p<0.05. The expression of 64% of the central obesity genes and 70% of Type 2 Diabetes genes was higher in the obese compared to control groups. The differences were more pronounced in the younger obese group. Insulin resistance may develop in early stage of childhood obesity and in very young children may be associated with higher expression of the central obesity and Type 2 Diabetes genes. © Georg Thieme Verlag KG Stuttgart · New York.

Work, diabetes and obesity: a seven year follow-up study among Danish health care workers.

PubMed

Poulsen, Kjeld; Cleal, Bryan; Clausen, Thomas; Andersen, Lars L

2014-01-01

The rise in prevalence of diabetes is alarming and research ascribes most of the increase to lifestyle. However, little knowledge exists about the influence of occupational factors on the risk for developing diabetes. This study estimates the importance of work and lifestyle as risk factors for developing diabetes mellitus among healthcare workers and explores the association of work factors and obesity, which is a risk factor for diabetes. Questionnaire-based prospective cohort study among 7,305 health care workers followed for seven years in the Danish National Diabetes Register. We used bivariate comparisons to give an unadjusted estimate of associations, followed by adjusted survival analysis and logistic regression models to estimate the influences of potential risk factors related to job, health and lifestyle on diabetes and obesity. During seven years of follow up, 3.5% of participants developed diabetes, associated with obesity (HR  =  6.53; 95% CI 4.68-9.10), overweight (HR  =  2.89; CI 2.11-3.96) age 50-69 y (HR  =  2.27; 95% CI 1.57-3.43) and high quality of leadership (HR  =  1.60; CI 1.19-2.16). Obesity at baseline was most common among the youngest employees, and was mainly associated with developing diabetes (OR  =  3.84; CI 2.85-5.17), impaired physical capacity and physical inactivity. In the occupational setting, obesity was associated with shift work, severe musculoskeletal pain, low influence, but also by good management, fewer role conflicts and a positive work-life balance. Looking only at non-smokers, removed the influence of age and pain. However, non-smokers also had higher depression scores and more role conflicts. Confirming obesity as the strongest risk factor for developing diabetes, the present study identified few occupational risk factors. However, obesity, the key risk factor for diabetes, had a more variable relation with work than did diabetes.

Work, Diabetes and Obesity: A Seven Year Follow-Up Study among Danish Health Care Workers

PubMed Central

Poulsen, Kjeld; Cleal, Bryan; Clausen, Thomas; Andersen, Lars L.

2014-01-01

Objectives The rise in prevalence of diabetes is alarming and research ascribes most of the increase to lifestyle. However, little knowledge exists about the influence of occupational factors on the risk for developing diabetes. This study estimates the importance of work and lifestyle as risk factors for developing diabetes mellitus among healthcare workers and explores the association of work factors and obesity, which is a risk factor for diabetes. Methods Questionnaire-based prospective cohort study among 7,305 health care workers followed for seven years in the Danish National Diabetes Register. We used bivariate comparisons to give an unadjusted estimate of associations, followed by adjusted survival analysis and logistic regression models to estimate the influences of potential risk factors related to job, health and lifestyle on diabetes and obesity. Results During seven years of follow up, 3.5% of participants developed diabetes, associated with obesity (HR  =  6.53; 95% CI 4.68–9.10), overweight (HR  =  2.89; CI 2.11–3.96) age 50–69 y (HR  =  2.27; 95% CI 1.57–3.43) and high quality of leadership (HR  =  1.60; CI 1.19–2.16). Obesity at baseline was most common among the youngest employees, and was mainly associated with developing diabetes (OR  =  3.84; CI 2.85–5.17), impaired physical capacity and physical inactivity. In the occupational setting, obesity was associated with shift work, severe musculoskeletal pain, low influence, but also by good management, fewer role conflicts and a positive work-life balance. Looking only at non-smokers, removed the influence of age and pain. However, non-smokers also had higher depression scores and more role conflicts. Conclusions Confirming obesity as the strongest risk factor for developing diabetes, the present study identified few occupational risk factors. However, obesity, the key risk factor for diabetes, had a more variable relation with work than did diabetes. PMID:25068830

Obesity and diabetes: from genetics to epigenetics.

PubMed

Burgio, Ernesto; Lopomo, Angela; Migliore, Lucia

2015-04-01

Obesity is becoming an epidemic health problem. During the last years not only genetic but also, and primarily, environmental factors have been supposed to contribute to the susceptibility to weight gain or to develop complications such as type 2 diabetes. In spite of the intense efforts to identify genetic predisposing variants, progress has been slow and success limited, and the common obesity susceptibility variants identified only explains a small part of the individual variation in risk. Moreover, there is evidence that the current epidemic of obesity and diabetes is environment-driven. Recent studies indicate that normal metabolic regulation during adulthood besides requiring a good balance between energy intake and energy expenditure, can be also affected by pre- and post-natal environments. In fact, maternal nutritional constraint during pregnancy can alter the metabolic phenotype of the offspring by means of epigenetic regulation of specific genes, and this can be passed to the next generations. Studies focused on epigenetic marks in obesity found altered methylation and/or histone acetylation levels in genes involved in specific but also in more general metabolic processes. Recent researches point out the continuous increase of "obesogens", in the environment and food chains, above all endocrine disruptors, chemicals that interfere with many homeostatic mechanisms. Taken into account the already existing data on the effects of obesogens, and the multiple potential targets with which they might interfere daily, it seems likely that the exposure to obesogens can have an important role in the obesity and diabesity pandemic.

Hypoxia induced VEGF synthesis in visceral adipose depots of obese diabetic patients.

PubMed

Fusaru, Ana Marina; Pisoschi, Cătălina Gabriela; Bold, Adriana; Taisescu, C; Stănescu, R; Hîncu, Mihaela; Crăiţoiu, Stefania; Baniţă, Ileana Monica

2012-01-01

VEGF is one the pro-inflammatory adipokines synthesized by the "adipose secretoma" of obese subjects as a response to hypoxic conditions; but the main function of VEGF is angiogenesis, being recognized as the most important factor increasing blood capillaries in the adipose tissue by stimulating endothelial cell growth. In this paper, we propose a comparative study of the vascular response to VEGF synthesis in the subcutaneous and central-peritoneal adipose depots in lean, obese and obese diabetic patients. We used CD31 to label the endothelial cells in order to evaluate the response of the vascular network to VEGF synthesis. Our results showed an increase of VEGF protein synthesis in obese and obese-diabetic patients compared to lean subjects where the protein was absent. The positivity for VEGF in obese diabetic samples was observed in numerous structures from the adipose depots, both in the stromal vascular fraction--blood vessels and stromal cells--as well as in the cytoplasm of adipocytes. Positivity in the vascular wall was observed more frequently in areas of perivascular and intralobular fibrosis. Obese and diabetic patients showed similar incidence of CD31 immunoreactivity with lean subjects in both subcutaneous and peritoneal depots. In conclusion, human adipose depots show a different incidence of VEGF positive cells in relation with their disposal and the metabolic status. VEGF synthesis in visceral adipose tissue is inefficient being not followed by angiogenesis to counterbalance tissue hypoxia. We suggest that may be a pathogenic link between the degrees of intralobular fibrosis in adipose depots and VEGF expression.

Approach to the obese adolescent with new-onset diabetes.

PubMed

Zeitler, Philip

2010-12-01

The prevalence of both type 1 and type 2 diabetes among children and adolescents has been steadily increasing over the last few decades. However, as the general pediatric population becomes more obese and more ethnically diverse, reliance on phenotypic characteristics for distinguishing between these types of diabetes is becoming increasingly untenable. Yet, the recognition of differences in treatment strategies, associated disorders, and both short- and long-term diabetes and cardiovascular outcomes supports the importance of diagnostic efforts to make a distinction between diabetes types. An approach to determination of diabetes type is discussed, focused on the presence or absence of autoimmunity and assessment of β-cell function. At the time of diagnosis, it is generally not possible to be certain of diabetes type, and therefore, initial treatment decisions must be made based on aspects of the presenting physiology, with adjustments in treatment approach made as the individual's course proceeds and additional information becomes available. The apparent overlap between type 1 and type 2 diabetes that occurs in obese adolescents has resulted in some controversy regarding mixed forms of diabetes that are ultimately semantic, but this does raise interesting questions about the treatment of type 1 diabetes in the presence of an insulin-resistant phenotype. Finally, the lack of information about the efficacy of treatment of cardiovascular risk factors, such as dyslipidemia and hypertension, along with the well-documented challenges in adherence to chronic illness treatment in this population, creates substantial challenges.

The effects of obesity and type 2 diabetes mellitus on cardiac structure and function in adolescents and young adults.

PubMed

Shah, A S; Khoury, P R; Dolan, L M; Ippisch, H M; Urbina, E M; Daniels, S R; Kimball, T R

2011-04-01

We sought to evaluate the effects of obesity and obesity-related type 2 diabetes mellitus on cardiac geometry (remodelling) and systolic and diastolic function in adolescents and young adults. Cardiac structure and function were compared by echocardiography in participants who were lean, obese or obese with type 2 diabetes (obese diabetic), in a cross sectional study. Group differences were assessed using ANOVA. Independent determinants of cardiac outcome measures were evaluated with general linear models. Adolescents with obesity and obesity-related type 2 diabetes were found to have abnormal cardiac geometry compared with lean controls (16% and 20% vs <1%, p < 0.05). These two groups also had increased systolic function. Diastolic function decreased from the lean to obese to obese diabetic groups with the lowest diastolic function observed in the obese diabetic group (p < 0.05). Regression analysis showed that group, BMI z score (BMIz), group × BMIz interaction and systolic BP z score (BPz) were significant determinants of cardiac structure, while group, BMIz, systolic BPz, age and fasting glucose were significant determinants of the diastolic function (all p < 0.05). Adolescents with obesity and obesity-related type 2 diabetes demonstrate changes in cardiac geometry consistent with cardiac remodelling. These two groups also demonstrate decreased diastolic function compared with lean controls, with the greatest decrease observed in those with type 2 diabetes. Adults with diastolic dysfunction are known to be at increased risk of progressing to heart failure. Therefore, our findings suggest that adolescents with obesity-related type 2 diabetes may be at increased risk of progressing to early heart failure compared with their obese and lean counterparts.

Changes in diagnosed diabetes, obesity, and physical inactivity prevalence in US counties, 2004-2012

PubMed Central

Kirtland, Karen; Lin, Ji; Shrestha, Sundar; Thompson, Ted; Albright, Ann; Gregg, Edward W.

2017-01-01

Recent studies suggest that prevalence of diagnosed diabetes in the United States reached a plateau or slowed around 2008, and that this change coincided with obesity plateaus and increases in physical activity. However, national estimates can obscure important variations in geographic subgroups. We examine whether a slowing or leveling off in diagnosed diabetes, obesity, and leisure time physical inactivity prevalence is also evident across the 3143 counties of the United States. We used publicly available county estimates of the age-adjusted prevalence of diagnosed diabetes, obesity, and leisure-time physical inactivity, which were generated by the Centers for Disease Control and Prevention (CDC). Using a Bayesian multilevel regression that included random effects by county and year and applied cubic splines to smooth these estimates over time, we estimated the average annual percentage point change (APPC) from 2004 to 2008 and from 2008 to 2012 for diabetes, obesity, and physical inactivity prevalence in each county. Compared to 2004–2008, the median APPCs for diabetes, obesity, and physical inactivity were lower in 2008–2012 (diabetes APPC difference = 0.16, 95%CI 0.14, 0.18; obesity APPC difference = 0.65, 95%CI 0.59, 0.70; physical inactivity APPC difference = 0.43, 95%CI 0.37, 0.48). APPCs and APPC differences between time periods varied among counties and U.S. regions. Despite improvements, levels of these risk factors remained high with most counties merely slowing rather than reversing, which suggests that all counties would likely benefit from reductions in these risk factors. The diversity of trajectories in the prevalence of these risk factors across counties underscores the continued need to identify high risk areas and populations for preventive interventions. Awareness of how these factors are changing might assist local policy makers in targeting and tracking the impact of efforts to reduce diabetes, obesity and physical inactivity. PMID

Changes in diagnosed diabetes, obesity, and physical inactivity prevalence in US counties, 2004-2012.

PubMed

Geiss, Linda S; Kirtland, Karen; Lin, Ji; Shrestha, Sundar; Thompson, Ted; Albright, Ann; Gregg, Edward W

2017-01-01

Recent studies suggest that prevalence of diagnosed diabetes in the United States reached a plateau or slowed around 2008, and that this change coincided with obesity plateaus and increases in physical activity. However, national estimates can obscure important variations in geographic subgroups. We examine whether a slowing or leveling off in diagnosed diabetes, obesity, and leisure time physical inactivity prevalence is also evident across the 3143 counties of the United States. We used publicly available county estimates of the age-adjusted prevalence of diagnosed diabetes, obesity, and leisure-time physical inactivity, which were generated by the Centers for Disease Control and Prevention (CDC). Using a Bayesian multilevel regression that included random effects by county and year and applied cubic splines to smooth these estimates over time, we estimated the average annual percentage point change (APPC) from 2004 to 2008 and from 2008 to 2012 for diabetes, obesity, and physical inactivity prevalence in each county. Compared to 2004-2008, the median APPCs for diabetes, obesity, and physical inactivity were lower in 2008-2012 (diabetes APPC difference = 0.16, 95%CI 0.14, 0.18; obesity APPC difference = 0.65, 95%CI 0.59, 0.70; physical inactivity APPC difference = 0.43, 95%CI 0.37, 0.48). APPCs and APPC differences between time periods varied among counties and U.S. regions. Despite improvements, levels of these risk factors remained high with most counties merely slowing rather than reversing, which suggests that all counties would likely benefit from reductions in these risk factors. The diversity of trajectories in the prevalence of these risk factors across counties underscores the continued need to identify high risk areas and populations for preventive interventions. Awareness of how these factors are changing might assist local policy makers in targeting and tracking the impact of efforts to reduce diabetes, obesity and physical inactivity.

Diabetes screening in overweight and obese children and adolescents: choosing the right test.

PubMed

Ehehalt, Stefan; Wiegand, Susanna; Körner, Antje; Schweizer, Roland; Liesenkötter, Klaus-Peter; Partsch, Carl-Joachim; Blumenstock, Gunnar; Spielau, Ulrike; Denzer, Christian; Ranke, Michael B; Neu, Andreas; Binder, Gerhard; Wabitsch, Martin; Kiess, Wieland; Reinehr, Thomas

2017-01-01

Type 2 diabetes can occur without any symptoms, and health problems associated with the disease are serious. Screening tests allowing an early diagnosis are desirable. However, optimal screening tests for diabetes in obese youth are discussed controversially. We performed an observational multicenter analysis including 4848 (2668 female) overweight and obese children aged 7 to 17 years without previously known diabetes. Using HbA1c and OGTT as diagnostic criteria, 2.4% (n = 115, 55 female) could be classified as having diabetes. Within this group, 68.7% had HbA1c levels ≥48 mmol/mol (≥6.5%). FPG ≥126 mg/dl (≥7.0 mmol/l) and/or 2-h glucose levels ≥200 mg/dl (≥11.1 mmol/l) were found in 46.1%. Out of the 115 cases fulfilling the OGTT and/or HbA1c criteria for diabetes, diabetes was confirmed in 43.5%. For FPG, the ROC analysis revealed an optimal threshold of 98 mg/dl (5.4 mmol/l) (sensitivity 70%, specificity 88%). For HbA1c, the best cut-off value was 42 mmol/mol (6.0%) (sensitivity 94%, specificity 93%). HbA1c seems to be more reliable than OGTT for diabetes screening in overweight and obese children and adolescents. The optimal HbA1c threshold for identifying patients with diabetes was found to be 42 mmol/mol (6.0%). What is Known: • The prevalence of obesity is increasing and health problems related to type 2 DM can be serious. However, an optimal screening test for diabetes in obese youth seems to be controversial in the literature. What is New: • In our study, the ROC analysis revealed for FPG an optimal threshold of 98 mg/dl (5.4 mmol/l, sensitivity 70%, specificity 88%) and for HbA1c a best cut-off value of 42 mmol/mol (6.0%, sensitivity 94%, specificity 93%) to detect diabetes. Thus, in overweight and obese children and adolescents, HbA1c seems to be a more reliable screening tool than OGTT.

New insights on diabetes mellitus and obesity in Africa-part 1: prevalence, pathogenesis and comorbidities.

PubMed

Kengne, Andre Pascal; Echouffo-Tcheugui, Justin-Basile; Sobngwi, Eugene; Mbanya, Jean-Claude

2013-07-01

Evidence continues to accumulate on the rising burden of diabetes mellitus at a higher pace in Africa. In a series of two papers, we sought to summarise recent evidence on diabetes and obesity in Africa based on a systematic review of studies published between January 2002 and October 2012. This first paper on the prevalence, pathogenesis and comorbidities shows that the increase in diabetes prevalence has paralleled that of obesity in Africa. Recent surveys on diabetes and obesity have been largely suboptimal. Hence, the need for more representative and robust continent-wide prevalence figures, which may be somehow achieved through pooling of existing data. Prospective studies linking environmental risk factors to disease occurrence and outcomes remain scarce, and genetic factors for diabetes or obesity have not been extensively assessed. The health consequences of diabetes are manifold, and include a complex interaction with other conditions like HIV infection and sickle cell disease/trait.

MHC-mismatched mixed chimerism restores peripheral tolerance of noncross-reactive autoreactive T cells in NOD mice

PubMed Central

Zhang, Mingfeng; Racine, Jeremy J.; Lin, Qing; Liu, Yuqing; Tang, Shanshan; Qin, Qi; Qi, Tong; Riggs, Arthur D.; Zeng, Defu

2018-01-01

Autoimmune type 1 diabetes (T1D) and other autoimmune diseases are associated with particular MHC haplotypes and expansion of autoreactive T cells. Induction of MHC-mismatched but not -matched mixed chimerism by hematopoietic cell transplantation effectively reverses autoimmunity in diabetic nonobese diabetic (NOD) mice, even those with established diabetes. As expected, MHC-mismatched mixed chimerism mediates deletion in the thymus of host-type autoreactive T cells that have T-cell receptor (TCR) recognizing (cross-reacting with) donor-type antigen presenting cells (APCs), which have come to reside in the thymus. However, how MHC-mismatched mixed chimerism tolerizes host autoreactive T cells that recognize only self-MHC–peptide complexes remains unknown. Here, using NOD.Rag1−/−.BDC2.5 or NOD.Rag1−/−.BDC12-4.1 mice that have only noncross-reactive transgenic autoreactive T cells, we show that induction of MHC-mismatched but not -matched mixed chimerism restores immune tolerance of peripheral noncross-reactive autoreactive T cells. MHC-mismatched mixed chimerism results in increased percentages of both donor- and host-type Foxp3+ Treg cells and up-regulated expression of programmed death-ligand 1 (PD-L1) by host-type plasmacytoid dendritic cells (pDCs). Furthermore, adoptive transfer experiments showed that engraftment of donor-type dendritic cells (DCs) and expansion of donor-type Treg cells are required for tolerizing the noncross-reactive autoreactive T cells in the periphery, which are in association with up-regulation of host-type DC expression of PD-L1 and increased percentage of host-type Treg cells. Thus, induction of MHC-mismatched mixed chimerism may establish a peripheral tolerogenic DC and Treg network that actively tolerizes autoreactive T cells, even those with no TCR recognition of the donor APCs. PMID:29463744

The influence of indigenous status and community indigenous composition on obesity and diabetes among Mexican adults.

PubMed

Stoddard, Pamela; Handley, Margaret A; Vargas Bustamante, Arturo; Schillinger, Dean

2011-12-01

In many high-income countries, indigenous populations bear a higher burden of obesity and diabetes than non-indigenous populations. Less is known about these patterns in lower- and middle-income countries. We assessed the hypothesis that obesity and diabetes were less prevalent among indigenous than non-indigenous adults in Mexico, home to the largest indigenous population in Latin America. We investigated socioeconomic explanations for differences. In a related line of inquiry, we examine whether adults in communities with higher versus lower percentages of indigenous residents were buffered against these conditions. We assessed whether differences were partially explained by lower development in higher-indigenous communities. Obesity was based on measured height and weight, and diabetes on a diagnosis from a healthcare professional. The analysis for obesity included 19 577 adults aged 20 and older from the Mexican Family Life Survey (2002), a nationally representative survey of Mexican households and communities; for diabetes, we restricted analysis to adults with health insurance. We used multilevel logistic regression to estimate the odds of obesity and diabetes by indigenous status and community percent indigenous. Results suggest that indigenous adults had significantly lower odds of obesity and diabetes than non-indigenous adults. This advantage was not explained by the lower socioeconomic status of indigenous individuals. A higher percentage of indigenous individuals in communities provided protection against obesity, although not for diabetes. Differences for obesity were not accounted for by community development. Findings suggest that an opportunity may exist to prevent disparities in obesity and diabetes from developing by indigenous characteristics in Mexico. Identifying the sources of protective effects of individual and community indigenous characteristics relative to these health conditions should be a priority, given global implications for

Differential impact of obesity and diabetes mellitus on survival after liver resection for colorectal cancer metastases.

PubMed

Amptoulach, Sousana; Gross, Gillis; Kalaitzakis, Evangelos

2015-12-01

Data on the potential effect of obesity and diabetes mellitus on survival after liver resection due to colorectal cancer (CRC) metastases are very limited. Patients undergoing liver resection for CRC metastases in a European institution in 2004-2011 were retrospectively enrolled. Relevant data, such as body mass index, extent of resection, chemotherapy, and perioperative outcome, were collected from medical records. The relation of obesity and diabetes mellitus with overall and disease-free survival was assessed using adjusted Cox models. Thirty of 207 patients (14.4%) included in the study were obese (BMI ≥30 kg/m(2)) and 25 (12%) had diabetes mellitus. Major hepatectomy was performed in 46%. Although both obese patients and those with diabetes had higher American Society of Anesthesiologist scores (P < 0.05 for both), neither obesity nor diabetes was significantly related to primary tumor characteristics, liver metastasis features, extent or radicality of resection, extrahepatic disease at hepatectomy, preoperative or postoperative oncologic therapy, or perioperative outcome (P > 0.05 for all). Patients were followed up for a median of 39 mo posthepatectomy (interquartile range, 13-56 mo). After adjustment for confounders, obesity was an independent predictor of improved (hazard ratio, 0.305, 95% confidence interval, 0.103-0.902) and diabetes of worse overall survival (hazard ratio, 3.298, 95% confidence interval, 1.306-8.330). Obese patients with diabetes had also worse disease-free survival compared with the rest of the cohort (P < 0.05). After hepatectomy for CRC metastases, obesity does not seem to be associated to poor outcome while diabetes mellitus has a negative impact on prognosis. Copyright © 2015 Elsevier Inc. All rights reserved.

Association of Oxidative Stress and Obesity with Insulin Resistance in Type 2 Diabetes Mellitus.

PubMed

Das, P; Biswas, S; Mukherjee, S; Bandyopadhyay, S K

2016-01-01

Oxidative stress occurs due to delicate imbalance between pro-oxidant and anti oxidant forces in our system. It has been found to be associated with many morbidities but its association with obesity and insulin resistance is still controversial. Here in our study we examined 167 patients of recent onset type 2 diabetes mellitus and 60 age sex matched non-diabetic control. Body Mass Index (BMI), abdominal circumference, fasting blood glucose, serum insulin and plasma Malondealdehyde (MDA, marker for oxidative stress) were measured in them. On the basis of BMI, subjects were divided into obese (BMI≥25) and non obese (BMI<25) groups. Insulin resistance scores were calculated by Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) method. Physical parameters (BMI, abdominal circumference) as well as levels of insulin and MDA were found to be significantly higher in subjects with diabetes than their non diabetic controls. The said parameters also showed significant difference in obese and non-obese sub groups. Insulin resistance score showed positive correlation with BMI, abdominal circumference, and plasma MDA, strength of association being highest with abdominal circumference. Plasma MDA was found to have positive correlation with physical parameters. Study concludes that, obesity mainly central type may predispose to insulin resistance and oxidative stress may be a crucial factor in its pathogenesis. Thus, oxidative stress may be the connecting link between obesity and type 2 diabetes mellitus, two on going global epidemics.

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

PubMed

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. Copyright © 2014. Published by Elsevier Inc.

Innate biology versus lifestyle behaviour in the aetiology of obesity and type 2 diabetes: the GLACIER Study.

PubMed

Poveda, Alaitz; Koivula, Robert W; Ahmad, Shafqat; Barroso, Inês; Hallmans, Göran; Johansson, Ingegerd; Renström, Frida; Franks, Paul W

2016-03-01

We compared the ability of genetic (established type 2 diabetes, fasting glucose, 2 h glucose and obesity variants) and modifiable lifestyle (diet, physical activity, smoking, alcohol and education) risk factors to predict incident type 2 diabetes and obesity in a population-based prospective cohort of 3,444 Swedish adults studied sequentially at baseline and 10 years later. Multivariable logistic regression analyses were used to assess the predictive ability of genetic and lifestyle risk factors on incident obesity and type 2 diabetes by calculating the AUC. The predictive accuracy of lifestyle risk factors was similar to that yielded by genetic information for incident type 2 diabetes (AUC 75% and 74%, respectively) and obesity (AUC 68% and 73%, respectively) in models adjusted for age, age(2) and sex. The addition of genetic information to the lifestyle model significantly improved the prediction of type 2 diabetes (AUC 80%; p = 0.0003) and obesity (AUC 79%; p < 0.0001) and resulted in a net reclassification improvement of 58% for type 2 diabetes and 64% for obesity. These findings illustrate that lifestyle and genetic information separately provide a similarly high degree of long-range predictive accuracy for obesity and type 2 diabetes.

The complexities of obesity, diabetes, and the development and progression of pancreatic cancer

PubMed Central

Bao, Bin; Wang, Zhiwei; Li, Yiwei; Kong, Dejuan; Ali, Shadan; Banerjee, Sanjeev; Ahmad, Aamir; Sarkar, Fazlul H.

2011-01-01

Pancreatic cancer (PC) is one of the most lethal malignant diseases with the worst prognosis. It is ranked as the fourth leading cause of cancer-related deaths in the United States. Many risk factors have been associated with PC. Interestingly, large numbers of epidemiological studies suggest that obesity and diabetes, especially type-2 diabetes, are positively associated with increased risk of PC. Similarly, these chronic diseases (obesity, diabetes and cancer) are also a major public health concern. In the U.S. population, 50 percent are overweight, 30 percent are medically obese and 10 percent have diabetes mellitus (DM). Therefore, obesity and DM have been considered as potential risk factors for cancers; however, the focus of this article is restricted to PC. Although the mechanisms responsible for the development of these chronic diseases leading to the development of PC are not fully understood, the biological importance of the activation of insulin, insulin like growth factor-1 (IGF-1) and its receptor (IGF-1R) signaling pathways in insulin resistance mechanism and subsequent induction of compensatory hyperinsulinemia has been proposed. Therefore, targeting insulin/IGF-1 signaling with anti-diabetic drugs for lowering blood insulin levels and reversal of insulin-resistance could be useful strategy for the prevention and/or treatment of PC. A large number of studies have demonstrated that the administration of anti-diabetic drugs such as metformin and thiazolidinediones (TZD) class of PPAR-γ agonists decreases the risk of cancers, suggesting that these agents might be useful anti-tumor agents for the treatment of PC. In this review article, we will discuss the potential roles of metformin and TZD anti-diabetic drugs as anti-tumor agents in the context of PC, and will further discuss the complexities and the possible roles of microRNAs (miRNAs) in the pathogenesis of obesity, diabetes and PC. PMID:21129444

CD28 co-stimulation restores T cell responsiveness in NOD mice by overcoming deficiencies in Rac-1/p38 mitogen-activated protein kinase signaling and IL-2 and IL-4 gene transcription.

PubMed

Zhang, J; Salojin, K V; Delovitch, T L

2001-03-01

Previously, we reported that T cell hyporesponsiveness induced by TCR ligation is causal to autoimmune diabetes in NOD mice. Neonatal CD28 co-stimulation reverses T cell hyporesponsiveness and protects NOD mice from diabetes by an IL-4-mediated mechanism, indicating that a deficiency in TCR signaling may be overcome by CD28/B7-2 co-stimulation in NOD T cells. To investigate which co-stimulation-induced signaling events mediate this protection, we analyzed the activity of Ras, Rac-1, mitogen-activated protein kinases (MAPK) and several transcription factors in TCR-activated NOD T cells in the presence or absence of CD28 co-stimulation. We show that CD28 co-stimulation restores normal TCR-induced activation of Rac-1 and p38 MAPK in NOD T cells. Deficiencies in TCR-induced nuclear expression of activating protein (AP)-1 binding proteins as well as activation of AP-1 and NF-AT in the IL-2 and IL-4 P1 promoters are also corrected by CD28 co-stimulation. Thus, CD28 co-stimulation reverses NOD T cell hyporesponsiveness by restoring TCR signaling leading to the activation of AP-1 and NF-AT during IL-2 and IL-4 gene transcription. Our findings provide additional evidence that CD28 co-stimulation amplifies signals delivered by the TCR and further explain the mechanism by which CD28 co-stimulation may protect against autoimmune diabetes.

Obesity, insulin resistance, and type 1 diabetes mellitus.

PubMed

Polsky, Sarit; Ellis, Samuel L

2015-08-01

To summarize recent studies about obesity, insulin resistance, and type 1 diabetes mellitus (T1DM). Overweight and obesity continue to be prevalent among individuals with T1DM. Obesity rates appear to have reached a plateau among children with T1DM in some parts of the world. The risk for development of T1DM is increased by obesity and may occur at an earlier age among obese individuals with a predisposition. Obesity increases the risk for comorbidities among individuals with T1DM, especially metabolic syndrome, and microvascular and macrovascular diseases. Metformin, glucagon-like peptide-1 agonist therapy, sodium glucose cotransporter-2 inhibitor therapy, and bariatric surgery may be beneficial therapies for glucose control, comorbidity management, and obesity among adults with T1DM. Insulin resistance may be improved among obese individuals with T1DM by biguanides (metformin) and glucagon-like peptide-1 agonists (exenatide). We review the last 18 months of literature on obesity, insulin resistance, and T1DM to highlight new epidemiologic results and treatments.

Genes-environment interactions in obesity- and diabetes-associated pancreatic cancer: a GWAS data analysis.

PubMed

Tang, Hongwei; Wei, Peng; Duell, Eric J; Risch, Harvey A; Olson, Sara H; Bueno-de-Mesquita, H Bas; Gallinger, Steven; Holly, Elizabeth A; Petersen, Gloria M; Bracci, Paige M; McWilliams, Robert R; Jenab, Mazda; Riboli, Elio; Tjønneland, Anne; Boutron-Ruault, Marie Christine; Kaaks, Rudolf; Trichopoulos, Dimitrios; Panico, Salvatore; Sund, Malin; Peeters, Petra H M; Khaw, Kay-Tee; Amos, Christopher I; Li, Donghui

2014-01-01

Obesity and diabetes are potentially alterable risk factors for pancreatic cancer. Genetic factors that modify the associations of obesity and diabetes with pancreatic cancer have previously not been examined at the genome-wide level. Using genome-wide association studies (GWAS) genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study of 2,028 cases and 2,109 controls to examine gene-obesity and gene-diabetes interactions in relation to pancreatic cancer risk by using the likelihood-ratio test nested in logistic regression models and Ingenuity Pathway Analysis (IPA). After adjusting for multiple comparisons, a significant interaction of the chemokine signaling pathway with obesity (P = 3.29 × 10(-6)) and a near significant interaction of calcium signaling pathway with diabetes (P = 1.57 × 10(-4)) in modifying the risk of pancreatic cancer were observed. These findings were supported by results from IPA analysis of the top genes with nominal interactions. The major contributing genes to the two top pathways include GNGT2, RELA, TIAM1, and GNAS. None of the individual genes or single-nucleotide polymorphism (SNP) except one SNP remained significant after adjusting for multiple testing. Notably, SNP rs10818684 of the PTGS1 gene showed an interaction with diabetes (P = 7.91 × 10(-7)) at a false discovery rate of 6%. Genetic variations in inflammatory response and insulin resistance may affect the risk of obesity- and diabetes-related pancreatic cancer. These observations should be replicated in additional large datasets. A gene-environment interaction analysis may provide new insights into the genetic susceptibility and molecular mechanisms of obesity- and diabetes-related pancreatic cancer.

A "Family-Based" Approach to the Treatment of Obese Type II Diabetic Patients.

ERIC Educational Resources Information Center

Wing, Rena R.; And Others

1991-01-01

Assigned 49 obese diabetic patients with obese spouses (diabetic or nondiabetic) to an alone or together (with spouses) treatment condition of behavioral weight control program. Found no significant differences in weight losses of patients at posttreatment or one-year followup, but did find that women did better when treated with their spouses,…

Diabetes mellitus with obesity is a predictor of recurrence in patients with non-metastatic renal cell carcinoma.

PubMed

Fukushima, Hiroshi; Masuda, Hitoshi; Yokoyama, Minato; Tatokoro, Manabu; Yoshida, Soichiro; Ishioka, Junichiro; Matsuoka, Yoh; Numao, Noboru; Koga, Fumitaka; Saito, Kazutaka; Fujii, Yasuhisa; Kihara, Kazunori

2013-07-01

To investigate the associations of diabetes mellitus with recurrence and prognosis after surgery for non-metastatic renal cell carcinoma and the effect modification of obesity on the above relationships. We retrospectively evaluated 543 patients with non-metastatic renal cell carcinoma (pT1-4N0M0) who underwent radical or partial nephrectomy. The association of diabetes mellitus with recurrence was analyzed using the Kaplan-Meier method and the Cox regression model. We also examined whether the above relationships were modified by obesity using subgroup analysis and tests of interaction. For subgroup analysis, the body mass index was categorized as non-obese (<25 kg/m(2)) and obese (≥25 kg/m(2)). Eighty-two patients (15.1%) had a history of diabetes mellitus. During the mean follow-up of 66.7 months, 68 patients (12.5%) developed recurrence. Although the body mass index was not associated with recurrence, diabetes mellitus was an independent predictor of recurrence in multivariate analysis (hazard ratio 2.43, P = 0.003), along with tumor diameter, grade and pathological T stage. In further subgroup analysis, the same relationship between diabetes mellitus and recurrence was clearly shown in the obese group (hazard ratio 4.07, P = 0.010), but not in the non-obese group (hazard ratio 1.95, P = 0.125). At the same time, obesity modified the effect of diabetes mellitus on recurrence with a trend (P-interaction = 0.086). In the obese group, 5-year recurrence-free survival rates were 75.3 and 91.9% for diabetes mellitus and non-diabetes mellitus patients, respectively (P < 0.001). Restricting analyses to patients with clear cell type histology did not materially change these results. Diabetes mellitus is a predictor of recurrence following surgery for non-metastatic renal cell carcinoma, especially in obese patients.

Type 2 diabetes and pre-diabetes are associated with obstructive sleep apnea in extremely obese subjects: a cross-sectional study.

PubMed

Fredheim, Jan Magnus; Rollheim, Jan; Omland, Torbjørn; Hofsø, Dag; Røislien, Jo; Vegsgaard, Kristian; Hjelmesæth, Jøran

2011-09-25

Obstructive sleep apnea (OSA) is a common yet underdiagnosed condition. The aim of our study is to test whether prediabetes and type 2 diabetes are associated with obstructive sleep apnea (OSA) in extremely obese (BMI ≥ 40 kg/m²) subjects. One hundred and thirty seven consecutive extremely obese patients (99 females) from a controlled clinical trial [MOBIL-study (Morbid Obesity treatment, Bariatric surgery versus Intensive Lifestyle intervention Study) (ClinicalTrials.gov number NCT00273104)] underwent somnography with Embletta® and a 2-hour oral glucose tolerance test (OGTT). OSA was defined by an apnea-hypopnea index (AHI) ≥ 5 events/hour. Patients were categorized into three groups according to criteria from the American Diabetes Association: normal glucose tolerance, pre-diabetes and type 2 diabetes. Multiple logistic regression analysis was used to identify possible determinants of OSA. The patients had a mean (SD) age of 43 (11) years and a body mass index (BMI) of 46.9 (5.7) kg/m². Males had significantly higher AHI than females, 29 (25) vs 12 (17) events/hour, p < 0.001. OSA was observed in 81% of men and in 55% of women, p = 0.008. Twenty-nine percent of subjects had normal glucose tolerance, 42% had pre-diabetes and 29% had type 2 diabetes. Among the patients with normal glucose tolerance 33% had OSA, while 67% of the pre-diabetic patients and 78% of the type 2 diabetic patients had OSA, p < 0.001. After adjusting for age, gender, BMI, high sensitive CRP and HOMA-IR, both pre-diabetes and type 2 diabetes were still associated with OSA, odds ratios 3.18 (95% CI 1.00, 10.07), p = 0.049 and 4.17 (1.09, 15.88), p = 0.036, respectively. Mean serum leptin was significantly lower in the OSA than in the non-OSA group, while other measures of inflammation did not differ significantly between groups. Type 2 diabetes and pre-diabetes are associated with OSA in extremely obese subjects. MOBIL-study (Morbid Obesity treatment, Bariatric surgery versus Intensive

Periodontitis is associated with diabetic retinopathy in non-obese adults.

PubMed

Song, Su Jeong; Lee, Seong-Su; Han, Kyungdo; Park, Jun-Beom

2017-04-01

Patients with diabetes retinopathy appear to show increased susceptibility to periodontal disease. This study was performed to assess the relationship between periodontitis and the prevalence of diabetic retinopathy in a large probability sample of the Korean population. A subgroup analysis was performed using body mass index <25 kg/m 2 as the criterion to evaluate the effect of obesity on this relationship. This study is based on data from the Korean National Health and Nutrition Examination Survey of the Korean population, conducted between 2008 and 2010. The presence of diabetic retinopathy in relation to demographic variables and anthropometric characteristics of the participants is presented as means with their standard errors. The presence of periodontitis and presence of retinopathy categorized by body mass index (<25 and ≥25 kg/m 2 ) were evaluated. Multiple logistic regression analyses were used to assess the associations between periodontitis and diabetic retinopathy after adjustment with variables, including age, sex, smoking, drinking, exercise, hypertension, metabolic syndrome, HbA1c, and duration of diabetes mellitus. There was a statistically significant increase in the prevalence of periodontitis in individuals who had proliferative diabetic retinopathy. The odds ratios [95% confidence intervals] of prevalence of diabetic retinopathy were 1.193 [0.757-1.881] for the whole population after adjustments with confounding factors. Subgroup analysis after adjustments with confounding factors showed that the odds ratios [95% confidence intervals] of prevalence were 2.206 [1.114-4.366] and 0.588 [0.326-1.061] among participants with body mass index <25 kg/m 2 and body mass index 37 ≥25 kg/m 2 , respectively. The diabetic retinopathy was positively associated with the presence of periodontitis in non-obese diabetic Korean adults after adjustment with confounding variables. Our findings suggest that when a periodontist finds the presence of

[Overweight, obesity and metabolic syndrome in children with type 1 diabetes melllitus].

PubMed

Luczyński, Włodzimierz; Szypowska, Agnieszka; Bossowski, Artur; Ramotowska, Anna; Rećko, Przemysław; Rembińska, Małgorzata; Tercjak, Magdalena; Blecharczyk, Bernadetta; Lachowska, Urszula; Suchoń, Paweł; Wiśniewska, Karolina; Bernatowicz, Paweł; Głowińska-Olszewska, Barbara

2010-01-01

Obesity can be an additional risk factor for developing cardiovascular diseases in patients with diabetes. Aim of the study was the assessment of overweight, obesity and other elements of the metabolic syndrome in children with type 1 diabetes mellitus. 300 children treated with insulin at least one year were enrolled in the study. In the examined group anthropometric data, data concerned with diabetes and additional laboratory tests including risk factors for cardiovascular diseases were assessed. The median age of the examined group was 13.7 years. The body mass deficiency was noted in 0.66%, normal body mass in 71.6%, overweight in 15.3% and obesity in 12.3%. The abdominal obesity was noted in 16.0% of children. The rise in the body weight between 3-6 months from the beginning of the insulin therapy and the present assessment was statistically significant. Children with normal weight had a better metabolic control in comparison to children with overweight/obesity. Girls had a higher rise in body mass index values between the time of diagnosis and the present investigation compared to boys. Higher values of blood pressure or hypertension were noted in 16.6% of children. Altogether in 25.3% of children some dyslipidemia was observed. The metabolic syndrome criteria were noted in: 28.0% - one criterion, 13.0% - two criteria, and 0.3% - three criteria. The population of children with type 1 diabetes is characterized by high frequency of overweight/obesity, abdominal obesity, dyslipidemia and hypertension. The features of metabolic syndrome are less frequent. It is worthwhile to monitor the risk for development of cardiovascular diseases in this group of children.

Antibiotics in early life alter the gut microbiome and increase disease incidence in a spontaneous mouse model of autoimmune insulin-dependent diabetes.

PubMed

Candon, Sophie; Perez-Arroyo, Alicia; Marquet, Cindy; Valette, Fabrice; Foray, Anne-Perrine; Pelletier, Benjamin; Milani, Christian; Milani, Cristian; Ventura, Marco; Bach, Jean-François; Chatenoud, Lucienne

2015-01-01

Insulin-dependent or type 1 diabetes is a prototypic autoimmune disease whose incidence steadily increased over the past decades in industrialized countries. Recent evidence suggests the importance of the gut microbiota to explain this trend. Here, non-obese diabetic (NOD) mice that spontaneously develop autoimmune type 1 diabetes were treated with different antibiotics to explore the influence of a targeted intestinal dysbiosis in the progression of the disease. A mixture of wide spectrum antibiotics (i.e. streptomycin, colistin and ampicillin) or vancomycin alone were administered orally from the moment of conception, treating breeding pairs, and during the postnatal and adult life until the end of follow-up at 40 weeks. Diabetes incidence significantly and similarly increased in male mice following treatment with these two antibiotic regimens. In NOD females a slight yet not significant trend towards an increase in disease incidence was observed. Changes in gut microbiota composition were assessed by sequencing the V3 region of bacterial 16S rRNA genes. Administration of the antibiotic mixture resulted in near complete ablation of the gut microbiota. Vancomycin treatment led to increased Escherichia, Lactobacillus and Sutterella genera and decreased members of the Clostridiales order and Lachnospiraceae, Prevotellaceae and Rikenellaceae families, as compared to control mice. Massive elimination of IL-17-producing cells, both CD4+TCRαβ+ and TCRγδ+ T cells was observed in the lamina propria of the ileum and the colon of vancomycin-treated mice. These results show that a directed even partial ablation of the gut microbiota, as induced by vancomycin, significantly increases type 1 diabetes incidence in male NOD mice thus prompting for caution in the use of antibiotics in pregnant women and newborns.

Th17 polarized cells from nonobese diabetic mice following mycobacterial adjuvant immunotherapy delay type 1 diabetes.

PubMed

Nikoopour, Enayat; Schwartz, Jordan A; Huszarik, Katrina; Sandrock, Christian; Krougly, Olga; Lee-Chan, Edwin; Singh, Bhagirath

2010-05-01

IL-17-producing T cells are regarded as potential pathogenic T cells in the induction of autoimmune diseases. Previously, we have shown that injection of adjuvants containing Mycobacterium, such as CFA or bacillus Calmette-Guérin, can prevent type 1 diabetes in NOD mice. We injected NOD mice with mycobacterial products s.c. and analyzed the IL-17-producing cells from the draining lymph nodes and spleen by restimulating whole-cell populations or CD4(+) T cells in vitro with or without IL-17-polarizing cytokines. Mice receiving CFA had a concomitant rise in the level of IL-17, IL-22, IL-10, and IFN-gamma in the draining lymph node and spleen. Adoptive transfer of splenocytes from CFA-injected NOD mice polarized with TGF-beta plus IL-6 or IL-23 delayed the development of diabetes in recipient mice. IL-17-producing cells induced by CFA maintained their IL-17-producing ability in the recipient mice. Injection of CFA also changed the cytokine profile of cells in pancreatic tissue by increasing IL-17, IL-10, and IFN-gamma cytokine gene expression. We suggest that the rise in the level of IL-17 after adjuvant therapy in NOD mice has a protective effect on type 1 diabetes development.

Maternal overweight and obesity are associated with increased risk of type 1 diabetes in offspring of parents without diabetes regardless of ethnicity.

PubMed

Hussen, Hozan I; Persson, Martina; Moradi, Tahereh

2015-07-01

The incidence of type 1 diabetes in children is increasing in Sweden, as is the prevalence of maternal overweight/obesity. Therefore, the aim of this study was to investigate if maternal overweight/obesity increases the risk of type 1 diabetes in offspring of parents with and without diabetes, and of different ethnicities. The study cohort comprised 1,263,358 children, born in Sweden between 1992 and 2004. Children were followed from birth until diagnosis of type 1 diabetes, emigration, death or end of follow-up in 2009, whichever occurred first. First trimester maternal BMI was calculated (kg/m(2)). Poisson regression was used to calculate incidence rate ratios (IRRs) with 95% CI for type 1 diabetes in the offspring. The risk of type 1 diabetes was increased in offspring of parents with any type of diabetes regardless of parental ethnicity. High first trimester maternal BMI was associated with increased risk of type 1 diabetes only in offspring of parents without diabetes (IRR 1.33 [95% CI 1.20, 1.48]). Increasing incidence of type 1 diabetes in children with non-diabetic parents may partly be explained by increasing prevalence of maternal overweight/obesity.

The effect of educational status on the relationship between obesity and risk of type 2 diabetes.

PubMed

Madjid, I S; Backholer, K; Williams, E D; Magliano, D J; Shaw, J E; Peeters, A

2014-01-01

Obesity trends are likely to increase social disparities in diabetes. The magnitude of this effect depends on the strength of the relationship between obesity and diabetes across categories of disadvantage. This study aims to test the hypothesis that education level moderates the association between obesity and fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), HbA1c level, and diabetes prevalence. We used the baseline data from the Australian Obesity, Diabetes, and Lifestyle study in 2000 (n = 8646). We performed multiple linear regression analysis adjusted for confounding factors and stratified by education level. Body mass index (BMI) and waist circumference (WC) were positively associated with FPG, 2hPG, HbA1c and prevalence of diabetes. No moderating effect of education on these relationships was observed in the total population. In never smokers free of diagnosed diabetes at baseline the association of WC with 2hPG and HbA1c and of BMI with HbA1c was stronger in those with a lower level of education. Overall, these results suggest that the association between obesity and diabetes risk is independent of educational status. However, inconsistent results suggest that further analyses of an adequately powered longitudinal study of never smokers free of diabetes would be useful to further explore this hypothesis. © 2014 Asian Oceanian Association for the Study of Obesity . Published by Elsevier Ltd. All rights reserved.

Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling

PubMed Central

Yadav, Hariom; Quijano, Celia; Kamaraju, Anil K.; Gavrilova, Oksana; Malek, Rana; Chen, Weiping; Zerfas, Patricia; Zhigang, Duan; Wright, Elizabeth C.; Stuelten, Christina; Sun, Peter; Lonning, Scott; Skarulis, Monica; Sumner, Anne E.; Finkel, Toren; Rane, Sushil G.

2011-01-01

SUMMARY Imbalances in glucose and energy homeostasis are at the core of the worldwide epidemic of obesity and diabetes. Here, we illustrate an important role of the TGF-β/Smad3 signaling pathway in regulating glucose and energy homeostasis. Smad3 deficient mice are protected from diet-induced obesity and diabetes. Interestingly, the metabolic protection is accompanied by Smad3−/− white adipose tissue acquiring the bioenergetic and gene expression profile of brown fat/skeletal muscle. Smad3−/− adipocytes demonstrate a marked increase in mitochondrial biogenesis, with a corresponding increase in basal respiration, and Smad3 acts as a repressor of PGC-1α expression. We observe significant correlation between TGF-β1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-β1 signaling protects mice from obesity, diabetes and hepatic steatosis. Together, these results demonstrate that TGF-β signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-β1 activity might be an effective treatment strategy for obesity and diabetes. PMID:21723505

Inflammation in maternal obesity and gestational diabetes mellitus.

PubMed

Pantham, P; Aye, I L M H; Powell, T L

2015-07-01

The prevalence of maternal obesity is rising rapidly worldwide and constitutes a major obstetric problem, increasing mortality and morbidity in both mother and offspring. Obese women are predisposed to pregnancy complications such as gestational diabetes mellitus (GDM), and children of obese mothers are more likely to develop cardiovascular and metabolic disease in later life. Maternal obesity and GDM may be associated with a state of chronic, low-grade inflammation termed "metainflammation", as opposed to an acute inflammatory response. This inflammatory environment may be one mechanism by which offspring of obese women are programmed to develop adult disorders. Herein we review the evidence that maternal obesity and GDM are associated with changes in the maternal, fetal and placental inflammatory profile. Maternal inflammation in obesity and GDM may not always be associated with fetal inflammation. We propose that the placenta 'senses' and adapts to the maternal inflammatory environment, and plays a central role as both a target and producer of inflammatory mediators. In this manner, maternal obesity and GDM may indirectly program the fetus for later disease by influencing placental function. Published by Elsevier Ltd.

Cardiac abnormalities in youth with obesity and type 2 diabetes

USDA-ARS?s Scientific Manuscript database

Childhood obesity has been linked to cardiovascular disease (CVD) risk in adulthood. Of great concern is the expected increase in the population's CVD burden in relation to childhood obesity. This is compounded by the risk related to chronic hyperglycemia exposure in youth with type 2 diabetes. We h...

Does exposure to hyperglycaemia in utero increase the risk of obesity and diabetes in the offspring? A critical reappraisal.

PubMed

Donovan, L E; Cundy, T

2015-03-01

The idea that exposure to hyperglycaemia in utero is an important factor in the development of obesity and diabetes in the offspring has become entrenched as popular belief. To appraise the literature supporting this hypothesis in the light of recent studies that have clarified the main drivers of obesity in children and adolescents. A review of published evidence from animal studies, human observational studies, systematic reviews and experimental trials that address the impact of diabetes (Types 1 and 2, genetic or gestational) on the future risk of obesity and/or glucose intolerance in the offspring. Some animal studies support a relationship between exposure to hyperglycaemia in utero and future development of obesity and diabetes, but the results are inconsistent. Most of the human studies claiming to show a relationship have not taken into account important known confounders, such as maternal and paternal BMI. Evidence supporting a dose-response relationship between maternal hyperglycaemia exposure and obesity and diabetes in the offspring is weak, and there is no convincing evidence that treating gestational diabetes reduces the later risk of offspring obesity or glucose intolerance. Exposure to hyperglycaemia in utero has minimal direct effect on the later risk of obesity and Type 2 diabetes. The increased risk of obesity in the offspring of women with Type 2 or gestational diabetes can be explained by confounding factors, such as parental obesity. © 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.

Personalized exercise for adolescents with diabetes or obesity.

PubMed

Faulkner, Melissa Spezia; Michaliszyn, Sara Fleet; Hepworth, Joseph T; Wheeler, Mark D

2014-01-01

This study examined adherence to a personalized, community-based exercise intervention by sedentary adolescents with type 1 or type 2 diabetes or those with obesity. We conducted a pretest-posttest investigation to explore the application of an individualized exercise prescription based upon current fitness level for 39 adolescents (20 with type 1 diabetes, 9 with type 2 diabetes, and 10 obese) over 16 weeks in community settings. Subjects were recruited from a university-based pediatric endocrinology clinic in the southwestern United States. Adherence to the exercise prescription was monitored using accelerometers over the entire intervention period. Moderate-to-vigorous physical activity (MVPA) levels significantly increased over sedentary baseline values (p < .001), but the average of 42.5 ± 22.1 min/day of MVPA determined at the end of the study was still less than the recommended 60 min/day. Perceptions of health were significantly increased for the total group following the intervention (p = .008). For those with type 1 diabetes, there was a significant association between MVPA duration and percentage change in HbA1c (r = -.526, p = .02). Recruitment and retention of adolescent participation in daily exercise is challenging. Personalized approaches that include adolescent choices with family support and ongoing motivation can improve individual exercise adherence and a sense of personal health.

Prevalence of obesity and systemic hypertension among diabetes mellitus patients attending an out-patient diabetes clinic in a Ghanaian Teaching Hospital.

PubMed

Mogre, Victor; Abedandi, Robert; Salifu, Zenabankara S

2014-01-01

Diabetes Mellitus is now a prevalent disease in both developed and developing countries. Overweight/obesity and hypertension are potential modifiable risk factors for diabetes mellitus and persist during the course of the disease. This study was aimed at reporting the prevalence of overweight/obesity and systemic hypertension and their association to blood glucose levels in persons with diabetes mellitus attending a diabetic clinic in Ghanaian Teaching Hospital. This cross-sectional study was conducted among 100 previously diagnosed diabetes mellitus patients attending a diabetic clinic at the Tamale Teaching Hospital, Ghana. Anthropometric variables of age, weight and height were measured with appropriate instruments, computed into BMI and classified according to WHO classifications. Systolic and diastolic blood pressures were measured by an appropriate instrument and classified by WHO standards. Fasting plasma glucose levels of the study participants were recorded from their personal health folder. All data was analysed by GraphPad prism version 5. In general, 7.0% of the participants were underweight and 32.0% were overweight or obese. The mean±SD weight, height and BMI of the participants were 67.53±13.32, 1.68±0.12 and 24.18±5.32. Twenty-one percent of the studied participants were hypertensive. Mean±SD fasting plasma glucose of 7.94±2.82 was observed among the diabetic patients. As the prevalence of hyperglycaemia was higher among patients aged ≤40 years (88.9% vs. 75.8%), normoglycaemia (11.1% vs. 24.2%) was higher among those over 40 years. The differences were not significant. The prevalence of hyperglycaemia was significantly higher in participants with overweight/obese (0.0% vs. 41.6%, p<0.0001) than those with underweight (26.1% vs. 1.3%, p=0.0005) and normal weight (73.9% vs. 57.1%, p=0.2228). A high prevalence of overweight/obesity and systemic hypertension was found. Hyperglycaemia was more prevalent among overweight/obese participants

Diabetes, Obesity, and Other Medical Diseases - Is Surgery the Answer?

PubMed

Pohl, Dieter; Bloomenthal, Aaron

2017-03-01

For many physicians, the concept of surgery as the best treatment for a medical disease such as diabetes, cardiovascular problems, hyperlipidemia, sleep apnea, hepatosteatosis, GERD, osteoarthritis, psoriasis, rheumatoid arthritis, or infertility, still sounds wrong and just a ploy by surgeons to increase their business. Since 2011, however, several non-surgical societies have recommended Weight Loss Surgery - The International Diabetes Federation, The American Diabetes Association, American Heart Association, and Obesity Society in 2015 for patients with body mass index (BMI) greater than 35 and diabetes, and to decrease cardiovascular risk factors.1 The concept is to treat the common underlying problem, which is obesity, with the most effective method for immediate and long-term weight loss, which is surgery. The term "metabolic" surgery was therefore coined to accurately describe the effects of weight loss (bariatric) surgery. Our specialty society named itself the American Society for Metabolic and Bariatric Surgery (ASMBS). [Full article available at http://rimed.org/rimedicaljournal-2017-03.asp].

ELECTROCARDIOGRAPHIC ABNORMALITIES AMONG MEXICAN AMERICANS: CORRELATIONS WITH DIABETES, OBESITY, AND THE METABOLIC SYNDROME.

PubMed

Queen, Saulette R; Smulevitz, Beverly; Rentfro, Anne R; Vatcheva, Kristina P; Kim, Hyunggun; McPherson, David D; Hanis, Craig L; Fisher-Hoch, Susan P; McCormick, Joseph B; Laing, Susan T

2012-04-01

Resting ischemic electrocardiographic abnormalities have been associated with cardiovascular mortality. Simple markers of abnormal autonomic tone have also been associated with diabetes, obesity, and the metabolic syndrome in some populations. Data on these electrocardiographic abnormalities and correlations with coronary risk factors are lacking among Mexican Americans wherein these conditions are prevalent. This study aimed to evaluate the prevalent resting electrocardiographic abnormalities among community-dwelling Mexican Americans, and correlate these findings with coronary risk factors, particularly diabetes, obesity, and the metabolic syndrome. Study subjects (n=1280) were drawn from the Cameron County Hispanic Cohort comprised of community-dwelling Mexican Americans living in Brownsville, Texas at the United States-Mexico border. Ischemic electrocardiographic abnormalities were defined as presence of ST/T wave abnormalities suggestive of ischemia, abnormal Q waves, and left bundle branch block. Parameters that reflect autonomic tone, such as heart rate-corrected QT interval and resting heart rate, were also measured. Ischemic electrocardiographic abnormalities were more prevalent among older persons and those with hypertension, diabetes, obesity, and the metabolic syndrome. Subjects in the highest quartiles of QTc interval and resting heart rate were also more likely to be diabetic, hypertensive, obese, or have the metabolic syndrome. Among Mexican Americans, persons with diabetes, obesity, and the metabolic syndrome were more likely to have ischemic electrocardiographic abnormalities, longer QTc intervals, and higher resting heart rates. A resting electrocardiogram can play a complementary role in the comprehensive evaluation of cardiovascular risk in this minority population.

Elimination of the NLRP3-ASC Inflammasome Protects against Chronic Obesity-Induced Pancreatic Damage

PubMed Central

Youm, Yun-Hee; Adijiang, Ayinuer; Vandanmagsar, Bolormaa; Burk, David; Ravussin, Anthony

2011-01-01

Clinical evidence that the blockade of IL-1β in type-2 diabetic patients improves glycemia is indicative of an autoinflammatory mechanism that may trigger adiposity-driven pancreatic damage. IL-1β is a key contributor to the obesity-induced inflammation and subsequent insulin resistance, pancreatic β-cell dysfunction, and the onset of type 2 diabetes. Our previous studies demonstrated that the ceramides activate the Nod-like receptor family, pyrin domain containing 3 (Nlrp3) inflammasome to cause the generation of mature IL-1β and ablation of the Nlrp3 inflammasome in diet-induced obesity improves insulin signaling. However, it remains unclear whether the posttranslational processing of active IL-1β in pancreas is regulated by the NLRP3 inflammasome or whether the alternate mechanisms play a dominant role in chronic obesity-induced pancreatic β-cell exhaustion. Here we show that loss of ASC, a critical adaptor required for the assembly of the NLRP3 and absent in melanoma 2 inflammasome substantially improves the insulin action. Surprisingly, despite lower insulin resistance in the chronically obese NLRP3 and ASC knockout mice, the insulin levels were substantially higher when the inflammasome pathway was eliminated. The obesity-induced increase in maturation of pancreatic IL-1β and pancreatic islet fibrosis was dependent on the NLRP3 inflammasome activation. Furthermore, elimination of NLRP3 inflammasome protected the pancreatic β-cells from cell death caused by long-term high-fat feeding during obesity with significant increase in the size of the islets of Langerhans. Collectively, this study provides direct in vivo evidence that activation of the NLRP3 inflammasome in diet-induced obesity is a critical trigger in causing pancreatic damage and is an important mechanism of progression toward type 2 diabetes. PMID:21862613

NOD2: a potential target for regulating liver injury.

PubMed

Body-Malapel, Mathilde; Dharancy, Sébastien; Berrebi, Dominique; Louvet, Alexandre; Hugot, Jean-Pierre; Philpott, Dana J; Giovannini, Marco; Chareyre, Fabrice; Pages, Gilles; Gantier, Emilie; Girardin, Stephen E; Garcia, Irène; Hudault, Sylvie; Conti, Filoména; Sansonetti, Philippe J; Chamaillard, Mathias; Desreumaux, Pierre; Dubuquoy, Laurent; Mathurin, Philippe

2008-03-01

The recent discovery of bacterial receptors such as NOD2 that contribute to crosstalk between innate and adaptive immune systems in the digestive tract constitutes an important challenge in our understanding of liver injury mechanisms. The present study focuses on NOD2 functions during liver injury. NOD2, TNF-alpha and IFN-gamma mRNA were quantified using real-time PCR in liver samples from patients and mice with liver injury. We evaluated the susceptibility of concanavalin A (ConA) challenge in NOD2-deficient mice (Nod2-/-) compared to wild-type littermates. We tested the effect of muramyl dipeptide (MDP), the specific activator of NOD2, on ConA-induced liver injury in C57BL/6 mice. We studied the cellular distribution and the role of NOD2 in immune cells and hepatocytes. We demonstrated that NOD2, TNF-alpha and IFN-gamma were upregulated during liver injury in mice and humans. Nod2-/- mice were resistant to ConA-induced hepatitis compared to their wild-type littermates, through reduced IFN-gamma production by immune cells. Conversely, administration of MDP exacerbated ConA-induced liver injury. MDP was a strong inducer of IFN-gamma in freshly isolated human PBMC, splenocytes and hepatocytes. Our study supports the hypothesis that NOD2 contributes to liver injury via a regulatory mechanism affecting immune cells infiltrating the liver and hepatocytes. Taken together, our results indicate that NOD2 may represent a new therapeutic target in liver diseases.

Caloric restriction or telmisartan control dyslipidemia and nephropathy in obese diabetic Zücker rats

PubMed Central

2014-01-01

Background The obese Zücker diabetic fatty male rat (ZDF:Gmi™-fa) is an animal model of type II diabetes associated with obesity and related metabolic disturbances like dyslipidaemia and diabetic nephropathy. In addition, diabetic dyslipidaemia has been linked to vascular and glomerular damage too. Dietary fat restriction is a current strategy to tackle obesity and, telmisartan, as a renoprotective agent, may mediate cholesterol efflux by activating PPARγ. To test the hypothesis that both therapeutical alternatives may influence dyslipidaemia and nephropathy in the ZDF rat, we studied their effect on development of diabetes. Methods Male Zücker Diabetic Fatty (ZDF) rats received a low-calorie diet, vehicle or telmisartan for 9 weeks. Blood samples were obtained for analyses of lipids and lipoproteins, LDL-oxidisability, HDL structural and functional properties. Urinalysis was carried out to estimate albumin loss. At the end of the experimental period, rats were sacrificed, liver extracted and APOA1 mRNA quantified. Results Results indicated that low-calorie diet and telmisartan can slower the onset of overt hyperglycaemia and renal damage assessed as albuminuria. Both interventions decreased the oxidative susceptibility of LDL and hepatic APOA1 mRNA expression but only dietary restriction lowered hyperlipidaemia. Conclusion Either a dietary or pharmacologic interventions with telmisartan have important beneficial effects in terms of LDL oxidative susceptibility and progression of albuminuria in obesity related type II diabetes. PMID:24468233

[Urinary excretion of catecholamines in obese subjects and in diabetics (author's transl)].

PubMed

Giorgino, R; Nardelli, G M; Scardapane, R

1976-03-01

95 obese subjects, 40 diabetics and 22 normal controls were investigated. The weight of all obese subjects was at least 20% higher than the ideal weight. Catecholamine excretion was determined a few days after hospitalization to minimize the influence of environmental changes. Spectrofluorimetric estimation of adrenaline and noradrenaline in the urine was carried out according to the method of von Euler and Lihajko. Statistical analysis of the results showed a significant increase in both adrenaline and noradrenaline excretion in the group of obeses subjects compared with the diabetics. The increased catecholamine excretion may represent the response of the adrenal medulla to the stress of the disease. Such an increase may be responsible for perpheral insulin resistence and hence acts as a diabetogenic factor. The results obtained emphasize the influence of catecholamines on insulin responsiveness, possibly constituting a major contribution to the diabetic state.

NLR Nod1 signaling promotes survival of BCR-engaged mature B cells through up-regulated Nod1 as a positive outcome

PubMed Central

Asano, Masanao; Li, Yue-Sheng; Núñez, Gabriel

2017-01-01

Although B cell development requires expression of the B cell antigen receptor (BCR), it remains unclear whether engagement of self-antigen provides a positive impact for most B cells. Here, we show that BCR engagement by self-ligand during development in vivo results in up-regulation of the Nod-like receptor member Nod1, which recognizes the products of intestinal commensal bacteria. In anti-thymocyte/Thy-1 autoreactive BCR knock-in mice lacking self–Thy-1 ligand, immunoglobulin light chain editing occurred, generating B cells with up-regulated Nod1, including follicular and marginal zone B cells with natural autoreactivity. This BCR editing with increased Nod1 resulted in preferential survival. In normal adult mice, most mature B cells are enriched for Nod1 up-regulated cells, and signaling through Nod1 promotes competitive survival of mature B cells. These findings demonstrate a role for microbial products in promoting survival of mature B cells through up-regulated Nod1, providing a positive effect of BCR engagement on development of most B cells. PMID:28878001

Microstructural abnormalities in white and gray matter in obese adolescents with and without type 2 diabetes.

PubMed

Nouwen, Arie; Chambers, Alison; Chechlacz, Magdalena; Higgs, Suzanne; Blissett, Jacqueline; Barrett, Timothy G; Allen, Harriet A

2017-01-01

In adults, type 2 diabetes and obesity have been associated with structural brain changes, even in the absence of dementia. Some evidence suggested similar changes in adolescents with type 2 diabetes but comparisons with a non-obese control group have been lacking. The aim of the current study was to examine differences in microstructure of gray and white matter between adolescents with type 2 diabetes, obese adolescents and healthy weight adolescents. Magnetic resonance imaging data were collected from 15 adolescents with type 2 diabetes, 21 obese adolescents and 22 healthy weight controls. Volumetric differences in the gray matter between the three groups were examined using voxel based morphology, while tract based spatial statistics was used to examine differences in the microstructure of the white matter. Adolescents with type 2 diabetes and obese adolescents had reduced gray matter volume in the right hippocampus, left putamen and caudate, bilateral amygdala and left thalamus compared to healthy weight controls. Type 2 diabetes was also associated with significant regional changes in fractional anisotropy within the corpus callosum, fornix, left inferior fronto-occipital fasciculus, left uncinate, left internal and external capsule. Fractional anisotropy reductions within these tracts were explained by increased radial diffusivity, which may suggest demyelination of white matter tracts. Mean diffusivity and axial diffusivity did not differ between the groups. Our data shows that adolescent obesity alone results in reduced gray matter volume and that adolescent type 2 diabetes is associated with both white and gray matter abnormalities.

Role of PUFAs, the precursors of endocannabinoids, in human obesity and type 2 diabetes.

PubMed

Dain, Alejandro; Repossi, Gaston; Das, Undurti N; Eynard, Aldo Renato

2010-06-01

Polyunsaturated fatty acids (PUFAs) serve as precursors of the endocannabinoids (ECs) that are bioactive lipids molecules. Recent studies revealed that ECs participate in several physiological and pathological processes including obesity and type 2 diabetes mellitus. Here we review the experimental and clinical aspects of the role of endocannabinoids in obesity and type 2 diabetes mellitus and the modification of the endocannabinoids by exogenously administered PUFAs. Based on these evidences, we propose that the endocannabinoid system (ECS) can be modulated by exogenous manipulation of PUFAs that could help in the prevention and management of human diseases such as obesity, metabolic syndrome and type 2 diabetes mellitus.

Serum adiposity-induced biomarkers in obese and lean children with recently diagnosed autoimmune type 1 diabetes.

PubMed

Redondo, M J; Rodriguez, L M; Haymond, M W; Hampe, C S; Smith, E O; Balasubramanyam, A; Devaraj, S

2014-12-01

Obesity increases the risk of cardiovascular disease and diabetic complications in type 1 diabetes. Adipokines, which regulate obesity-induced inflammation, may contribute to this association. We compared serum adipokines and inflammatory cytokines in obese and lean children with new-onset autoimmune type 1 diabetes. We prospectively studied 32 lean and 18 obese children (age range: 2-18 yr) with new-onset autoimmune type 1 diabetes and followed them for up to 2 yr. Serum adipokines [leptin, total and high molecular weight (HMW) adiponectin, omentin, resistin, chemerin, visfatin], cytokines [interferon (IFN)-gamma, interleukin (IL)-10, IL-12, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha] and C-reactive protein (CRP) were measured at a median of 7 wk after diagnosis (range: 3-16 wk). Lean children were 71.9% non-Hispanic White, 21.9% Hispanic, and 6.3% African-American, compared with 27.8, 55.6, and 16.7%, respectively, for obese children (p = 0.01). Compared with lean children, obese children had significantly higher serum leptin, visfatin, chemerin, TNF-alpha and CRP, and lower total adiponectin and omentin after adjustment for race/ethnicity and Tanner stage. African-American race was independently associated with higher leptin among youth ≥10 yr (p = 0.007). Leptin levels at onset positively correlated with hemoglobin A1c after 1-2 yr (p = 0.0001) independently of body mass index, race/ethnicity, and diabetes duration. Higher TNF-alpha was associated with obesity and female gender, after adjustment for race/ethnicity (p = 0.0003). Obese children with new-onset autoimmune type 1 diabetes have a proinflammatory profile of circulating adipokines and cytokines that may contribute to the development of cardiovascular disease and diabetic complications. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Obesity measures, metabolic profiles and dietary fatty acids in lean and obese postmenopausal diabetic Asian Indian women.

PubMed

Ghosh, Arnab

2009-03-01

The present investigation was aimed to compare anthropometric, metabolic and dietary fatty acids profiles in lean and obese postmenopausal diabetic Asian Indian women. A total of 125 postmenopausal Asian Indian women (Group I: lean postmenopausal control, n = 50; Group II: lean postmenopausal diabetic, n = 40 and Group III: obese postmenopausal diabetic, n = 35) aged 40 years and above were studied. Anthropometric [height, weight, waist (WC) and hip circumference] metabolic [total cholesterol (TC), triglyceride (TG), high (HDL), low density lipoprotein (LDL) and fasting plasma glucose (FPG)] and dietary profiles were collected from each participant. Body mass index (BMI), waist-hip ratio (WHR) and conicity index (CI) were subsequently computed. Obesity was defined as women having a BMI > or = 25 kg/m2. An open-ended 24 h food recall schedule was used to collect nutrient information from each participant. Daily intake of nutrients including saturated (SFA), monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA) were also estimated on weekly and monthly basis. Group I had significantly lower mean than both Group II and Group III for WC, WHR, CI, TC, TG, LDL, FPG and total carbohydrates. On the other hand, Group I had significantly greater mean than both Group II and Group III for UFA/SFA, MUFA/SFA and PUFA/SFA. Discriminant analysis had revealed that overall 88% of all cases were correctly (positively) classified in three groups using fatty acids and their ratios. It seems reasonable to argue that while dealing with postmenopausal diabetic women, clinicians should consider obesity measures, lipids and dietary fatty acids simultaneously to better comprehend clinical assessments and risk stratification.

Bariatric surgery for people with diabetes and morbid obesity: an evidence-based analysis.

PubMed

2009-01-01

In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry's newly released Diabetes Strategy.After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/masabout.html,DIABETES STRATEGY EVIDENCE PLATFORM: Summary of Evidence-Based AnalysesContinuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based AnalysisBehavioural Interventions for Type 2 Diabetes: An Evidence-Based AnalysisBARIATRIC SURGERY FOR PEOPLE WITH DIABETES AND MORBID OBESITY: An Evidence-Based SummaryCommunity-Based Care for the Management of Type 2 Diabetes: An Evidence-Based AnalysisHome Telemonitoring for Type 2 Diabetes: An Evidence-Based AnalysisApplication of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario The purpose of this evidence-based analysis was to examine the effectiveness and cost-effectiveness of bariatric surgery for the management of diabetes in morbidly obese people. This report summarized evidence specific to bariatric surgery and the

TLR4, NOD1 and NOD2 mediate immune recognition of putative newly identified periodontal pathogens.

PubMed

Marchesan, Julie; Jiao, Yizu; Schaff, Riley A; Hao, Jie; Morelli, Thiago; Kinney, Janet S; Gerow, Elizabeth; Sheridan, Rachel; Rodrigues, Vinicius; Paster, Bruce J; Inohara, Naohiro; Giannobile, William V

2016-06-01

Periodontitis is a polymicrobial inflammatory disease that results from the interaction between the oral microbiota and the host immunity. Although the innate immune response is important for disease initiation and progression, the innate immune receptors that recognize both classical and putative periodontal pathogens that elicit an immune response have not been elucidated. By using the Human Oral Microbe Identification Microarray (HOMIM), we identified multiple predominant oral bacterial species in human plaque biofilm that strongly associate with severe periodontitis. Ten of the identified species were evaluated in greater depth, six being classical pathogens and four putative novel pathogens. Using human peripheral blood monocytes (HPBM) and murine bone-marrow-derived macrophages (BMDM) from wild-type (WT) and Toll-like receptor (TLR)-specific and MyD88 knockouts (KOs), we demonstrated that heat-killed Campylobacter concisus, Campylobacter rectus, Selenomonas infelix, Porphyromonas endodontalis, Porphyromonas gingivalis, and Tannerella forsythia mediate high immunostimulatory activity. Campylobacter concisus, C. rectus, and S. infelix exhibited robust TLR4 stimulatory activity. Studies using mesothelial cells from WT and NOD1-specific KOs and NOD2-expressing human embryonic kidney cells demonstrated that Eubacterium saphenum, Eubacterium nodatum and Filifactor alocis exhibit robust NOD1 stimulatory activity, and that Porphyromonas endodontalis and Parvimonas micra have the highest NOD2 stimulatory activity. These studies allowed us to provide important evidence on newly identified putative pathogens in periodontal disease pathogenesis showing that these bacteria exhibit different immunostimulatory activity via TLR4, NOD1, and NOD2 (Clinicaltrials.gov NCT01154855). © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

TLR4, NOD1 and NOD2 Mediate Immune Recognition of Putative Newly-Identified Periodontal Pathogens

PubMed Central

Schaff, Riley A.; Hao, Jie; Morelli, Thiago; Kinney, Janet S.; Gerow, Elizabeth; Sheridan, Rachel; Rodrigues, Vinicius; Paster, Bruce J.; Inohara, Naohiro; Giannobile, William V.

2015-01-01

SUMMARY Periodontitis is a polymicrobial inflammatory disease that results from the interaction between the oral microbiota and the host immunity. While the innate immune response is important for disease initiation and progression, the innate immune receptors that recognize both classical and putative periodontal pathogens that elicit an immune response have not been elucidated. By using the Human Oral Microbe Identification Microarray (HOMIM), we identified multiple predominant oral bacterial species in human plaque biofilm that strongly associate with severe periodontitis. Ten of the identified species were evaluated in greater depth, 6 being classical pathogens and 4 putative novel pathogens. Using human peripheral blood monocytes (HPBM) and murine bone marrow–derived macrophages (BMDM) from wild-type (WT) and toll-like receptor (TLR)-specific and MyD88 knockouts (KOs), we demonstrated that heat-killed Campylobacter concisus, Campylobacter rectus, Selenomonas infelix, Porphyromonas endodontalis, Porphyromonas gingivalis, and Tannerella forsythia mediate high immunostimulatory activity. C. concisus, C. rectus, and S. infelix exhibited robust TLR4 stimulatory activity. Studies using mesothelial cells from WT and NOD1-specific KOs and NOD2-expressing human embryonic kidney (HEK) cells demonstrated that Eubacterium saphenum, Eubacterium nodatum and Filifactor alocis exhibit robust NOD1 stimulatory activity, and that Porphyromonas endodontalis and Parvimonas micra have the highest NOD2-stimulatory activity. These studies allowed us to provide important evidence on newly-identified putative pathogens in periodontal disease pathogenesis showing that these bacteria exhibit different immunostimulatory activity via TLR4, NOD1, and NOD2 (Clinicaltrials.gov NCT01154855). PMID:26177212

Physical training in the prophylaxis and treatment of obesity, hypertension and diabetes.

PubMed

Krotkiewski, M

1983-01-01

The results of physical training in 600 obese and 100 diabetic patients are described and discussed. Three months of physical training (55 min 3 times/week) without dietary restriction did not result in any change in body weight and composition either in obese or diabetic female patients. However, the male patients remained their body weight unchanged and body fat decreased and lean body mass increased after training. The combination of exercise with a very low calorie diet in obese women neither prevents the erosion of lean body mass nor the diet-induced decrease in oxygen uptake. Local exercise could not evoke a local decrease in the thickness of adipose tissue. The addition of physical training to the low calorie diet leads to better social and psychological compliance and a more equal distribution of adipose tissue. A close relationship has been found between the muscle morphology and glucose metabolism in obese patients. Insulin concentration appeared to be positively correlated to the percentage of FTb fibers and inversely correlated to the capillary density. The decrease in the percentage of FTb muscle fibers and the increase in the number of capillaries were correlated to the decrease in plasma insulin levels. The capillary density appeared to be reduced with decreasing degrees of glucose tolerance. In patients with diabetes type I it was found diminished so much that the diffusion distance in muscle increased after training. The most interesting results related to glucose metabolism were found otherwise as follows: The sum of insulin (276.4 +/- 20.1 before and 255.1 +/- 19.0 after p less than 0.05) and glucose levels (but not fasting values) decreased (28.3 +/- 1.6 before and 27.8 +/- 1.4 after p less than 0.01) after training in obesity. In obese and diabetic patients with initially high insulin values physical training resulted in a decrease in insulin level, while in those patients with initially low values it resulted in an increase. As judged from the

Obese adolescents with type 2 diabetes perform worse than controls on cognitive and behavioral assessments.

PubMed

Brady, Cassandra C; Vannest, Jennifer J; Dolan, Lawrence M; Kadis, Darren S; Lee, Gregory R; Holland, Scott K; Khoury, Jane C; Shah, Amy S

2017-06-01

Children with type 1 diabetes demonstrate worse cognitive performance compared with their peers. Little is known regarding the cognitive and behavioral performance in obese adolescents with type 2 diabetes. Cross sectional evaluation of 20 obese adolescents with type 2 diabetes and 20 healthy adolescents was performed in Cincinnati, Ohio. Cognitive tests that included measures of processing speed, working memory, verbal and semantic fluency and parent reports of executive function and problem behavior were compared. Academic achievement and the relationship between cognitive/behavioral scores and diabetes duration and diabetes control (hemoglobin A1c) were assessed in the type 2 diabetes group only. The type 2 diabetes group had mean duration of diabetes of 2.8 ± 2.2 yr and hemoglobin A1c of 7.9 ± 2.2%. Adolescents with type 2 diabetes scored lower than controls on tests of working and verbal memory and processing speed (all p < 0.05) and worse for Internalizing, Externalizing, and Total Problems behaviors on the Child Behavior Checklist (all p < 0.05). Adolescents with type 2 diabetes scored below the population mean in academic achievement, most notably calculation. Working memory and processing speed were negatively correlated with duration of diabetes (r = -0.50 and -0.47, respectively, p < 0.05). Obese youth with type 2 diabetes score poorly compared with controls on multiple assessments of cognitive function and adaptive behavior. Further work is needed to determine if these effects are driven by obesity, diabetes or other demographic and socioeconomic risk factors. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Association of obesity with hypertension and dyslipidemia in type 2 diabetes mellitus subjects.

PubMed

Anari, Razieh; Amani, Reza; Latifi, Seyed Mahmoud; Veissi, Masoud; Shahbazian, Hajieh

Obesity and diabetes are contributed to cardiovascular disease risk. The current study was performed to evaluate the association of central and general obesity and cardio-metabolic risk factors, including dyslipidemia and hypertension in T2DM patients. This was a cross-sectional study in T2DM adults. Body mass index (BMI) was used to identify general obesity and waist circumference (WC) was measured to define abdominal obesity (based on ATP III). Biochemical analyses, and anthropometric and blood pressure measurements were done for all participants. Participants with central obesity showed significantly higher systolic (132.5mmHg vs. 125.4mmHg, p=0.024) and diastolic blood pressures (84.9mmHg vs. 80mmHg, p=0.007) than participants without obesity. Dyslipidemia was more prevalent in all participants either by BMI (98.3% vs. 97%, 95% CI: 0.18-17.53) or by WC (97.2% vs. 98%, 95% CI: 0.07-7.19). Abdominal adiposity in diabetic subjects showed significant reverse association with high level of physical activity (OR=0.22, 95% CI: 0.06-0.85). Hypertriglyceridemia rate was increased with both central (OR=2.11; p=0.040) and general obesity (OR=2.68; p=0.021). After adjustment for energy intake and age, females had higher risk of general (OR=4.57, 95% CI=1.88-11.11) and central obesity (OR=7.93, 95% CI=3.48-18.08). Females were more susceptible to obesity. Hypertension was associated with both obesity measures. Dyslipidemia, except for hypertriglyceridemia, was correlated to neither abdominal nor general obesity. Copyright © 2016 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Diabetes burden in Brazil: fraction attributable to overweight, obesity, and excess weight.

PubMed

Flor, Luísa Sorio; Campos, Monica Rodrigues; Oliveira, Andreia Ferreira de; Schramm, Joyce Mendes de Andrade

2015-01-01

OBJECTIVE To estimate the burden of type 2 diabetes mellitus and its percentage attributable to overweight and obesity in Brazil. METHODS The burden of diabetes mellitus was described in terms of disability-adjusted life years, which is the sum of two components: years of life lost and years lived with disability. To calculate the fraction of diabetes mellitus attributable to overweight, obesity, and excess weight, we used the prevalence of these risk factors according to sex and age groups (> 20 years) obtained from the 2008 Pesquisa Dimensões Sociais das Desigualdades (Social Dimensions of Inequality Survey) and the relative risks derived from the international literature. RESULTS Diabetes mellitus accounted for 5.4% of Brazilian disability-adjusted life years in 2008, with the largest fraction attributed to the morbidity component (years lived with disability). Women exhibited higher values for disability-adjusted life years. In Brazil, 49.2%, 58.3%, and 70.6% of diabetes mellitus in women was attributable to overweight, obesity, and excess weight, respectively. Among men, these percentages were 40.5%, 45.4%, and 60.3%, respectively. Differences were observed with respect to Brazilian regions and age groups. CONCLUSIONS A large fraction of diabetes mellitus was attributable to preventable individual risk factors and, in about six years, the contribution of these factors significant increased, particularly among men. Policies aimed at promoting healthy lifestyle habits, such as a balanced diet and physical activity, can have a significant impact on reducing the burden of diabetes mellitus in Brazil.

Salivary inflammatory markers and microbiome in normoglycemic lean and obese children compared to obese children with type 2 diabetes.

PubMed

Janem, Waleed F; Scannapieco, Frank A; Sabharwal, Amarpeet; Tsompana, Maria; Berman, Harvey A; Haase, Elaine M; Miecznikowski, Jeffrey C; Mastrandrea, Lucy D

2017-01-01

There is emerging evidence linking diabetes with periodontal disease. Diabetes is a well-recognized risk factor for periodontal disease. Conversely, pro-inflammatory molecules released by periodontally-diseased tissues may enter the circulation to induce insulin resistance. While this association has been demonstrated in adults, there is little information regarding periodontal status in obese children with and without type 2 diabetes (T2D). We hypothesized that children with T2D have higher rates of gingivitis, elevated salivary inflammatory markers, and an altered salivary microbiome compared to children without T2D. Three pediatric cohorts ages 10-19 years were studied: lean (normal weight-C), obese (Ob), and obese with T2D (T2D). Each subject completed an oral health survey, received a clinical oral examination, and provided unstimulated saliva for measurement of inflammatory markers and microbiome analysis. The diabetes group was less likely to have had a dental visit within the last six months. Body mass index (BMI) Z-scores and waist circumference/height ratios were similar between Ob and T2D cohorts. The number of carious lesions and fillings were similar for all three groups. The gingival index was greater in the T2D group compared to the Ob and C groups. Although salivary microbial diversity was minimal between groups, a few differences in bacterial genus composition were noted. Obese children with T2D show a trend toward poorer oral health compared to normal weight and obese children without T2D. This study characterizes the salivary microbiome of children with and without obesity and T2D. This study supports a modest link between T2D and periodontal inflammation in the pediatric population.

The importance of obesity in diabetes and its treatment with sibutramine.

PubMed

Van Gaal, L F; Peiffer, F W

2001-12-01

Weight gain is a known risk factor for the development of type 2 diabetes and even modest weight reduction can reduce the risk of developing diabetes, so controlling body weight is an important public health goal in the fight against diabetes and its comorbidities. Weight reduction is also a cornerstone of diabetes management, improving glycaemic control and reducing other risk factors associated with this disease. Pharmacotherapies such as sibutramine contribute to the management of type 2 diabetes in overweight and obese patients.

Association between obesity and depression in patients with diabetes mellitus type 2; a study protocol.

PubMed

De la Cruz-Cano, Eduardo; Tovilla-Zarate, Carlos Alfonso; Reyes-Ramos, Emilio; Gonzalez-Castro, Thelma Beatriz; Juarez-Castro, Isela; López-Narváez, Maria Lilia; Fresan, Ana

2015-01-01

Diabetes mellitus and depression are highly prevalent conditions throughout the world and have significant impact on health outcomes. It has been estimated that diabetes mellitus type 2 affects about 246 million people in the world; nevertheless, incidence varies among countries. There is evidence that depression is associated with a poor metabolic control in patients with type 2 diabetes mellitus that present other health problems (such as hypertension and obesity). The aim of this study protocol is to determine if obesity increases the risk for depression in patient with diabetes type 2. The analysis will be reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).The studies suitable for inclusion will be assessed by the Newcastle-Ottawa Scale (NOS) to determine their methodological quality. To identify the studies of interest, we will search on PubMed and EBSCO databases. We will use the following keyword combinations: "Diabetes Mellitus type 2 AND obesity AND depression", "depression AND Diabetes Mellitus type 2", "Diabetes Mellitus type 2 AND body mass index cross sectional study", "depression AND obesity cross-sectional study". Causes for exclusion will be publications that studied patients diagnosed with diabetes mellitus type 1; articles that focused on the treatment and complications of diabetes mellitus type 2; publications that have studied other clinical or psychiatric conditions (for instance, seizure disorder or history of schizophrenia, bipolar disorder, psychotic symptoms or dementia). The results of this study will form the basis for a better understanding of the association between obesity and depression in patients with diabetes mellitus type 2, and will allow development of prediction tools and better interventions. It is evident that several modifiable and non-modifiable risk factors play an important role in the pathogenesis of diabetes among population. Currently, evidence for the deleterious effects

[Obesity as a factor in the development of cancer in type 2 diabetes].

PubMed

Łukasiewicz, Dorota; Chodorowska, Marlena; Jakubowska, Iwona

2015-03-01

The aim of this study was to evaluate the prevalence of malignant tumors in patients with type 2 diabetes and the factors contributing to the development of cancer. Medical records of 1087 patients with type 2 diabetes were retrospectively analyzed and a group of 74 (6.8%) patients with malignant tumor were found during treatment of diabetes. The most common sites of malignancies in patients with type 2 diabetes were: kidney (33.3%) and colorectal cancer (26.7%). The highest mean body mass index (BMI) was in the group of patients with uterus cancer and amounted to 36.1 kg/m². The next highest BMI recorded in the case of breast cancer - 32.6 kg/m², cancer of the kidney - 31.6 kg/m² and colorectal cancer - 31.3 kg/m². The lowest BMI values were observed in gallbladder cancer - 25.2 kg/m² and lung cancer - 26.4 kg/m². BMI in the various types of cancer were not statistically significant. In the group with normal BMI prostate cancer was most common. In the group of overweight and obesity patients kidney and colon cancers occurred more frequently, while in obese women - breast and uterus tumors. More than 80% of patients with type 2 diabetes who were diagnosed with cancer were overweight or obese. In the group of obese patients the highest average glycated hemoglobin was observed and if compared to those with normal weight it was significantly higher (p = 0.01). In the group of obese patients, the most common tumors were renal and colorectal cancer, and cancer of the breast and uterus in a group of obese women. The use of metformin in the presence of other risk factors do not protect against the development of cancer. © 2015 MEDPRESS.

Ending SNAP subsidies for sugar-sweetened beverages could reduce obesity and type 2 diabetes.

PubMed

Basu, Sanjay; Seligman, Hilary Kessler; Gardner, Christopher; Bhattacharya, Jay

2014-06-01

To reduce obesity and type 2 diabetes rates, lawmakers have proposed modifying Supplemental Nutrition Assistance Program (SNAP) benefits to encourage healthier food choices. We examined the impact of two proposed policies: a ban on using SNAP dollars to buy sugar-sweetened beverages; and a subsidy in which for every SNAP dollar spent on fruit and vegetables, thirty cents is credited back to participants' SNAP benefit cards. We used nationally representative data and models describing obesity, type 2 diabetes, and determinants of food consumption among a sample of over 19,000 SNAP participants. We found that a ban on SNAP purchases of sugar-sweetened beverages would be expected to significantly reduce obesity prevalence and type 2 diabetes incidence, particularly among adults ages 18-65 and some racial and ethnic minorities. The subsidy policy would not be expected to have a significant effect on obesity and type 2 diabetes, given available data. Such a subsidy could, however, more than double the proportion of SNAP participants who meet federal vegetable and fruit consumption guidelines. Project HOPE—The People-to-People Health Foundation, Inc.

Diabetes Mellitus, Obesity, and Diagnosis of Amyotrophic Lateral Sclerosis: A Population-Based Study.

PubMed

Kioumourtzoglou, Marianthi-Anna; Rotem, Ran S; Seals, Ryan M; Gredal, Ole; Hansen, Johnni; Weisskopf, Marc G

2015-08-01

Although prior studies have suggested a role of cardiometabolic health on pathogenesis of amyotrophic lateral sclerosis (ALS), the association with diabetes mellitus has not been widely examined. Amyotrophic lateral sclerosis is the most common motor neuron disorder. Several vascular risk factors have been associated with decreased risk for ALS. Although diabetes is also a risk factor for vascular disease, the few studies of diabetes and ALS have been inconsistent. To examine the association between diabetes and obesity, each identified through International Statistical Classification of Diseases, Eighth or Tenth Revision codes in a hospital registry, and ALS using data from the Danish National Registers. Population-based nested case-control study of 3650 Danish residents diagnosed as having ALS between January 1, 1982, and December 31, 2009, and 365,000 controls (100 for each ALS case) matched on age and sex. The analysis was conducted in September and October 2014. Adjusted odds ratio for ALS associated with diabetes or obesity diagnoses at least 3 years prior to the ALS diagnosis date. When considering diabetes and our obesity indicator together, the estimated odds ratio for ALS was 0.61 (95% CI, 0.46-0.80) for diabetes and 0.81 (95% CI, 0.57-1.16) for obesity. We observed no effect modification on the association with diabetes by sex. We did find a significant modification by age at ALS diagnosis and age at first mention of diabetes in the hospital registers. The protective association was stronger with increasing age at ALS diagnosis (P = .01), and the odds ratio for first mention of diabetes was 1.66 (95% CI, 0.85-3.21) before age 40 years but 0.52 (95% CI, 0.39-0.70) for older ages. These results are consistent with different associations for type 1 vs type 2 diabetes. In this Danish nationwide study to investigate the association between diabetes and ALS diagnosis, our findings are in agreement with previous reports of a protective association between

Adverse effect on syngeneic islet transplantation by transgenic coexpression of decoy receptor 3 and heme oxygenase-1 in the islet of NOD mice.

PubMed

Huang, S-H; Lin, G-J; Chien, M-W; Chu, C-H; Yu, J-C; Chen, T-W; Hueng, D-Y; Liu, Y-L; Sytwu, H-K

2013-03-01

Decoy receptor 3 (DcR3) blocks both Fas ligand- and LIGHT-induced pancreatic β-cell damage in autoimmune diabetes. Heme oxygenase 1 (HO-1) possesses antiapoptotic, anti-inflammatory, and antioxidative effects that protect cells against various forms of attack by the immune system. Previously, we have demonstrated that transgenic islets overexpressing DcR3 or murine HO-1 (mHO-1) exhibit longer survival times than nontransgenic islets in syngeneic islet transplantation. In this study, we evaluated whether DcR3 and mHO-1 double-transgenic islets of NOD mice could provide better protective effects and achieve longer islet graft survival than DcR3 or mHO-1 single-transgenic islets after islet transplantation. We generated DcR3 and mHO-1 double-transgenic NOD mice that specifically overexpress DcR3 and HO-1 in islets. Seven hundred islets isolated from double-transgenic, single-transgenic, or nontransgenic NOD mice were syngeneically transplanted into the kidney capsules of newly diabetic female recipients. Unexpectedly, there was no significant difference in the survival time between double-transgenic or nontransgenic NOD islet grafts, and the survival times of double-transgenic NOD islet grafts were even shorter than those of DcR3 or mHO-1 single-transgenic islets. Our data indicate that transplantation of double-transgenic islets that coexpress HO-1 and DcR3 did not result in a better outcome. On the contrary, this strategy even caused an adverse effect in syngeneic islet transplantation. Copyright © 2013 Elsevier Inc. All rights reserved.

Geographic distribution of childhood diabetes and obesity relative to the supply of pediatric endocrinologists in the United States.

PubMed

Lee, Joyce M; Davis, Matthew M; Menon, Ram K; Freed, Gary L

2008-03-01

To determine the geographic distribution of childhood diabetes and obesity relative to the supply of US pediatric endocrinologists. Estimation of observed and "index" ratios of children with diabetes (by region and division) and obesity (body mass index >/=95th % for age and sex) (by region and state) to board-certified pediatric endocrinologists. At the national level, the ratio of children with diabetes to pediatric endocrinologists is 290:1, and the ratio of obese children to pediatric endocrinologists is 17,741:1. Ratios of children with diabetes to pediatric endocrinologists in the Midwest (370:1), South (335:1), and West (367:1) are twice as high as in the Northeast (144:1). Across states, there is up to a 19-fold difference in the observed ratios of obese children to pediatric endocrinologists. Under conditions of equitably distributed endocrinologist supply, variation across states would be mitigated considerably. The distribution of children with diabetes and obesity does not parallel the distribution of pediatric endocrinologists in the United States, due largely to geographic disparities in endocrinologist supply. Given the large burden of obese children to endocrinologists, multidisciplinary models of care delivery are essential for the US health care system to address the needs of children with diabetes and obesity.

Short-term very low calorie diet reduces oxidative stress in obese type 2 diabetic patients.

PubMed

Skrha, J; Kunesová, M; Hilgertová, J; Weiserová, H; Krízová, J; Kotrlíková, E

2005-01-01

Oxidative stress is higher in obese diabetic than in non-diabetic subjects. This pilot study evaluates oxidative stress during short-term administration of a very low calorie diet in obese persons. Nine obese Type 2 diabetic patients (age 55+/-5 years, BMI 35.9+/-1.9 kg/m2) and nine obese non-diabetic control subjects (age 52+/-6 years, BMI 37.3+/-2.1 kg/m2) were treated by a very low calorie diet (600 kcal daily) during 8 days stay in the hospital. Serum cholesterol, triglycerides, non-esterified fatty acids (NEFA), beta-hydroxybutyrate (B-HB), ascorbic acid (AA), alpha-tocopherol (AT), plasma malondialdehyde (MDA) and superoxide dismutase (SOD) activity in erythrocytes were measured before and on day 3 and 8 of very low calorie diet administration. A decrease of serum cholesterol and triglyceride concentrations on day 8 was associated with a significant increase of NEFA (0.30+/-0.13 vs. 0.47+/-0.11 micromol/l, p<0.001) and B-HB (0.36+/-.13 vs. 2.23+/-1.00 mmol/l, p<0.001) in controls but only of B-HB (1.11+/-0.72 vs. 3.02+/-1.95 mmol/l, p<0.001) in diabetic patients. A significant decrease of plasma MDA and serum AT together with an increase of SOD activity and AA concentration (p<0.01) was observed in control persons, whereas an increase of SOD activity (p<0.01) was only found in diabetic patients after one week of the very low calorie diet. There was a significant correlation between NEFA or B-HB and SOD activity (p<0.01). We conclude that one week of a very low calorie diet administration decreases oxidative stress in obese non-diabetic but only partly in diabetic persons. Diabetes mellitus causes a greater resistance to the effects of a low calorie diet on oxidative stress.

Associations between diet quality, health status and diabetic complications in patients with type 2 diabetes and comorbid obesity.

PubMed

Mangou, Apostolis; Grammatikopoulou, Maria G; Mirkopoulou, Daphne; Sailer, Nikolaos; Kotzamanidis, Charalambos; Tsigga, Maria

2012-02-01

Patients with type 2 diabetes (T2DM) demonstrate low dietary adherence and this is further aggravated with comorbid obesity. The aim of the present study was to assess diet quality in patients with T2DM and comorbid obesity compared to patients with T2DM alone and to examine the associations between comorbidities and diet quality. The sample consisted of 59 adult patients with diabesity (T2DM and comorbid obesity) and 94 patients with T2DM alone. All diabetes comorbidities and complications were recorded and diet quality was assessed with the Healthy Eating Index (HEI). Mean raw HEI of the diabese subjects was 81.9±7.1 and the diabetic subjects was 80.2±6.9. When HEI was adjusted to the sex, age and weight status, the diabese demonstrated a higher HEI. Among comorbidities, only renal disease decreased HEI. According to the principal component analysis of the total sample, adequate diet quality was explained by cardiovascular disease, cigarette smoking, alcohol consumption, peptic ulcer, sex, diabesity and diabetic foot syndrome. In the diabese, adequate HEI was explained by diabetic foot syndrome, smoking, drinking alcohol and having a family history of diabetes. Adult patients with T2DM demonstrate adequate diet quality. Different factors are associated with the adoption of a high quality diet between the diabese and the T2DM alone. Copyright © 2011 SEEN. Published by Elsevier Espana. All rights reserved.

Transient B-Cell Depletion with Anti-CD20 in Combination with Proinsulin DNA Vaccine or Oral Insulin: Immunologic Effects and Efficacy in NOD Mice

PubMed Central

Sarikonda, Ghanashyam; Sachithanantham, Sowbarnika; Manenkova, Yulia; Kupfer, Tinalyn; Posgai, Amanda; Wasserfall, Clive; Bernstein, Philip; Straub, Laura; Pagni, Philippe P.; Schneider, Darius; Calvo, Teresa Rodriguez; Coulombe, Marilyne; Herold, Kevan; Gill, Ronald G.; Atkinson, Mark; Nepom, Gerald; Ehlers, Mario; Staeva, Teodora; Garren, Hideki; Steinman, Lawrence; Chan, Andrew C.; von Herrath, Matthias

2013-01-01

A recent type 1 diabetes (T1D) clinical trial of rituximab (a B cell-depleting anti-CD20 antibody) achieved some therapeutic benefit in preserving C-peptide for a period of approximately nine months in patients with recently diagnosed diabetes. Our previous data in the NOD mouse demonstrated that co-administration of antigen (insulin) with anti-CD3 antibody (a T cell-directed immunomodulator) offers better protection than either entity alone, indicating that novel combination therapies that include a T1D-related autoantigen are possible. To accelerate the identification and development of novel combination therapies that can be advanced into the clinic, we have evaluated the combination of a mouse anti-CD20 antibody with either oral insulin or a proinsulin-expressing DNA vaccine. Anti-CD20 alone, given once or on 4 consecutive days, produced transient B cell depletion but did not prevent or reverse T1D in the NOD mouse. Oral insulin alone (twice weekly for 6 weeks) was also ineffective, while proinsulin DNA (weekly for up to 12 weeks) showed a trend toward modest efficacy. Combination of anti-CD20 with oral insulin was ineffective in reversing diabetes in NOD mice whose glycemia was controlled with SC insulin pellets; these experiments were performed in three independent labs. Combination of anti-CD20 with proinsulin DNA was also ineffective in diabetes reversal, but did show modest efficacy in diabetes prevention (p = 0.04). In the prevention studies, anti-CD20 plus proinsulin resulted in modest increases in Tregs in pancreatic lymph nodes and elevated levels of proinsulin-specific CD4+ T-cells that produced IL-4. Thus, combination therapy with anti-CD20 and either oral insulin or proinsulin does not protect hyperglycemic NOD mice, but the combination with proinsulin offers limited efficacy in T1D prevention, potentially by augmentation of proinsulin-specific IL-4 production. PMID:23405091

[Pathological changes in hepatocytes of mice with obesity-induced type 2 diabetes by monosodium glutamate].

PubMed

Nakadate, Kazuhiko; Motojima, Kento; Kamata, Sumito; Yoshida, Testuro; Hikita, Masaaki; Wakamatsu, Hisanori

2014-01-01

Type 2 diabetes caused by chronic obesity is a major lifestyle-related disease. The present study aimed to determine the pathological changes in hepatocytes in chronic obesity. To develop our type 2 diabetes mouse model, we induced chronic obesity to mice by monosodium glutamate. By overeating, the mice significantly increased their body weight compared with age-matched healthy animals. To analyze the pathological changes in hepatocytes of chronic obesity before preclinical stage of type 2 diabetes, the mice were analyzed by hematoxylin-eosin staining of tissue sections at 15 w of age. In these mice, we observed eosin-negative accumulations of hepatocytes around central veins in the hepatic lobule. By Oil-Red O staining, the eosin-negative granules were identified in the lipid droplets. We then ascertained whether these lipid droplets of hepatocytes in the obese mice could be modified by diet. After 24 h of diet restriction, the lipid droplets of hepatocytes in the obese mice were swollen. Furthermore, after 48 h of the diet restriction, the lipid droplets continued swelling and the autophagy-like structures that were found in the healthy mice under the same condition in the obese mice were not observed. These results suggest that the obese mice might have delayed energy metabolism, which might have influenced the mechanisms of hepatocytes. These findings provide new insight into the functional changes in chronic obesity-induced type 2 diabetes and it is possible that the pathological feature make a contribution to promise the target of pharmacological therapy.

Serum N(1)-Methylnicotinamide Is Associated With Obesity and Diabetes in Chinese.

PubMed

Liu, Ming; Li, Lihua; Chu, Jihong; Zhu, Boyu; Zhang, Qingtao; Yin, Xueyan; Jiang, Weimin; Dai, Guoliang; Ju, Wenzheng; Wang, Zhenxing; Yang, Qin; Fang, Zhuyuan

2015-08-01

Nicotinamide N-methyltransferase (NNMT) is a novel histone methylation modulator that regulates energy metabolism, and NNMT knockdown prevents diet-induced obesity in mice. However, whether NNMT plays a role in human obesity and type 2 diabetes (T2DM) remains to be elucidated. NNMT catalyzes methylation of nicotinamide to generate N(1)-methylnicotinamide (me-NAM). We aimed to investigate the associations of serum me-NAM with obesity and T2DM in Chinese. The study subjects (n = 1160) were recruited from Dali, a city of Yunnan Province, in southwest China. Anthropometric phenotypes, fasting glucose, and serum lipids were measured. Serum me-NAM was measured by liquid chromatography-mass spectrometry. Serum me-NAM was positively correlated with body mass index and waist circumference and negatively with high-density lipoprotein (P ≤ .03). The correlations remained highly significant in the multivariate adjusted correlation analyses. In men (n = 691), positive correlations between me-NAM and fasting glucose, low-density lipoprotein, liver function, and serum creatinine levels were also observed in both simple and multivariate adjusted correlation analyses. In multiple logistic regression analyses, elevated serum me-NAM was associated with higher risks for overweight/obesity (odds ratios, 2.36 and 5.78; 95% confidence intervals, 1.10-5.08 and 1.78-18.76 for men and women, respectively; P ≤ .03) and diabetes (odds ratios, 1.56 and 1.86; 95% confidence intervals, 1.10-2.22 and 1.05-3.31 for men and women, respectively; P ≤ .03). This first large-scale population study shows that me-NAM, as an indicator of NNMT activity, is strongly associated with obesity and diabetes, supporting NNMT as a potential target for treating obesity and diabetes in humans.

Fasting and post-prandial adipose tissue lipoprotein lipase and hormone-sensitive lipase in obesity and type 2 diabetes.

PubMed

Costabile, G; Annuzzi, G; Di Marino, L; De Natale, C; Giacco, R; Bozzetto, L; Cipriano, P; Santangelo, C; Masella, R; Rivellese, A A

2011-05-01

Fasting and post-prandial abnormalities of adipose tissue (AT) lipoprotein lipase (LPL) and hormone- sensitive lipase (HSL) activities may have pathophysiological relevance in insulin-resistant conditions. The aim of this study was to evaluate activity and gene expression of AT LPL and HSL at fasting and 6 h after meal in two insulin-resistant groups - obese with Type 2 diabetes and obese without diabetes - and in non-diabetic normal-weight controls. Nine obese subjects with diabetes, 10 with obesity alone, and 9 controls underwent measurements of plasma levels of glucose, insulin, and triglycerides before and after a standard fat-rich meal. Fasting and post-prandial (6 h) LPL and HSL activities and gene expressions were determined in abdominal subcutaneous AT needle biopsies. The diabetic obese subjects had significantly lower fasting and post-prandial AT heparin-releasable LPL activity than only obese and control subjects (p<0.05) as well as lower mRNA LPL levels. HSL activity was significantly reduced in the 2 groups of obese subjects compared to controls in both fasting condition and 6 h after the meal (p<0.05), while HSL mRNA levels were not different. There were no significant changes between fasting and 6 h after meal measurements in either LPL or HSL activities and gene expressions. Lipolytic activities in AT are differently altered in obesity and Type 2 diabetes being HSL alteration associated with both insulin-resistant conditions and LPL with diabetes per se. These abnormalities are similarly observed in the fasting condition and after a fat-rich meal.

[Obesity and diabetes mellitus].

PubMed

Tron'ko, N D; Zak, K P

2013-12-01

New literature data and the results of own researches concerning the role of excessive body weight and the development of type 2 diabetes mellitus in humans are presented in the analytical review. Inaccordance with current insights, obesity and type 2 diabetes are considered diseases of inflammatory nature, characterized by systemic chronic low-grade inflammation, where different kinds of cytokines are cardinally involved. Unfavourable life style, i.e. excessive, high-energy, and irrational nutrition--an excessive consumption of animal fats and foods containing the high amount of glucose and starch with an insufficient use of high fiber vegetables, fish and vitamin D, and also sedentary, inactive life style leads to adipocyte hypertrophy and migration of M1 macrophages into the adipose tissue (AT). As a result, there is a low-grade inflammation accompanied by an increased production of proinflammatory cytokines (IL-1, IL-6, TNF-α, etc.), adipokines (leptin, resistin, visfatin etc.) and chemokines (CCL2, CCL5, CCL26 and CX3C). Under the influence of these cytokines, on the one hand, IR "is emerged", and on the other--there is apoptosis of the β-cells, that should be followed by the occurrence of clinically diagnosed type 2 diabetes. However, there is also the opposite system in humans, protecting the organism from the development of type 2 diabetes, and including an increase in the formation of M2 macrophages and the increased formation of secretion of antidiabetic cytokines (IL-4, IL-10, IL-13, etc.) and adiponectin.

The Best Obesity Indices to Discriminate Type 2 Diabetes Mellitus.

PubMed

Motamed, Nima; Rabiee, Behnam; Keyvani, Hossein; Hemasi, Gholam Reza; Khonsari, Mahmood; Saeedian, Fatemeh Sima; Maadi, Mansooreh; Zamani, Farhad

2016-06-01

It is expected that the number of people with diabetes will reach 435 million by 2030. Obesity is considered the most important predictor of type 2 diabetes mellitus (T2DM). We conducted the present study to determine the best usual discriminator indices of obesity to diagnose diabetes mellitus (DM). Of 6143 subjects aged 10-90 years from a baseline cohort study, the data of 5772 participants aged >18 years and without history of type 1 diabetes were utilized to analyze in this study. The cohort study was carried out in northern Iran and sampling frame was provided from related local health centers. The capability of obesity indices, including body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and body adiposity index (BAI), in the discrimination of DM was evaluated. Discriminatory capabilities were evaluated using the receiver operating characteristic (ROC) curve. Logistic regression analysis was performed to determine the strength of association between obesity indices and DM. The areas under ROC curve of BAI, BMI, WC, and WHR were 0.6244 (0.5918-0.6570), 0.6214 (0.5908-0.6520), 0.6636 (0.6341-0.6930), and 0.7303 (0.7032-0.7575) in men and 0.5961 (0.5674-0.6249), 0.5963 (0.5690-0.6235), 0.6850 (0.6593-0.7108), and 0.7529 (0.7297-0.7761) in women, respectively. In the multivariate model, one unit increase in Z-score of BMI, WC, and WHR increased the chance of DM by 49%, 65%, and 51% in men and by 17%, 51%, and 67% in women, respectively. No association was found between DM and BAI in this model. While WHR had an appropriate discriminatory capability for T2DM in the population of northern Iran, BAI and BMI did not.

The role of Gut Microbiota in the development of obesity and Diabetes.

PubMed

Baothman, Othman A; Zamzami, Mazin A; Taher, Ibrahim; Abubaker, Jehad; Abu-Farha, Mohamed

2016-06-18

Obesity and its associated complications like type 2 diabetes (T2D) are reaching epidemic stages. Increased food intake and lack of exercise are two main contributing factors. Recent work has been highlighting an increasingly more important role of gut microbiota in metabolic disorders. It's well known that gut microbiota plays a major role in the development of food absorption and low grade inflammation, two key processes in obesity and diabetes. This review summarizes key discoveries during the past decade that established the role of gut microbiota in the development of obesity and diabetes. It will look at the role of key metabolites mainly the short chain fatty acids (SCFA) that are produced by gut microbiota and how they impact key metabolic pathways such as insulin signalling, incretin production as well as inflammation. It will further look at the possible ways to harness the beneficial aspects of the gut microbiota to combat these metabolic disorders and reduce their impact.

Obesity and Diabetes as Accelerators of Functional Decline; Can Lifestyle Interventions Maintain Functional Status in High Risk Older Adults?

PubMed Central

Anton, Stephen D.; Karabetian, Christy; Naugle, Kelly; Buford, Thomas W.

2013-01-01

Obesity and diabetes are known risk factors for the development of physical disability among older adults. With the number of seniors with these conditions rising worldwide, the prevention and treatment of physical disability in these persons has become a major public health challenge. Sarcopenia, the progressive loss of muscle mass and strength, has been identified as a common pathway associated with the initial onset and progression of physical disability among older adults. A growing body of evidence suggests that metabolic dysregulation associated with obesity and diabetes accelerates the progression of sarcopenia, and subsequently functional decline in older adults. The focus of this brief review is on the contributions of obesity and diabetes in accelerating sarcopenia and functional decline among older adults. We also briefly discuss the underexplored interaction between obesity and diabetes that may further accelerate sarcopenia and place obese older adults with diabetes at particularly high risk of disability. Finally, we review findings from studies that have specifically tested the efficacy of lifestyle-based interventions in maintaining the functional status of older persons with obesity and/or diabetes. PMID:23832077

Family history: an opportunity for early interventions and improved control of hypertension, obesity and diabetes.

PubMed Central

van der Sande, M. A.; Walraven, G. E.; Milligan, P. J.; Banya, W. A.; Ceesay, S. M.; Nyan, O. A.; McAdam, K. P.

2001-01-01

OBJECTIVE: To examine whether a family history of high-risk groups for major noncommunicable diseases (NCDs) was a significant risk factor for these conditions among family members in a study population in the Gambia, where strong community and family coherence are important determinants that have to be taken into consideration in promoting lifestyle changes. METHODS: We questioned 5389 adults as to any first-degree family history of major noncommunicable diseases (hypertension, obesity, diabetes and stroke), and measured their blood pressure (BP) and body mass index (BMI). Total blood cholesterol, triglyceride, uric acid, and creatinine concentrations were measured in a stratified subsample, as well as blood glucose (2 hours after ingesting 75 g glucose) in persons aged > or = 35 years. FINDINGS: A significant number of subjects reported a family history of hypertension (8.0%), obesity (5.4%), diabetes (3.3%) and stroke (1.4%), with 14.6% of participants reporting any of these NCDs. Subjects with a family history of hypertension had a higher diastolic BP and BMI, higher cholesterol and uric acid concentrations, and an increased risk of obesity. Those with a family history of obesity had a higher BMI and were at increased risk of obesity. Individuals with a family history of diabetes had a higher BMI and higher concentrations of glucose, cholesterol, triglycerides and uric acid, and their risk of obesity and diabetes was increased. Subjects with a family history of stroke had a higher BMI, as well as higher cholesterol, triglyceride and uric acid concentrations. CONCLUSIONS: A family history of hypertension, obesity, diabetes, or stroke was a significant risk factor for obesity and hyperlipidaemia. With increase of age, more pathological manifestations can develop in this high-risk group. Health professionals should therefore utilize every opportunity to include direct family members in health education. PMID:11357211

Prevalence of type 2 diabetes and obesity in rural Mapuche population from Chile.

PubMed

Pérez-Bravo, F; Carrasco, E; Santos, J L; Calvillán, M; Larenas, G; Albala, C

2001-03-01

The aim of this study was to estimate the prevalence of Type 2 diabetes, impaired glucose tolerance (IGT), and obesity in the Mapuche natives from rural areas in Chile. This cross-sectional study involved men (n = 95) and women (n = 224) older than 20 y from an aboriginal ethnic group (Mapuches), residing in rural communities from the south of Chile. Prevalence of Type 2 diabetes and IGT was calculated according to the World Health Organization criteria. Data on age, degree of ancestral purity, obesity, and hypertension were also obtained. The prevalence of Type 2 diabetes in rural Mapuche natives was estimated as 3.2% (95% CI: 0.7--9.0) in men and 4.5% (95% CI: 2.2--8.1) in women. The overall prevalence of obesity was 56.1% (95% CI: 50.5--61.6): 40.0% (95% CI: 30.1--40.8) in men and 62.9% (95% CI: 56.3--69.3) in women (P value < 0.001). These data suggest that the prevalence of obesity and Type 2 diabetes has been increasing during recent years in the Mapuche communities. The prevalence estimated in this study is higher than that reported 15 y ago. This suggests an important role of lifestyle changes as a possible explanation for epidemiologic transition.

Incretin secretion in obese Korean children and adolescents with newly diagnosed type 2 diabetes.

PubMed

Park, So Hyun; Jung, Min Ho; Cho, Won Kyoung; Park, Mi Sun; Suh, Byung Kyu

2016-01-01

The role of incretins in type 2 diabetes is controversial. This study investigated the association between incretin levels in obese Korean children and adolescents newly diagnosed with type 2 diabetes. We performed a 2-hr oral glucose tolerance test (OGTT) in obese children and adolescents with type 2 diabetes and with normal glucose tolerance. Twelve obese children and adolescents with newly diagnosed type 2 diabetes (DM group) and 12 obese age-matched subjects without type 2 diabetes (NDM group) were included. An OGTT was conducted and insulin, C-peptide, glucagon, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were measured during the OGTT. The mean age of the patients was 13·8 ± 2·0 years, and the mean body mass index (BMI) Z-score was 2·1 ± 0·5. The groups were comparable in age, sex, BMI Z-score and waist:hip ratio. The DM group had significantly lower homeostasis model assessment of β and insulinogenic index values (P < 0·001). The homeostasis model assessment of insulin resistance index was not different between the two groups. Insulin and C-peptide secretions were significantly lower in the DM group than in the NDM group (P < 0·001). Total GLP-1 secretion was significantly higher in the DM group while intact GLP-1 and GIP secretion values were not significantly different between the two groups. Impaired insulin secretion might be important in the pathogenesis of type 2 diabetes in obese Korean children and adolescents, however, which may not be attributed to incretin secretion. © 2015 John Wiley & Sons Ltd.

Diabetes burden in Brazil: fraction attributable to overweight, obesity, and excess weight

PubMed Central

Flor, Luísa Sorio; Campos, Monica Rodrigues; de Oliveira, Andreia Ferreira; Schramm, Joyce Mendes de Andrade

2015-01-01

OBJECTIVE To estimate the burden of type 2 diabetes mellitus and its percentage attributable to overweight and obesity in Brazil. METHODS The burden of diabetes mellitus was described in terms of disability-adjusted life years, which is the sum of two components: years of life lost and years lived with disability. To calculate the fraction of diabetes mellitus attributable to overweight, obesity, and excess weight, we used the prevalence of these risk factors according to sex and age groups (> 20 years) obtained from the 2008 Pesquisa Dimensões Sociais das Desigualdades (Social Dimensions of Inequality Survey) and the relative risks derived from the international literature. RESULTS Diabetes mellitus accounted for 5.4% of Brazilian disability-adjusted life years in 2008, with the largest fraction attributed to the morbidity component (years lived with disability). Women exhibited higher values for disability-adjusted life years. In Brazil, 49.2%, 58.3%, and 70.6% of diabetes mellitus in women was attributable to overweight, obesity, and excess weight, respectively. Among men, these percentages were 40.5%, 45.4%, and 60.3%, respectively. Differences were observed with respect to Brazilian regions and age groups. CONCLUSIONS A large fraction of diabetes mellitus was attributable to preventable individual risk factors and, in about six years, the contribution of these factors significant increased, particularly among men. Policies aimed at promoting healthy lifestyle habits, such as a balanced diet and physical activity, can have a significant impact on reducing the burden of diabetes mellitus in Brazil. PMID:26018787

[New markers of progression of chronic heart failure in patients with myocardial infarction, type 2 diabetes and obesity].

PubMed

Kravchun, P P; Kadykova, O I; Gabisonia, T N

2015-01-01

Currently identified a large number of biomarkers that are closely linked with the development of chronic heart failure, some of which are clusterin and fractalkine. Accordingly, the purpose of our study was - to evaluate the role of clusterin and fractalkine in progression of chronic heart failure in patients with postinfarction cardiosclerosis, type 2 diabetes and obesity. We investigated 71 patients with postinfarction cardiosclerosis, type 2 diabetes and obesity. All patients with postinfarction cardiosclerosis, diabetes and obesity were divided into groups according to the functional class of chronic heart failure (CHF). It was found that an increase the level of fractalkine and reduced clusterin leads due to the development of systolic dysfunction and heart failure progression in patients with postinfarction cardiosclerosis, type 2 diabetes and obesity. Fractalkine and clusterin play an important role in progression of the heart failure in patients with postinfarction cardiosclerosis, type 2 diabetes and obesity, and this gives them the right to be considered indicators of the severity of CHF.

Analyzing the some biochemical parameters of diabetes mellitus and obese patients who applied to Siirt State Hospital endocrine polyclinic and their prevalence

NASA Astrophysics Data System (ADS)

Karageçili, Hasan; Yerlikaya, Emrah; Aydin, Ruken Zeynep

2016-04-01

Obesity and diabetes are major public health problems throughout the World. Obese individuals body mass index (BMI) is >30 kg/m2. Obesity is characterized by increased waist circumference, total body fat and hyperglycemia. The increased triglyceride and cholesterol level is also shown in obese individuals. The development of obesity is largely due to the consumption of high energy food and sedentary lifestyle. This study was held with the participation of patients applied to Siirt State Hospital endocrine policlinic for treatment. Our aim is to try to determine the biochemical relation and border line of obese and obese+diabetes mellitus patients. Patients and control group lipid profiles were studied in the hospital biochemisty laboratory. Laboratory results of diabetes+obese, obese and control groups were evaluated. Patients and control samples blood serum levels were compared according to their lipid profiles. In 2015, 735 diabetes mellitus type 2 patients applied to Endocrine polyclinic. Some of these patient's serum levels were evaluated. Difference between diabetes+obese and diabetes groups were near critical level for LDL and trigliserid. There were not observed statistically significant difference between groups in terms of HDL and cholesterol. There were found significant difference between groups for blood glucose p<0.003, age p<0.001. According to gender between women and men serum levels, ALT and AST levels; p<0.006 and cholesterol; p<0.04 were detected. According to participants education level blood biochemistry levels were observed statisticaly different p<0.001 with non-literacy group. In conclusion, obese and obese+diabetes patients blood serum values nearly close to each other. Obese subjects were been diabetic obese with age. In women obesity and diabetes mellitus prevalence were seen too much.

Metabolic effects of sleep disruption, links to obesity and diabetes.

PubMed

Nedeltcheva, Arlet V; Scheer, Frank A J L

2014-08-01

To highlight the adverse metabolic effects of sleep disruption and to open ground for research aimed at preventive measures. This area of research is especially relevant given the increasing prevalence of voluntary sleep curtailment, sleep disorders, diabetes, and obesity. Epidemiological studies have established an association between decreased self-reported sleep duration and an increased incidence of type 2 diabetes (T2D), obesity, and cardiovascular disease. Experimental laboratory studies have demonstrated that decreasing either the amount or quality of sleep decreases insulin sensitivity and decreases glucose tolerance. Experimental sleep restriction also causes physiological and behavioral changes that promote a positive energy balance. Although sleep restriction increases energy expenditure because of increased wakefulness, it can lead to a disproportionate increase in food intake, decrease in physical activity, and weight gain. Sleep disruption has detrimental effects on metabolic health. These insights may help in the development of new preventive and therapeutic approaches against obesity and T2D based on increasing the quality and/or quantity of sleep.

Obesity-induced diabetes in mouse strains treated with gold thioglucose: a novel animal model for studying β-cell dysfunction.

PubMed

Karasawa, Hiroshi; Takaishi, Kiyosumi; Kumagae, Yoshihiro

2011-03-01

An obesity-induced diabetes model using genetically normal mouse strains would be invaluable but remains to be established. One reason is that several normal mouse strains are resistant to high-fat diet-induced obesity. In the present study, we show the effectiveness of gold thioglucose (GTG) in inducing hyperphagia and severe obesity in mice, and demonstrate the development of obesity-induced diabetes in genetically normal mouse strains. GTG treated DBA/2, C57BLKs, and BDF1 mice gained weight rapidly and exhibited significant increases in nonfasting plasma glucose levels 8-12 weeks after GTG treatment. These mice showed significantly impaired insulin secretion, particularly in the early phase after glucose load, and reduced insulin content in pancreatic islets. Interestingly, GTG treated C57BL/6 mice did not become diabetic and retained normal early insulin secretion and islet insulin content despite being as severely obese and insulin resistant as the other mice. These results suggest that the pathogenesis of obesity-induced diabetes in GTG-treated mice is attributable to the inability of their pancreatic β-cells to secrete enough insulin to compensate for insulin resistance. Mice developing obesity-induced diabetes after GTG treatment might be a valuable tool for investigating obesity-induced diabetes. Furthermore, comparing the genetic backgrounds of mice with different susceptibilities to diabetes may lead to the identification of novel genetic factors influencing the ability of pancreatic β-cells to secrete insulin.

Minireview: Epigenetics of obesity and diabetes in humans.

PubMed

Slomko, Howard; Heo, Hye J; Einstein, Francine H

2012-03-01

Understanding the determinants of human health and disease is overwhelmingly complex, particularly for common, late-onset, chronic disorders, such as obesity and diabetes. Elucidating the genetic and environmental factors that influence susceptibility to disruptions in energy homeostasis and metabolic regulation remain a challenge, and progress will entail the integration of multiple assessments of temporally dynamic environmental exposures in the context of each individual's genotype. To meet this challenge, researchers are increasingly exploring the epigenome, which is the malleable interface of gene-environment interactions. Epigenetic variation, whether innate or induced, contributes to variation in gene expression, the range of potential individual responses to internal and external cues, and risk for metabolic disease. Ultimately, advancement in our understanding of chronic disease susceptibility in humans will depend on refinement of exposure assessment tools and systems biology approaches to interpretation. In this review, we present recent progress in epigenetics of human obesity and diabetes, existing challenges, and the potential for new approaches to unravel the complex biology of metabolic dysregulation.

Effect of Diabetes and Obesity on Disparities in Prostate Cancer Outcomes

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-14-1-0503 TITLE: “Effect of Diabetes and Obesity on Disparities in Prostate Cancer Outcomes PRINCIPAL INVESTIGATOR: Bettina F...and Obesity on Disparities in Prostate Cancer Outcomes 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0503 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR...death by identifying potential modifiable factors. 15. SUBJECT TERMS Prostate cancer, disparities, VHA and VACCR data, obesity , mortality, survival

Obesity-Related Dietary Patterns and Health Status of Diabetes among At-Risk Latino College Students

ERIC Educational Resources Information Center

Santos, Silvia J.; Hurtado-Ortiz, Maria T.; Armendariz, Marina; vanTwist, Victoria; Castillo, Yessenia

2017-01-01

This study examined within-group differences in obesity-related dietary behaviors and the health status of 156 Latino students at risk for diabetes due to family history. Approximately 58% of students were overweight and/or obese, with female students reporting a greater risk for diabetes. Consumption of meats, fried potatoes, breads, and…

Beneficial effects of immunotherapy with extracts derived from Actinomycetales on rats with spontaneous obesity and diabetes.

PubMed

Tarrés, María Cristina; Gayol, María Del Carmen; Picena, Juan Carlos; Alet, Nicolás; Bottasso, Oscar; McIntyre, Graham; Stanford, Cynthia; Stanford, John

2012-05-01

To determine whether immunotherapy with heat-killed, selected Actinomycetales species could influence the progression of spontaneous Type 2 diabetes mellitus and obesity in a rat model. Preparations of either Gordonia bronchialis, Tsukamurella inchonensis or a saline placebo were given by three subcutaneous injections, 30 days apart, starting when rats were aged 120 days, just before development of Type 2 diabetes mellitus, and at day 440, when the disease was well established. Bodyweight, blood sugar, cholesterol, triglycerides and insulin levels were measured to determine the effects and at the end of the experiments, animals were subjected to necropsy. The development of Type 2 diabetes mellitus was prevented by both reagents, most effectively by T. inchonensis. In the treatment experiment, the effects of the disease were reduced by both treatments, markedly so by T. inchonensis. In both experiments obesity was reduced in treated animals. The possible mechanisms of action are discussed. Our findings suggest that Type 2 diabetes mellitus in the studied rats is associated with obesity, and that both diabetes and obesity can be prevented or improved by treatment with Actinomycetales immune modulators.

Obesity-Related Genomic Loci Are Associated with Type 2 Diabetes in a Han Chinese Population

PubMed Central

Zhao, Qi; He, Jiang; Chen, Li; Zhao, Zhigang; Li, Qiang; Ge, Jiapu; Chen, Gang; Guo, Xiaohui; Lu, Juming; Weng, Jianping; Jia, Weiping; Ji, Linong; Xiao, Jianzhong; Shan, Zhongyan; Liu, Jie; Tian, Haoming; Ji, Qiuhe; Zhu, Dalong; Zhou, Zhiguang; Shan, Guangliang; Yang, Wenying

2014-01-01

Background and Aims Obesity is a well-known risk factor for type 2 diabetes. Genome-wide association studies have identified a number of genetic loci associated with obesity. The aim of this study is to examine the contribution of obesity-related genomic loci to type 2 diabetes in a Chinese population. Methods We successfully genotyped 18 obesity-related single nucleotide polymorphisms among 5338 type 2 diabetic patients and 4663 controls. Both individual and joint effects of these single nucleotide polymorphisms on type 2 diabetes and quantitative glycemic traits (assessing β-cell function and insulin resistance) were analyzed using logistic and linear regression models, respectively. Results Two single nucleotide polymorphisms near MC4R and GNPDA2 genes were significantly associated with type 2 diabetes before adjusting for body mass index and waist circumference (OR (95% CI) = 1.14 (1.06, 1.22) for the A allele of rs12970134, P = 4.75×10−4; OR (95% CI) = 1.10 (1.03, 1.17) for the G allele of rs10938397, P = 4.54×10−3). When body mass index and waist circumference were further adjusted, the association of MC4R with type 2 diabetes remained significant (P = 1.81×10−2) and that of GNPDA2 was attenuated (P = 1.26×10−1), suggesting the effect of the locus including GNPDA2 on type 2 diabetes may be mediated through obesity. Single nucleotide polymorphism rs2260000 within BAT2 was significantly associated with type 2 diabetes after adjusting for body mass index and waist circumference (P = 1.04×10−2). In addition, four single nucleotide polymorphisms (near or within SEC16B, BDNF, MAF and PRL genes) showed significant associations with quantitative glycemic traits in controls even after adjusting for body mass index and waist circumference (all P values<0.05). Conclusions This study indicates that obesity-related genomic loci were associated with type 2 diabetes and glycemic traits in the Han Chinese population. PMID:25093408

Patterns of hemopoietic reconstitution in nonobese diabetic mice: dichotomy of allogeneic resistance versus competitive advantage of disease-resistant marrow.

PubMed

Kaufman, C L; Li, H; Ildstad, S T

1997-03-01

Complete replacement of the immune system via allogeneic bone marrow transplantation is sufficient to prevent diabetes in the nonobese diabetic (NOD) mouse model. In the present study we examined whether mixed allogeneic reconstitution would be sufficient to interrupt the autoimmune process with respect to occurrence of overt diabetes, as well as preexisting autoimmune insulitis. NOD mice were lethally irradiated and reconstituted with a mixture of NOD and B10.BR marrow. A relative resistance to allogeneic bone marrow engraftment was noted in NOD recipients of the mixed bone marrow inoculum, compared with disease-resistant controls. Moreover, unlike disease-resistant controls, all animals that initially repopulated as mixed donor/host chimeras became predominantly allogeneic by 4 mo, suggesting a competitive advantage for long term engraftment for disease-resistant marrow. All but one mouse in the group that engrafted with allogeneic marrow remained free of diabetes for the entire follow-up period (n = 22). Moreover, in all animals examined, virtually all islets were free of insulitis. In contrast, 74% of NOD mice that received similar conditioning and failed to engraft with donor marrow developed acute diabetes and intra-islet insulitis was present in all animals examined. These data suggest that NOD mice exhibit a relative resistance to engraftment compared with disease-resistant recipients. Conversely, animals that initially repopulated as a mixture of syngeneic and donor marrow become converted to virtually all donor by 4 mo. These data provide additional support that a defective stem cell is responsible for autoimmune diabetes in this experimental model.

Fetal myocardial deformation in maternal diabetes mellitus and obesity.

PubMed

Kulkarni, A; Li, L; Craft, M; Nanda, M; Lorenzo, J M M; Danford, D; Kutty, S

2017-05-01

Experimental evidence suggests that changes in the fetal myocardium result from intrauterine effects of maternal diabetes mellitus and obesity. The aim of this study was to assess fetal cardiac function using two-dimensional speckle-tracking echocardiography to determine the effects of maternal diabetes and obesity on the fetal myocardium. Comparative cross-sectional evaluation of myocardial function in fetuses of mothers with diabetes mellitus (FDM) or obesity (FO) and normal gestational age-matched control fetuses (FC) was performed using two-dimensional speckle-tracking echocardiography at two centers. In total, 178 fetuses (82 FDM, 26 FO and 70 FC) met the enrolment criteria. Mean gestational age at assessment was similar among groups: 25.3 ± 5.1 weeks for FDM, 25.0 ± 4.6 weeks for FO and 25.1 ± 4.9 weeks for FC. Mean maternal body mass index was significantly higher in FDM and FO groups compared with the FC group. Statistically significant differences in fetal cardiac function were detected between FDM and FC for global longitudinal strain (mean ± SD, -21.4 ± 6.5% vs -27.0 ± 5.2%; P < 0.001), global circumferential strain (mean ± SD, -22.6 ± 6.5% vs -26.2 ± 6.8%; P = 0.002), average longitudinal systolic strain rate (median, -1.4 (interquartile range (IQR), -1.7 to -1.1)/s vs -1.6 (IQR, -2.0 to -1.4)/s; P = 0.001) and average circumferential systolic strain rate (median, -1.4 (IQR, -1.9 to -1.1)/s vs -1.6 (IQR, -2.1 to -1.3)/s; P = 0.006). Cases of non-obese FDM also had abnormal strain parameters compared with FC. Global longitudinal strain (mean ± SD, -21.1 ± 7.5%) and average circumferential systolic strain rate (median, -1.3 (IQR, -1.8 to -1.1)/s) were significantly lower in FO compared with FC. Unfavorable changes occur in the fetal myocardium in response to both maternal diabetes mellitus and obesity. The long-term prognostic implications of these changes require further study

Candidatus Frankia Datiscae Dg1, the Actinobacterial Microsymbiont of Datisca glomerata, Expresses the Canonical nod Genes nodABC in Symbiosis with Its Host Plant

PubMed Central

Persson, Tomas; Battenberg, Kai; Demina, Irina V.; Vigil-Stenman, Theoden; Vanden Heuvel, Brian; Pujic, Petar; Facciotti, Marc T.; Wilbanks, Elizabeth G.; O'Brien, Anna; Fournier, Pascale; Cruz Hernandez, Maria Antonia; Mendoza Herrera, Alberto; Médigue, Claudine; Normand, Philippe; Pawlowski, Katharina; Berry, Alison M.

2015-01-01

Frankia strains are nitrogen-fixing soil actinobacteria that can form root symbioses with actinorhizal plants. Phylogenetically, symbiotic frankiae can be divided into three clusters, and this division also corresponds to host specificity groups. The strains of cluster II which form symbioses with actinorhizal Rosales and Cucurbitales, thus displaying a broad host range, show suprisingly low genetic diversity and to date can not be cultured. The genome of the first representative of this cluster, Candidatus Frankia datiscae Dg1 (Dg1), a microsymbiont of Datisca glomerata, was recently sequenced. A phylogenetic analysis of 50 different housekeeping genes of Dg1 and three published Frankia genomes showed that cluster II is basal among the symbiotic Frankia clusters. Detailed analysis showed that nodules of D. glomerata, independent of the origin of the inoculum, contain several closely related cluster II Frankia operational taxonomic units. Actinorhizal plants and legumes both belong to the nitrogen-fixing plant clade, and bacterial signaling in both groups involves the common symbiotic pathway also used by arbuscular mycorrhizal fungi. However, so far, no molecules resembling rhizobial Nod factors could be isolated from Frankia cultures. Alone among Frankia genomes available to date, the genome of Dg1 contains the canonical nod genes nodA, nodB and nodC known from rhizobia, and these genes are arranged in two operons which are expressed in D. glomerata nodules. Furthermore, Frankia Dg1 nodC was able to partially complement a Rhizobium leguminosarum A34 nodC::Tn5 mutant. Phylogenetic analysis showed that Dg1 Nod proteins are positioned at the root of both α- and β-rhizobial NodABC proteins. NodA-like acyl transferases were found across the phylum Actinobacteria, but among Proteobacteria only in nodulators. Taken together, our evidence indicates an Actinobacterial origin of rhizobial Nod factors. PMID:26020781

Prevalence of diabetes, obesity, and metabolic syndrome in subjects with and without schizophrenia (CURES-104).

PubMed

Subashini, R; Deepa, M; Padmavati, R; Thara, R; Mohan, V

2011-01-01

There are some reports that diabetes and metabolic syndrome (MS) are more prevalent among schizophrenia patients. However, there are very few studies in India which have estimated the prevalence of diabetes and MS in schizophrenia patients. The aim of this study was to determine the prevalence of diabetes, obesity, and MS in subjects with and without schizophrenia. This case control study comprised of "cases" i.e. subjects with schizophrenia recruited from a schizophrenia centre at Chennai and "controls" i.e. healthy age- and gender-matched subjects without psychiatric illness selected from an ongoing epidemiological study in Chennai in a 1:4 ratio of cases: Controls. Fasting plasma glucose and serum lipids were estimated for all subjects. Anthropometric measures including height, weight, and waist circumference were assessed. Diabetes and impaired fasting glucose (IFG) were defined using American Diabetes Association criteria. One-way ANOVA or student's "t" test was used to compare continuous variables and Chi-square test to compare proportion between two groups. The study group comprised of 655 subjects, 131 with schizophrenia and a control group of 524 subjects without schizophrenia. The prevalence of the diabetes, IFG, abdominal obesity and MS were significantly higher among subjects with schizophrenia compared to those without schizophrenia-diabetes (15.3% vs. 7.3%, P=0.003), IFG (31.3% vs. 8.6%, P<0.001), abdominal obesity (59.2% vs. 44.7%, P<0.001), and MS (34.4% vs. 24%, P=0.014). In subjects with schizophrenia, the prevalence of diabetes, IFG, abdominal obesity, and MS is significantly higher than in those without schizophrenia.

Obesity/Type II diabetes alters macrophage polarization resulting in a fibrotic tendon healing response

PubMed Central

Ackerman, Jessica E.; Geary, Michael B.; Orner, Caitlin A.; Bawany, Fatima

2017-01-01

Type II Diabetes (T2DM) dramatically impairs the tendon healing response, resulting in decreased collagen organization and mechanics relative to non-diabetic tendons. Despite this burden, there remains a paucity of information regarding the mechanisms that govern impaired healing of diabetic tendons. Mice were placed on either a high fat diet (T2DM) or low fat diet (lean) and underwent flexor tendon transection and repair surgery. Healing was assessed via mechanical testing, histology and changes in gene expression associated with collagen synthesis, matrix remodeling, and macrophage polarization. Obese/diabetic tendons healed with increased scar formation and impaired mechanical properties. Consistent with this, prolonged and excess expression of extracellular matrix (ECM) components were observed in obese/T2DM tendons. Macrophages are involved in both inflammatory and matrix deposition processes during healing. Obese/T2DM tendons healed with increased expression of markers of pro-inflammatory M1 macrophages, and elevated and prolonged expression of M2 macrophages markers that are involved in ECM deposition. Here we demonstrate that tendons from obese/diabetic mice heal with increased scar formation and increased M2 polarization, identifying excess M2 macrophage activity and matrix synthesis as a potential mechanism of the fibrotic healing phenotype observed in T2DM tendons, and as such a potential target to improve tendon healing in T2DM. PMID:28686669

Role of the gastrointestinal ecosystem in the development of Type 1 Diabetes

PubMed Central

Daft, Joseph G.; Lorenz, Robin G.

2015-01-01

A new emphasis has been put on the role of the gastrointestinal (GI) ecosystem in autoimmune diseases; however, there is limited knowledge about its role in type 1 diabetes (T1D). Distinct differences have been observed in intestinal permeability, epithelial barrier function, commensal microbiota, and mucosal innate and adaptive immunity of patients and animals with T1D, when compared to healthy controls. The non-obese diabetic (NOD) mouse and the BioBreeding diabetes prone (BBdp) rat are the most commonly used models to study T1D pathogenesis. With the increasing awareness of the importance of the GI ecosystem in systemic disease, it is critical to understand the basics, as well as the similarities and differences between rat and mouse models and human patients. This review examines the current knowledge of the role of the GI ecosystem in T1D and indicates the extensive opportunities for further investigation that could lead to biomarkers and therapeutic interventions for disease prevention and/or modulation. PMID:25952017

The induction of autoimmune hepatitis in the human leucocyte antigen‐DR4 non‐obese diabetic mice autoimmune hepatitis mouse model

PubMed Central

Yuksel, M.; Xiao, X.; Tai, N.; Vijay, G. M.; Gülden, E.; Beland, K.; Lapierre, P.; Alvarez, F.; Hu, Z.; Colle, I.; Ma, Y.

2016-01-01

Summary Autoimmune hepatitis (AIH) is a chronic liver disease characterized by progressive inflammation, female preponderance and seropositivity for autoantibodies such as anti‐smooth muscle actin and/or anti‐nuclear, anti‐liver kidney microsomal type 1 (anti‐LKM1) and anti‐liver cytosol type 1 (anti‐LC1) in more than 80% of cases. AIH is linked strongly to several major histocompatibility complex (MHC) alleles, including human leucocyte antigen (HLA)‐DR3, ‐DR7 and ‐DR13. HLA‐DR4 has the second strongest association with adult AIH, after HLA‐DR3. We investigated the role of HLA‐DR4 in the development of AIH by immunization of HLA‐DR4 (DR4) transgenic non‐obese diabetic (NOD) mice with DNA coding for human CYP2D6/FTCD fusion autoantigen. Immunization of DR4 mice leads to sustained mild liver injury, as assessed biochemically by elevated alanine aminotransferase, histologically by interface hepatitis, plasma cell infiltration and mild fibrosis and immunologically by the development of anti‐LKM1/anti‐LC1 antibodies. In addition, livers from DR4 mice had fewer regulatory T cells (Tregs), which had decreased programmed death (PD)‐1 expression. Splenic Tregs from these mice also showed impaired inhibitory capacity. Furthermore, DR4 expression enhanced the activation status of CD8+ T cells, macrophages and dendritic cells in naive DR4 mice compared to naive wild‐type (WT) NOD mice. Our results demonstrate that HLA‐DR4 is a susceptibility factor for the development of AIH. Impaired suppressive function of Tregs and reduced PD‐1 expression may result in spontaneous activation of key immune cell subsets, such as antigen‐presenting cells and CD8+ T effectors, facilitating the induction of AIH and persistent liver damage. PMID:27414259

The induction of autoimmune hepatitis in the human leucocyte antigen-DR4 non-obese diabetic mice autoimmune hepatitis mouse model.

PubMed

Yuksel, M; Xiao, X; Tai, N; Vijay, G M; Gülden, E; Beland, K; Lapierre, P; Alvarez, F; Hu, Z; Colle, I; Ma, Y; Wen, L

2016-11-01

Autoimmune hepatitis (AIH) is a chronic liver disease characterized by progressive inflammation, female preponderance and seropositivity for autoantibodies such as anti-smooth muscle actin and/or anti-nuclear, anti-liver kidney microsomal type 1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) in more than 80% of cases. AIH is linked strongly to several major histocompatibility complex (MHC) alleles, including human leucocyte antigen (HLA)-DR3, -DR7 and -DR13. HLA-DR4 has the second strongest association with adult AIH, after HLA-DR3. We investigated the role of HLA-DR4 in the development of AIH by immunization of HLA-DR4 (DR4) transgenic non-obese diabetic (NOD) mice with DNA coding for human CYP2D6/FTCD fusion autoantigen. Immunization of DR4 mice leads to sustained mild liver injury, as assessed biochemically by elevated alanine aminotransferase, histologically by interface hepatitis, plasma cell infiltration and mild fibrosis and immunologically by the development of anti-LKM1/anti-LC1 antibodies. In addition, livers from DR4 mice had fewer regulatory T cells (T regs ), which had decreased programmed death (PD)-1 expression. Splenic T regs from these mice also showed impaired inhibitory capacity. Furthermore, DR4 expression enhanced the activation status of CD8 + T cells, macrophages and dendritic cells in naive DR4 mice compared to naive wild-type (WT) NOD mice. Our results demonstrate that HLA-DR4 is a susceptibility factor for the development of AIH. Impaired suppressive function of T regs and reduced PD-1 expression may result in spontaneous activation of key immune cell subsets, such as antigen-presenting cells and CD8 + T effectors, facilitating the induction of AIH and persistent liver damage. © 2016 British Society for Immunology.

Metabolic signals and innate immune activation in obesity and exercise.

PubMed

Ringseis, Robert; Eder, Klaus; Mooren, Frank C; Krüger, Karsten

2015-01-01

The combination of a sedentary lifestyle and excess energy intake has led to an increased prevalence of obesity which constitutes a major risk factor for several co-morbidities including type 2 diabetes and cardiovascular diseases. Intensive research during the last two decades has revealed that a characteristic feature of obesity linking it to insulin resistance is the presence of chronic low-grade inflammation being indicative of activation of the innate immune system. Recent evidence suggests that activation of the innate immune system in the course of obesity is mediated by metabolic signals, such as free fatty acids (FFAs), being elevated in many obese subjects, through activation of pattern recognition receptors thereby leading to stimulation of critical inflammatory signaling cascades, like IκBα kinase/nuclear factor-κB (IKK/NF- κB), endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and NOD-like receptor P3 (NLRP3) inflammasome pathway, that interfere with insulin signaling. Exercise is one of the main prescribed interventions in obesity management improving insulin sensitivity and reducing obesity- induced chronic inflammation. This review summarizes current knowledge of the cellular recognition mechanisms for FFAs, the inflammatory signaling pathways triggered by excess FFAs in obesity and the counteractive effects of both acute and chronic exercise on obesity-induced activation of inflammatory signaling pathways. A deeper understanding of the effects of exercise on inflammatory signaling pathways in obesity is useful to optimize preventive and therapeutic strategies to combat the increasing incidence of obesity and its comorbidities. Copyright © 2015 International Society of Exercise and Immunology. All rights reserved.

Obesity, diabetes, and associated costs of exposure to endocrine-disrupting chemicals in the European Union.

PubMed

Legler, Juliette; Fletcher, Tony; Govarts, Eva; Porta, Miquel; Blumberg, Bruce; Heindel, Jerrold J; Trasande, Leonardo

2015-04-01

Obesity and diabetes are epidemic in the European Union (EU). Exposure to endocrine-disrupting chemicals (EDCs) is increasingly recognized as a contributor, independent of diet and physical activity. The objective was to estimate obesity, diabetes, and associated costs that can be reasonably attributed to EDC exposures in the EU. An expert panel evaluated evidence for probability of causation using weight-of-evidence characterization adapted from that applied by the Intergovernmental Panel on Climate Change. Exposure-response relationships and reference levels were evaluated for relevant EDCs, and biomarker data were organized from peer-reviewed studies to represent European exposure and burden of disease. Cost estimation as of 2010 utilized published cost estimates for childhood obesity, adult obesity, and adult diabetes. Setting, Patients and Participants, and Intervention: Cost estimation was performed from the societal perspective. The panel identified a 40% to 69% probability of dichlorodiphenyldichloroethylene causing 1555 cases of overweight at age 10 (sensitivity analysis: 1555-5463) in 2010 with associated costs of €24.6 million (sensitivity analysis: €24.6-86.4 million). A 20% to 39% probability was identified for dichlorodiphenyldichloroethylene causing 28 200 cases of adult diabetes (sensitivity analysis: 28 200-56 400) with associated costs of €835 million (sensitivity analysis: €835 million-16.6 billion). The panel also identified a 40% to 69% probability of phthalate exposure causing 53 900 cases of obesity in older women and €15.6 billion in associated costs. Phthalate exposure was also found to have a 40% to 69% probability of causing 20 500 new-onset cases of diabetes in older women with €607 million in associated costs. Prenatal bisphenol A exposure was identified to have a 20% to 69% probability of causing 42 400 cases of childhood obesity, with associated lifetime costs of €1.54 billion. EDC exposures in the EU contribute

The impact of folic acid intake on the association among diabetes mellitus, obesity, and spina bifida.

PubMed

Parker, Samantha E; Yazdy, Mahsa M; Tinker, Sarah C; Mitchell, Allen A; Werler, Martha M

2013-09-01

The purpose of this study was to investigate the relationship between spina bifida and 2 established risk factors (pregestational diabetes mellitus and obesity) in both the presence and absence of the recommended daily folic acid intake in the periconceptional period. Cases of spina bifida (n = 1154) and control subjects (n = 9439) from the Slone Epidemiology Center Birth Defects Study (1976-2011) were included. Information on preexisting diabetes mellitus (collected 1976-2011) and obesity (collected 1993-2011), defined as a body mass index of ≥30 kg/m(2), was collected through interviews that were conducted within 6 months of delivery. Periconceptional folic acid intake was calculated with both dietary and supplement information. Mothers were classified as consuming more or less than 400 μg/day of folic acid; food folate was included at a 30% discount for its lower bioavailability. Logistic regression models that were adjusted for maternal age, race, education, and study site were used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for the joint effects of low folic acid intake coupled with diabetes mellitus or obesity. Case mothers were more likely to have diabetes mellitus or be obese (0.7% and 19.0%, respectively) than control mothers (0.4% and 10.8%, respectively). The joint effect of diabetes mellitus and lower folic acid intake on spina bifida was larger (aOR, 3.95; 95% CI, 1.56-10.00) than that of diabetes mellitus and higher folic acid intake (aOR, 1.31; 95% CI, 0.17-10.30). Folic acid intake made little difference on the association between obesity and spina bifida. Our findings suggest that folic acid further attenuates, although does not eliminate, the risk of spina bifida that is associated with diabetes mellitus than the risk with obesity. Copyright © 2013 Mosby, Inc. All rights reserved.

Microbiota and epigenetic regulation of inflammatory mediators in type 2 diabetes and obesity.

PubMed

Remely, M; Aumueller, E; Jahn, D; Hippe, B; Brath, H; Haslberger, A G

2014-03-01

Metabolic syndrome is associated with alterations in the structure of the gut microbiota leading to low-grade inflammatory responses. An increased penetration of the impaired gut membrane by bacterial components is believed to induce this inflammation, possibly involving epigenetic alteration of inflammatory molecules such as Toll-like receptors (TLRs). We evaluated changes of the gut microbiota and epigenetic DNA methylation of TLR2 and TLR4 in three groups of subjects: type 2 diabetics under glucagon-like peptide-1 agonist therapy, obese individuals without established insulin resistance, and a lean control group. Clostridium cluster IV, Clostridium cluster XIVa, lactic acid bacteria, Faecalibacterium prausnitzii and Bacteroidetes abundances were analysed by PCR and 454 high-throughput sequencing. The epigenetic methylation in the regulatory region of TLR4 and TLR2 was analysed using bisulfite conversion and pyrosequencing. We observed a significantly higher ratio of Firmicutes/ Bacteroidetes in type 2 diabetics compared to lean controls and obese. Major differences were shown in lactic acid bacteria, with the highest abundance in type 2 diabetics, followed by obese and lean participants. In comparison, F. prausnitzii was least abundant in type 2 diabetics, and most abundant in lean controls. Methylation analysis of four CpGs in the first exon of TLR4 showed significantly lower methylation in obese individuals, but no significant difference between type 2 diabetics and lean controls. Methylation of seven CpGs in the promoter region of TLR2 was significantly lower in type 2 diabetics compared to obese subjects and lean controls. The methylation levels of both TLRs were significantly correlated with body mass index. Our data suggest that changes in gut microbiota and thus cell wall components are involved in the epigenetic regulation of inflammatory reactions. An improved diet targeted to induce gut microbial balance and in the following even epigenetic changes of

[Association of beta 3-adrenergic receptor gene with obesity in patients with type 2 diabetes mellitus].

PubMed

Chen, Y; Xu, Y; Zhou, L

2001-09-01

To investigate the association between the mutation of beta 3-adrenergoc receptor gene and obesity in patients with type 2 diabetes. Body mass, waist-hip ratio, blood pressure and blood lipids were measured in 154 type 2 diabetic patients. Polymerase chain reaction and the restriction fragment length polymorphism analysis were used to determine the wild, heterozygous and homozygous forms of beta 3-adrenergoc receptor gene. The frequency of the Trp64Arg mutation was 42.5% and the frequency of Arg64 allele was 22.6%. The mutation frequency of the genetic types was significantly different between the obese and non-obese type 2 diabetes mellitus patients. The body mass, systolic blood pressure, diastolic blood pressure, HDL-cholesterol were significantly different, when those with Trp64Arg heterozygous were compared with those with Trp64 homozygous. The genetic mutation of beta 3-adrenegoc receptor in patients with type 2 diabetes is probably related to obesity.

Prevalence of obesity and diabetes in the socioeconomic transition of rural Mayas of Yucatan from 1962 to 2000.

PubMed

Loria, Alvar; Arroyo, Pedro; Fernandez, Victoria; Pardio, Jeanette; Laviada, Hugo

2018-02-20

The Mayas of the State of Yucatan in Mexico are the only aboriginal group with obesity and diabetes data before 1997. To analyze socioeconomic trends associated with the increase in obesity and diabetes seen in rural Yucatan from 1962 to 2000. Body weight, height and venous Fasting Blood Glucose (FBG) were measured in 263 rural Maya adults participating in a 2000 nutrition survey. Diabetes (FBG > 125 mg/dL) and obesity (BMI ≥ 30 kg/m 2 ) were 10.6% and 35.7%, respectively. These results contrast with those of a 1962 survey where diabetic prevalence was 2.3% and 0% in women and men respectively, with widespread adult pellagra and malnutrition. An important socioeconomic transition that took place in Yucatan during this lapse appeared to be associated to the obesity and diabetes increase. Rural Yucatan evolved from malnutrition conditions to high prevalence of obesity and diabetes in less than 40 years. This change was associated with the transition from an agroindustry-based economy, characterized by high-energy expenditure and low protein intake, to lower energy requirements of a Government-subsidized economy with larger food supply.

Obesity and type 2 diabetes mellitus in a birth cohort of First Nation children born to mothers with pediatric-onset type 2 diabetes.

PubMed

Mendelson, Michael; Cloutier, Justin; Spence, Louise; Sellers, Elizabeth; Taback, Shayne; Dean, Heather

2011-05-01

Children who are born to mothers with pediatric-onset type 2 diabetes mellitus are exposed to a hyperglycemic intra-uterine environment throughout pregnancy. The growth patterns and risk of type 2 diabetes in these offspring may be influenced by unique gene-environment interactions during intra-uterine and postnatal life. We established a cohort of offspring of First Nation mothers with onset of type 2 diabetes before age 18 years in Manitoba, Canada. We measured height or length and weight at study entry and annually thereafter with fasting blood glucose in offspring aged ≥ 7 years. We collected birth and breastfeeding history and determined the population-specific hepatic nuclear factor-1α (HNF-1α) G319S genotype of offspring at age 7 years. From July 2003 to April 2008, we enrolled 76 offspring of 37 mothers. Sixty-four percent (23/36) of the offspring aged 2-19 years were obese at initial assessment. The rates of obesity remained constant throughout the 5 years. As of April 2008, 7/28 (25%) of the offspring aged 7-19 years have diabetes including 6/14 (43%) aged 10-19 years. Most offspring with diabetes (5/7, 71%) were obese at diagnosis. All of the 7 offspring with diabetes have 1 or 2 copies of the G319S polymorphism. The prevalence of type 2 diabetes in this cohort of offspring of First Nation women with pediatric-onset type 2 diabetes is the highest ever reported. Obesity is an important postnatal risk factor for type 2 diabetes in this population and may result from a unique gene-environment interaction. © 2011 John Wiley & Sons A/S.

The obesity epidemic and rising diabetes incidence in a low-income racially diverse southern US cohort.

PubMed

Conway, Baqiyyah N; Han, Xijing; Munro, Heather M; Gross, Amy L; Shu, Xiao-Ou; Hargreaves, Margaret K; Zheng, Wei; Powers, Alvin C; Blot, William J

2018-01-01

Obesity is known to be a major risk factor for diabetes, but the magnitude of risk and variation between blacks and whites are less well documented in populations heavily affected by obesity. Herein we assess rates and risks of incident diabetes in a diverse southern population where obesity is common. A total of 24,000 black and 14,064 white adults aged 40-79 in the Southern Community Cohort Study with no self-reported diabetes at study enrollment during 2002-2009 was followed for up to 10 (median 4.5) years. Incidence rates, odds ratios (OR) and accompanying 95% confidence intervals (CI) for medication-treated incident diabetes were determined according to body mass index (BMI) and other characteristics, including tobacco and alcohol consumption, healthy eating and physical activity indices, and socioeconomic status (SES). Risk of incident diabetes rose monotonically with increasing BMI, but the trends differed between blacks and whites (pinteraction < .0001). Adjusted ORs (CIs) for diabetes among those with BMI≥40 vs 20-25 kg/m2 were 11.9 (8.4-16.8) for whites and 4.0 (3.3-4.8) for blacks. Diabetes incidence was more than twice as high among blacks than whites of normal BMI, but the racial difference became attenuated as BMI rose, with estimated 5-year probabilities of developing diabetes approaching 20% for both blacks and whites with BMI≥40 kg/m2. Diabetes risk was also associated with low SES, significantly (pinteraction≤.02) more so for whites, current cigarette smoking, and lower healthy eating and physical activity indices, although high BMI remained the predominant risk factor among both blacks and whites. From baseline prevalence and 20-year projections of the incidence trends, we estimate that the large majority of surviving cohort participants with BMI≥40 kg/m2 will be diagnosed with diabetes. Even using conservative criteria to ascertain diabetes incidence (i.e., requiring diabetes medication use and ignoring undiagnosed cases), rates of

The Influence of Maternal Obesity on Pregnancy Complications and Neonatal Outcomes in Diabetic and Nondiabetic Women

PubMed Central

Timur, Burcu Budak; Timur, Hakan; Tokmak, Aytekin; Isik, Hatice; Eyi, Elif Gul Yapar

2018-01-01

Introduction This study aimed to investigate the influence of obesity on pregnancy complications and neonatal outcomes in diabetic and nondiabetic women. Materials and Methods This retrospective case control study was conducted on 1193 pregnant women and their neonates at a tertiary level maternity hospital between March 2007 and 2011. The pregnant women were classified into 2 groups according to the presence of diabetes mellitus. Six hundred and seven patients with gestational diabetes or pregestational diabetes formed the diabetic group (study group) and 586 patients were in the nondiabetic group (control group). Demographic characteristics, body mass index, gestational weight gain, obstetric history, smoking status, type of delivery, gestational ages, pregnancy complications, neonatal outcomes were recorded for each patient. Multivariable logistic regression analysis was performed to evaluate the effect of obesity and diabetes on the pregnancy complications and neonatal outcomes. Results The mean age and pre-pregnancy body mass indices of women with diabetes mellitus were significantly higher than the control groupʼs (p < 0.001). Gestational weight gain and number of smokers were similar among the groups. Multiparity and obesity were more prevalent in the diabetic group compared to controls (both p < 0.001). Although gestational age at birth was earlier in the diabetic group, birth weights were higher in this group than in the control group (both p < 0.001). Cesarean delivery rates, the incidence of macrosomia, and neonatal intensive care unit admission rates were significantly higher in the diabetes group both with normal and increased body mass index (all p < 0.001). However, adverse pregnancy outcomes were comparable between the groups (p = 0.279). Multivariable logistic regression analysis showed that obesity is a significant risk factor for pregnancy complications (OR = 1.772 [95% CI, 1.283 – 2.449], p = 0.001) but not for

The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance.

PubMed

Vandanmagsar, Bolormaa; Youm, Yun-Hee; Ravussin, Anthony; Galgani, Jose E; Stadler, Krisztian; Mynatt, Randall L; Ravussin, Eric; Stephens, Jacqueline M; Dixit, Vishwa Deep

2011-02-01

The emergence of chronic inflammation during obesity in the absence of overt infection or well-defined autoimmune processes is a puzzling phenomenon. The Nod-like receptor (NLR) family of innate immune cell sensors, such as the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (Nlrp3, but also known as Nalp3 or cryopyrin) inflammasome are implicated in recognizing certain nonmicrobial originated 'danger signals' leading to caspase-1 activation and subsequent interleukin-1β (IL-1β) and IL-18 secretion. We show that calorie restriction and exercise-mediated weight loss in obese individuals with type 2 diabetes is associated with a reduction in adipose tissue expression of Nlrp3 as well as with decreased inflammation and improved insulin sensitivity. We further found that the Nlrp3 inflammasome senses lipotoxicity-associated increases in intracellular ceramide to induce caspase-1 cleavage in macrophages and adipose tissue. Ablation of Nlrp3 in mice prevents obesity-induced inflammasome activation in fat depots and liver as well as enhances insulin signaling. Furthermore, elimination of Nlrp3 in obese mice reduces IL-18 and adipose tissue interferon-γ (IFN-γ) expression, increases naive T cell numbers and reduces effector T cell numbers in adipose tissue. Collectively, these data establish that the Nlrp3 inflammasome senses obesity-associated danger signals and contributes to obesity-induced inflammation and insulin resistance.

The NALP3/NLRP3 Inflammasome Instigates Obesity-Induced Autoinflammation and Insulin Resistance

PubMed Central

Vandanmagsar, Bolormaa; Youm, Yun-Hee; Ravussin, Anthony; Galgani, Jose E.; Stadler, Krisztian; Mynatt, Randall L.; Ravussin, Eric; Stephens, Jacqueline M.; Dixit, Vishwa Deep

2010-01-01

Emergence of chronic ‘sterile’ inflammation during obesity in absence of overt infection or autoimmune process is a puzzling phenomenon. The Nod Like Receptor (NLR) family of innate immune cell sensors like the Nlrp3 inflammasome are implicated in recognizing certain non-microbial origin ‘danger–signals’ leading to caspase-1 activation and subsequent IL-1β and IL-18 secretion. We show that reduction in adipose tissue expression of Nlrp3 is coupled with decreased inflammation and improved insulin–sensitivity in obese type-2 diabetic patients. The Nlrp3 inflammasome senses the lipotoxicity–associated ceramide to induce caspase-1 cleavage in macrophages and adipose tissue. Ablation of Nlrp3 prevented the obesity–induced inflammasome activation in fat depots and liver together with enhanced insulin–signalling. Furthermore, elimination of Nlrp3 in obesity reduced IL-18 and adipose tissue IFNγ along with an increase in naïve and reduction in effector adipose tissue T cells. Collectively, these data establish that Nlrp3 inflammasome senses obesity–associated ‘danger–signals’ and contributes to obesity–induced inflammation and insulin–resistance. PMID:21217695

Muramyl peptides activate innate immunity conjointly via YB1 and NOD2.

PubMed

Laman, Alexander G; Lathe, Richard; Shepelyakovskaya, Anna O; Gartseva, Alexandra; Brovko, Feodor A; Guryanova, Svetlana; Alekseeva, Ludmila; Meshcheryakova, Elena A; Ivanov, Vadim T

2016-11-01

Bacterial cell wall muramyl dipeptide (MDP) and glucosaminyl-MDP (GMDP) are potent activators of innate immunity. Two receptor targets, NOD2 and YB1, have been reported; we investigated potential overlap of NOD2 and YB1 pathways. Separate knockdown of NOD2 and YB1 demonstrates that both contribute to GMDP induction of NF-κB expression, a marker of innate immunity, although excess YB1 led to induction in the absence of NOD2. YB1 and NOD2 co-migrated on sucrose gradient centrifugation, and GMDP addition led to the formation of higher molecular mass complexes containing both YB1 and NOD2. Co-immunoprecipitation demonstrated a direct interaction between YB1 and NOD2, a major recombinant fragment of NOD2 (NACHT-LRR) bound to YB1, and complex formation was stimulated by GMDP. We also report subcellular colocalization of NOD2 and YB1. Although YB1 may have other binding partners in addition to NOD2, maximal innate immunity activation by muramyl peptides is mediated via an interaction between YB1 and NOD2.

Protective Effect of Gymnema sylvestre Ethanol Extract on High Fat Diet-induced Obese Diabetic Wistar Rats

PubMed Central

Kumar, V.; Bhandari, Uma; Tripathi, C. D.; Khanna, Geetika

2014-01-01

Obesity is associated with numerous co-morbidities such as cardiovascular diseases, type 2 diabetes, hypertension and others. Therefore, the present study was planned to investigate the effect of water- soluble fraction of Gymnema sylvestre ethanol extract on biochemical and molecular alterations in obese diabetic rats. Diabetes was induced by single i.v. injection of streptozotocin (45 mg/kg) via tail vein. Obesity was induced by oral feeding of high fat diet for a period of 28 days in diabetic rats. Body weight gain, food intake, water intake, hemodynamic parameters (systolic, diastolic, mean arterial blood pressures and heart rate), serum biochemical parameters (leptin, insulin, lipid levels, apolipoprotein B and glucose), cardiomyocyte apoptosis (cardiac caspase-3, Na+/K+ ATPase activity and DNA fragmentation) organs and visceral fat pad weight and oxidative stress parameters were measured. Oral treatment with water soluble fraction of Gymnema sylvestre ethanol extracts (120 mg/kg/p.o.) for a period of 21 days, resulted in significant reduction in heart rate, mean arterial pressure, serum leptin, insulin, apolipoprotein B, lipids, glucose, cardiac caspase-3 levels, Na+/K+ ATPase activity and DNA laddering, visceral fat pad and organ's weight and improved the antioxidant enzymes levels in the high fat diet induced obesity in diabetic rats. The results of present study reveal that water soluble fraction of Gymnema sylvestre ethanol extract could be useful intervention in the treatment of obesity and type-2 diabetes mellitus. PMID:25284929

Protective Effect of Gymnema sylvestre Ethanol Extract on High Fat Diet-induced Obese Diabetic Wistar Rats.

PubMed

Kumar, V; Bhandari, Uma; Tripathi, C D; Khanna, Geetika

2014-07-01

Obesity is associated with numerous co-morbidities such as cardiovascular diseases, type 2 diabetes, hypertension and others. Therefore, the present study was planned to investigate the effect of water- soluble fraction of Gymnema sylvestre ethanol extract on biochemical and molecular alterations in obese diabetic rats. Diabetes was induced by single i.v. injection of streptozotocin (45 mg/kg) via tail vein. Obesity was induced by oral feeding of high fat diet for a period of 28 days in diabetic rats. Body weight gain, food intake, water intake, hemodynamic parameters (systolic, diastolic, mean arterial blood pressures and heart rate), serum biochemical parameters (leptin, insulin, lipid levels, apolipoprotein B and glucose), cardiomyocyte apoptosis (cardiac caspase-3, Na(+)/K(+) ATPase activity and DNA fragmentation) organs and visceral fat pad weight and oxidative stress parameters were measured. Oral treatment with water soluble fraction of Gymnema sylvestre ethanol extracts (120 mg/kg/p.o.) for a period of 21 days, resulted in significant reduction in heart rate, mean arterial pressure, serum leptin, insulin, apolipoprotein B, lipids, glucose, cardiac caspase-3 levels, Na(+)/K(+) ATPase activity and DNA laddering, visceral fat pad and organ's weight and improved the antioxidant enzymes levels in the high fat diet induced obesity in diabetic rats. The results of present study reveal that water soluble fraction of Gymnema sylvestre ethanol extract could be useful intervention in the treatment of obesity and type-2 diabetes mellitus.

Obesity and type 1 diabetes mellitus management.

PubMed

Chillarón, J J; Benaiges, D; Mañé, L; Pedro-Botet, J; Flores Le-Roux, J A

2015-03-01

Patients with type 1 diabetes mellitus (T1DM) traditionally had a low body mass index and microangiopathic complications were common. The Diabetes Control and Complications Trial, published in 1993, demonstrated that therapy aimed at maintaining HbA1c levels as close to normal as feasible reduced the incidence of microangiopathy. Since then, the use of intensive insulin therapy to optimise metabolic control became generalised, with two main side effects: a higher rate of severe hypoglycaemia and increased weight gain. Approximately 50% of patients with T1DM are currently obese or overweight, which reduces or nullifies the benefits of good metabolic control, and which has other negative consequences; therefore, strategies to achieve weight control in patients with T1DM are necessary. At present, treatment with GLP-1 and SGLT-2 inhibitors has yielded promising short-term results that need to be confirmed in studies with larger numbers of patients and long-term follow-up. It is possible that, in coming years, the applicability of bariatric surgery in obese patients with T1DM will be similar to that of the general population or T2DM.

Obesity, Insulin Resistance and Diabetes: Sex Differences and Role of Estrogen Receptors

PubMed Central

Meyer, Matthias R.; Clegg, Deborah J.; Prossnitz, Eric R.; Barton, Matthias

2010-01-01

Obesity increases the risk of coronary artery disease through insulin resistance, diabetes, arterial hypertension, and dyslipidemia. The prevalence of obesity has increased worldwide and is particularly high among middle-aged women and men. After menopause, women are at an increased risk to develop visceral obesity due to the loss of endogenous ovarian hormone production. Effects of estrogens are classically mediated by the two nuclear estrogen receptors (ERs) α and β. In addition, more recent research has shown that the intracellular transmembrane G protein-coupled estrogen receptor, GPER, originally designated as GPR30, also mediates some of the actions attributed to estrogens. Estrogen and its receptors are important regulators of body weight and insulin sensitivity not only in women, but also in men as demonstrated by ER mutations in rodents and humans. This article reviews the role of sex hormones and estrogen receptors in the context of obesity, insulin sensitivity and diabetes as well as the related clinical issues in females and males. PMID:21281456

Birth weight predicts the risk of gestational diabetes mellitus and pregravid obesity.

PubMed

Ogonowski, Jarosław; Miazgowski, Tomasz; Engel, Karina; Celewicz, Zbigniew

2014-01-01

It has been suggested that birth weight may determine metabolic abnormalities later in life. The aim of the current study was to assess the association between birth weight and future risk of gestational diabetes mellitus (GDM) and pregravid obesity in a homogenous sample of Caucasian Polish women. In this retrospective study, we collected the medical reports of 787 women with GDM and 801 healthy pregnant women. We analyzed the following data: birth weight, age, pregravid weight, prior GDM, prior macrosomia, parity, and family history of diabetes. Birth weight was inversely associated with the risk of GDM; for each decrease in birth weight of 500 g, the risk increased by 11% (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.02-1.21). Birth weight was a strong predictor of GDM independent of other risk factors (OR, 1.19; 95% CI, 1.09-1.31), and it was positively correlated with pregravid weight (R = 0.21; P < 0.00001). An increase in birth weight of 500 g substantially increased the risk of overweight and obesity (OR, 1.17; 95% CI, 1.01-1.34 and OR, 1.35; 95% CI 1.11-1.64, respectively). Each of the traditional risk factors for GDM were also strong predictors of pregravid obesity: age (P < 0.0001), prior GDM (P < 0.01), prior macrosomia (P < 0.0001), multiparity (P < 0.0001), and maternal (but not paternal) history of diabetes (P < 0.0001). Among Caucasian Polish women, the risk of GDM is associated with low birth weight, and pregravid obesity is associated with high birth weight. Traditional risk factors for GDM, including maternal (but not paternal) history of diabetes, are also risk factors for pregravid obesity. Copyright © 2014 Elsevier Inc. All rights reserved.

The effect of rural-to-urban migration on obesity and diabetes in India: a cross-sectional study.

PubMed

Ebrahim, Shah; Kinra, Sanjay; Bowen, Liza; Andersen, Elizabeth; Ben-Shlomo, Yoav; Lyngdoh, Tanica; Ramakrishnan, Lakshmy; Ahuja, R C; Joshi, Prashant; Das, S Mohan; Mohan, Murali; Davey Smith, George; Prabhakaran, Dorairaj; Reddy, K Srinath

2010-04-27

Migration from rural areas of India contributes to urbanisation and may increase the risk of obesity and diabetes. We tested the hypotheses that rural-to-urban migrants have a higher prevalence of obesity and diabetes than rural nonmigrants, that migrants would have an intermediate prevalence of obesity and diabetes compared with life-long urban and rural dwellers, and that longer time since migration would be associated with a higher prevalence of obesity and of diabetes. The place of origin of people working in factories in north, central, and south India was identified. Migrants of rural origin, their rural dwelling sibs, and those of urban origin together with their urban dwelling sibs were assessed by interview, examination, and fasting blood samples. Obesity, diabetes, and other cardiovascular risk factors were compared. A total of 6,510 participants (42% women) were recruited. Among urban, migrant, and rural men the age- and factory-adjusted percentages classified as obese (body mass index [BMI] >25 kg/m(2)) were 41.9% (95% confidence interval [CI] 39.1-44.7), 37.8% (95% CI 35.0-40.6), and 19.0% (95% CI 17.0-21.0), respectively, and as diabetic were 13.5% (95% CI 11.6-15.4), 14.3% (95% CI 12.2-16.4), and 6.2% (95% CI 5.0-7.4), respectively. Findings for women showed similar patterns. Rural men had lower blood pressure, lipids, and fasting blood glucose than urban and migrant men, whereas no differences were seen in women. Among migrant men, but not women, there was weak evidence for a lower prevalence of both diabetes and obesity among more recent (obesity, which drive other risk factor changes. Migrants have adopted modes of life that put them at similar risk to the urban population. Gender differences in some risk factors by place of origin are unexpected and require further exploration. Please see later in the article for the Editors' Summary.

Physical Interactions and Expression Quantitative Traits Loci Identify Regulatory Connections for Obesity and Type 2 Diabetes Associated SNPs

PubMed Central

Fadason, Tayaza; Ekblad, Cameron; Ingram, John R.; Schierding, William S.; O'Sullivan, Justin M.

2017-01-01

The mechanisms that underlie the association between obesity and type 2 diabetes are not fully understood. Here, we investigated the role of the 3D genome organization in the pathogeneses of obesity and type-2 diabetes. We interpreted the combined and differential impacts of 196 diabetes and 390 obesity associated single nucleotide polymorphisms (SNPs) by integrating data on the genes with which they physically interact (as captured by Hi-C) and the functional [i.e., expression quantitative trait loci (eQTL)] outcomes associated with these interactions. We identified 861 spatially regulated genes (e.g., AP3S2, ELP5, SVIP, IRS1, FADS2, WFS1, RBM6, HORMAD1, PYROXD2), which are enriched in tissues (e.g., adipose, skeletal muscle, pancreas) and biological processes and canonical pathways (e.g., lipid metabolism, leptin, and glucose-insulin signaling pathways) that are important for the pathogenesis of type 2 diabetes and obesity. Our discovery-based approach also identifies enrichment for eQTL SNP-gene interactions in tissues that are not classically associated with diabetes or obesity. We propose that the combinatorial action of active obesity and diabetes spatial eQTL SNPs on their gene pairs within different tissues reduces the ability of these tissues to contribute to the maintenance of a healthy energy metabolism. PMID:29081791

Fasting glucose, obesity, and metabolic syndrome as predictors of type 2 diabetes: the Cooper Center Longitudinal Study.

PubMed

DeFina, Laura F; Vega, Gloria Lena; Leonard, David; Grundy, Scott M

2012-12-01

To determine risk for type 2 diabetes in subjects with fasting glucose levels in the ranges of normoglycemia, mild hyperglycemia, and intermediate hyperglycemia and to assess the effect of obesity and metabolic syndrome on this risk. Incidence of type 2 diabetes mellitus was evaluated in 28,209 relatively healthy subjects participating in the Cooper Center Longitudinal Study. They were included in the study if they had more than 1 fasting plasma glucose measurement, anthropometry, and other parameters of interest. Three subgroups were identified: normoglycemic (<5.6 mmol/L), mild hyperglycemia (5.6-6.0 mmol/L), and intermediate hyperglycemia (6.1-7.0 mmol/L). Diabetes incidence was calculated in categories of sex, age, obesity, and metabolic syndrome status. Incident diabetes was assessed at the earliest clinic visit at which the individual exhibited a blood glucose level of more than 7.0 mmol/L or reported a diagnosis of diabetes. Thirty-one percent of men and 15.9% of women had mild hyperglycemia and 11.9% of men and 3.6% of women had intermediate hyperglycemia. Yearly conversion rates to diabetes were low in individuals with normoglycemia and mild hyperglycemia but were strikingly higher in those with intermediate hyperglycemia. In subjects with intermediate hyperglycemia, presence of obesity and/or metabolic syndrome doubled conversion rates to diabetes. This study showed a marked difference in outcomes in subjects with mild and intermediate hyperglycemia. Moreover, obesity and metabolic syndrome were associated with strikingly elevated risk for diabetes in subjects with intermediate hyperglycemia. Thus intermediate hyperglycemia plus obesity/metabolic syndrome seemingly justifies intensive clinical intervention for prevention of both diabetes and cardiovascular disease.

DGAT: novel therapeutic target for obesity and type 2 diabetes mellitus.

PubMed

Subauste, Angela; Burant, Charles F

2003-12-01

Obesity is currently an exceptionally common problem in humans. The last several years have produced a significant number of breakthroughs in obesity related areas of investigation. Triglycerides are considered the main form of storage of excess calories in fat. A key enzyme in the synthesis of triglycerides is acylCoA: diacylglycerol acyltransferase (DGAT). Recent studies have shown that mice deficient in this enzyme are resistant to diet induced obesity and have increased insulin and leptin sensitivity. These effects suggest that inhibition of DGAT in vivo may be a novel therapeutic target not only for obesity but also for diabetes.

Fungal β-glucan, a Dectin-1 ligand, promotes protection from Type 1 Diabetes by inducing regulatory innate immune response1

PubMed Central

Karumuthil-Melethil, Subha; Gudi, Radhika; Johnson, Benjamin M.; Perez, Nicolas; Vasu, Chenthamarakshan

2014-01-01

Beta-glucans (β-glucans) are naturally occurring polysaccharides in cereal grains, mushrooms, algae, or microbes including bacteria, fungi, and yeast. Immune cells recognize these β-glucans through a cell surface pathogen recognition receptor (PRR) called Dectin-1. Studies using β-glucans and other Dectin-1 binding components have demonstrated the potential of these agents in activating the immune cells for cancer treatment and controlling infections. Here, we show that the β-glucan from Saccharomyces cerevisiae induces the expression of immune regulatory cytokines (IL-10, TGF-β1 and IL-2) and a tolerogenic enzyme (Indoleamine 2, 3-dioxygenase; IDO) in bone marrow derived DCs (BM DCs) as well as spleen cells. These properties can be exploited to modulate autoimmunity in non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). Treatment of pre-diabetic NOD mice with low dose β-glucan resulted in a profound delay in hyperglycemia and this protection was associated with increase in the frequencies of Foxp3-, LAP-, and GARP-positive T cells. Upon antigen presentation, β-glucan-exposed DCs induced a significant increase in Foxp3− and LAP− positive T cells in in vitro cultures. Further, systemic co-administration of β-glucan plus pancreatic β-cell-Ag resulted in an enhanced protection of NOD mice from T1D as compared to treatment with β-glucan alone. These observations demonstrate that the innate immune response induced by low dose β-glucan is regulatory in nature and can be exploited to modulate T cell response to β-cell-Ag for inducing an effective protection from T1D. PMID:25143443

Immune Cells Link Obesity-associated Type 2 Diabetes and Periodontitis

PubMed Central

Zhu, M.; Nikolajczyk, B.S.

2014-01-01

The clinical association between obesity-associated type 2 diabetes (T2D) and periodontitis, coupled with the increasing prevalence of these diseases, justifies studies to identify mechanisms responsible for the vicious feed-forward loop between systemic and oral disease. Changes in the immune system are critical for both obesity-associated T2D and periodontitis and therefore may link these diseases. Recent studies at the intersection of immunology and metabolism have greatly advanced our understanding of the role the immune system plays in the transition between obesity and obesity-associated T2D and have shown that immune cells exhibit similar functional changes in obesity/T2D and periodontitis. Furthermore, myeloid and lymphoid cells likely synergize to promote obesity/T2D-associated periodontitis despite complexities introduced by disease interaction. Thus the groundwork is being laid for researchers to exploit existing models to understand immune cell dysfunction and break the devastating relationship between obesity-associated T2D and oral disease. PMID:24393706

Carbon dioxide emissions and change in prevalence of obesity and diabetes in the United States: an ecological study.

PubMed

Zheutlin, Alexander R; Adar, Sara D; Park, Sung Kyun

2014-12-01

Recent studies suggest that increasing levels of the greenhouse gas, carbon dioxide (CO2), may influence weight gain and thus may play a role in rising trends in obesity and diabetes. We conducted an ecological study to examine the associations between CO2 emissions from fossil fuel combustion and changes in the prevalence of obesity and diabetes in the United States. County-level data on CO2 emissions, prevalence of obesity and diagnosed diabetes, other sociodemographic factors and neighborhood characteristics related to urbanicity, and fine particles (PM2.5) between 2004 and 2008 were obtained from the Vulcan Project, Centers for Disease Control and Prevention, and American Community Survey. Linear mixed effect modeling of 3019 counties for the associations between average CO2 emissions and changes in diabetes and obesity prevalence between 2004 and 2008 was performed. The average obesity and diabetes prevalence increased between 2004 and 2008 by 3.65% (SD: 1.88%) and 1.65% (SD: 1.70%), respectively. A marginally significant positive association between CO2 emission and changes in obesity prevalence was found with adjustment for sociodemographic factors, indicators of urbanicity and spatial autocorrelation (p-trend=0.06). The association became weaker and nonsignificant with further adjustment for PM2.5 (p-trend=0.17). There was a significant positive association between CO2 emission and changes in diabetes prevalence before controlling for PM2.5 (p-trend=0.05) but the association became null after controlling for PM2.5 (p-trend=0.49), suggesting that PM2.5 is a critical confounder in the association between CO2 emission and changes in diabetes prevalence. This study does not support the hypothesis that CO2 emissions, a leading driver of climate change, may be linked to increasing trends in obesity and diabetes, though there was an indication of possible link between CO2 and obesity. Copyright © 2014 Elsevier Ltd. All rights reserved.