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Sample records for aggravates insulin resistance

  1. Obesity does not aggravate osteoporosis or osteoblastic insulin resistance in orchiectomized rats.

    PubMed

    Potikanond, Saranyapin; Rattanachote, Pinyada; Pintana, Hiranya; Suntornsaratoon, Panan; Charoenphandhu, Narattaphol; Chattipakorn, Nipon; Chattipakorn, Siriporn

    2016-02-01

    The present study aimed to test the hypothesis that testosterone deprivation impairs osteoblastic insulin signaling, decreases osteoblast survival, reduces bone density, and that obesity aggravates those deleterious effects in testosterone-deprived rats. Twenty four male Wistar rats underwent either a bilateral orchiectomy (O, n=12) or a sham operation (S, n=12). Then the rats in each group were further divided into two subgroups fed with either a normal diet (ND) or a high-fat diet (HF) for 12 weeks. At the end of the protocol, blood samples were collected to determine metabolic parameters and osteocalcin ratios. The tibiae were collected to determine bone mass using microcomputed tomography and for osteoblast isolation. The results showed that rats fed with HF (sham-operated HF-fed rats (HFS) and ORX HF-fed rats (HFO)) developed peripheral insulin resistance and had decreased trabecular bone density. In ND-fed rats, only the ORX ND-fed rats (NDO) group had decreased trabecular bone density. In addition, osteoblastic insulin resistance, as indicated by a decrease in tyrosine phosphorylation of the insulin receptor and Akt, were observed in all groups except the sham-operated ND-fed rats (NDS) rats. Those groups, again with the exception of the NDS rats, also had decreased osteoblastic survival. No differences in the levels of osteoblastic insulin resistance and osteoblastic survival were found among the NDO, HFS, and HFO groups. These findings suggest that either testosterone deprivation or obesity alone can impair osteoblastic insulin signaling and decrease osteoblastic survival leading to the development of osteoporosis. However, obesity does not aggravate those deleterious effects in the bone of testosterone-deprived rats. PMID:26675491

  2. Trans-Fatty Acids Aggravate Obesity, Insulin Resistance and Hepatic Steatosis in C57BL/6 Mice, Possibly by Suppressing the IRS1 Dependent Pathway.

    PubMed

    Zhao, Xiaona; Shen, Cheng; Zhu, Hong; Wang, Cong; Liu, Xiangwei; Sun, Xiaolei; Han, Shasha; Wang, Peng; Dong, Zhen; Ma, Xin; Hu, Kai; Sun, Aijun; Ge, Junbo

    2016-01-01

    Trans-fatty acid consumption has been reported as a risk factor for metabolic disorders and targeted organ damages. Nonetheless, little is known about the roles and mechanisms of trans-fatty acids in obesity, insulin resistance (IR) and hepatic steatosis. Adult C57BL/6 male mice were fed with four different diets for 20 weeks: normal diet (ND), high fat diet (HFD), low trans-fatty acids diet (LTD) and high trans-fatty acid diet (HTD). The diet-induced metabolic disorders were assessed by evaluating body weight, glucose tolerance test, hepatic steatosis and plasma lipid profiles post 20-week diet. Histological (H&E, Oil-Red-O) staining and western blot analysis were employed to assess liver steatosis and potential signaling pathways. After 20-weeks of diet, the body weights of the four groups were 29.61 ± 1.89 g (ND), 39.04 ± 4.27 g (HFD), 34.09 ± 2.62 g (LTD) and 43.78 ± 4.27 g (HTD) (p < 0.05), respectively. HFD intake significantly impaired glucose tolerance, which was impaired further in the mice consuming the HTD diet. The effect was further exacerbated by HTD diet. Moreover, the HTD group exhibited significantly more severe liver steatosis compared with HFD group possibly through regulating adipose triglyceride lipase. The group consuming the HTD also exhibited significantly reduced levels of IRS1, phosphor-PKC and phosphor-AKT. These results support our hypothesis that consumption of a diet high in trans-fatty acids induces higher rates of obesity, IR and hepatic steatosis in male C57BL/6 mice, possibly by suppressing the IRS1dependent pathway. PMID:27248994

  3. Insulin resistance and insulin sensitizers.

    PubMed

    Stumvoll, M; Häring, H

    2001-01-01

    Insulin resistance is a key factor in the pathogenesis of type 2 diabetes mellitus and a co-factor in the development of dyslipidaemia, hypertension and atherosclerosis. The causes of insulin resistance include factors such as obesity and physical inactivity, and there may also be genetic factors. The mechanism of obesity-related insulin resistance involves the release of factors from adipocytes which exert a negative effect on glucose metabolism: free fatty acids, tumour necrosis factor-alpha and the recently discovered hormone, resistin. The two resulting abnormalities observed consistently in glucose-intolerant states are impaired suppression of endogenous glucose production, and impaired stimulation of glucose uptake. Among the genetic factors, a polymorphism (Pro12Ala) in the peroxisome proliferator-activated receptor (PPAR) gamma is associated with a reduced risk of type 2 diabetes mellitus and increased insulin sensitivity, primarily that of lipolysis. On the other hand, the association with insulin resistance of a common polymorphism (Gly972Arg) in the insulin receptor substrate 1, long believed to be a plausible candidate gene, is weak at best. This polymorphism may instead be associated with reduced insulin secretion, which, in view of the recent recognition of the insulin signalling system in beta-cells, results in the development of a novel pathogenic concept. Finally, fine-mapping and positional cloning of the susceptibility locus on chromosome 2 resulted in the identification of a polymorphism (UCSNP-43 G/A) in the calpain-10 gene. In non-diabetic Pima Indians, this polymorphism was associated with insulin resistance of glucose disposal. The pharmacological treatment of insulin resistance has recently acquired a novel class of agents: the thiazolidinediones. They act through regulation of PPARgamma-dependent genes and probably interfere favourably with factors released from adipocytes which mediate obesity-associated insulin resistance. PMID:11684868

  4. Inflammation and Insulin Resistance

    PubMed Central

    de Luca, Carl; Olefsky, Jerrold M.

    2008-01-01

    Obesity-induced chronic inflammation is a key component in the pathogenesis of insulin resistance and the Metabolic syndrome. In this review, we focus on the interconnection between obesity, inflammation and insulin resistance. Pro-inflammatory cytokines can cause insulin resistance in adipose tissue, skeletal muscle and liver by inhibiting insulin signal transduction. The sources of cytokines in insulin resistant states are the insulin target tissue themselves, primarily fat and liver, but to a larger extent the activated tissue resident macrophages. While the initiating factors of this inflammatory response remain to be fully determined, chronic inflammation in these tissues could cause localized insulin resistance via autocrine/paracrine cytokine signaling and systemic insulin resistance via endocrine cytokine signaling all of which contribute to the abnormal metabolic state. PMID:18053812

  5. All about Insulin Resistance

    MedlinePlus

    ... news is that cutting calories, being active, and losing weight can reverse insulin resistance and lower your ... you’ll lose weight. Studies have shown that losing even 7% of your weight, may help. For ...

  6. Insulin Resistance and Prediabetes

    MedlinePlus

    ... sleep apnea; and cigarette smoking. [ Top ] Does sleep matter? Yes. Studies show that untreated sleep problems, especially ... a severe form of insulin resistance may have dark patches of skin, usually on the back of ...

  7. Insulin Resistance of Puberty.

    PubMed

    Kelsey, Megan M; Zeitler, Philip S

    2016-07-01

    Puberty is a time of considerable metabolic and hormonal change. Notably, puberty is associated with a marked decrease in insulin sensitivity, on par with that seen during pregnancy. In otherwise healthy youth, there is a nadir in insulin sensitivity in mid-puberty, and then it recovers at puberty completion. However, there is evidence that insulin resistance (IR) does not resolve in youth who are obese going into puberty and may result in increased cardiometabolic risk. Little is known about the underlying pathophysiology of IR in puberty, and how it might contribute to increased disease risk (e.g., type 2 diabetes). In this review, we have outlined what is known about the IR in puberty in terms of pattern, potential underlying mechanisms and other mediating factors. We also outline other potentially related metabolic changes that occur during puberty, and effects of underlying insulin resistant states (e.g., obesity) on pubertal changes in insulin sensitivity. PMID:27179965

  8. Depression and Insulin Resistance

    PubMed Central

    Pearson, Sue; Schmidt, Mike; Patton, George; Dwyer, Terry; Blizzard, Leigh; Otahal, Petr; Venn, Alison

    2010-01-01

    OBJECTIVE To examine the association between depressive disorder and insulin resistance in a sample of young adults using the Composite International Diagnostic Interview to ascertain depression status. RESEARCH DESIGN AND METHODS Cross-sectional data were collected from 1,732 participants aged between 26 and 36 years. Insulin resistance was derived from blood chemistry measures of fasting insulin and glucose using the homeostasis model assessment method. Those identified with mild, moderate, or severe depression were classified as having depressive disorder. RESULTS The 12-month prevalence of depressive disorder was 5.4% among men and 11.7% among women. In unadjusted models mean insulin resistance was 17.2% (95% CI 0.7–36.0%, P = 0.04) higher in men and 11.4% (1.5–22.0%, P = 0.02) higher in women with depressive disorder. After adjustment for behavioral and dietary factors, the increased level of insulin resistance associated with depressive disorder was 13.2% (−3.1 to 32.3%, P = 0.12) in men and 6.1% (−4.1 to 17.4%, P = 0.25) in women. Waist circumference was identified as a mediator in the relationship between depression and insulin resistance, reducing the β coefficient in the fully adjusted models in men by 38% and in women by 42%. CONCLUSIONS A positive association was found between depressive disorder and insulin resistance in this population-based sample of young adult men and women. The association seemed to be mediated partially by waist circumference. PMID:20185745

  9. Insulin Resistance in Alzheimer's Disease

    PubMed Central

    Dineley, Kelly T; Jahrling, Jordan B; Denner, Larry

    2014-01-01

    Insulin is a key hormone regulating metabolism. Insulin binding to cell surface insulin receptors engages many signaling intermediates operating in parallel and in series to control glucose, energy, and lipids while also regulating mitogenesis and development. Perturbations in the function of any of these intermediates, which occur in a variety of diseases, cause reduced sensitivity to insulin and insulin resistance with consequent metabolic dysfunction. Chronic inflammation ensues which exacerbates compromised metabolic homeostasis. Since insulin has a key role in learning and memory as well as directly regulating ERK, a kinase required for the type of learning and memory compromised in early Alzheimer's disease (AD), insulin resistance has been identified as a major risk factor for the onset of AD. Animal models of AD or insulin resistance or both demonstrate that AD pathology and impaired insulin signaling form a reciprocal relationship. Of note are human and animal model studies geared toward improving insulin resistance that have led to the identification of the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) as an intervention tool for early AD. Strategic targeting of alternate nodes within the insulin signaling network has revealed disease-stage therapeutic windows in animal models that coalesce with previous and ongoing clinical trial approaches. Thus, exploiting the connection between insulin resistance and AD provides powerful opportunities to delineate therapeutic interventions that slow or block the pathogenesis of AD. PMID:25237037

  10. Selective Insulin Resistance in Adipocytes*

    PubMed Central

    Tan, Shi-Xiong; Fisher-Wellman, Kelsey H.; Fazakerley, Daniel J.; Ng, Yvonne; Pant, Himani; Li, Jia; Meoli, Christopher C.; Coster, Adelle C. F.; Stöckli, Jacqueline; James, David E.

    2015-01-01

    Aside from glucose metabolism, insulin regulates a variety of pathways in peripheral tissues. Under insulin-resistant conditions, it is well known that insulin-stimulated glucose uptake is impaired, and many studies attribute this to a defect in Akt signaling. Here we make use of several insulin resistance models, including insulin-resistant 3T3-L1 adipocytes and fat explants prepared from high fat-fed C57BL/6J and ob/ob mice, to comprehensively distinguish defective from unaffected aspects of insulin signaling and its downstream consequences in adipocytes. Defective regulation of glucose uptake was observed in all models of insulin resistance, whereas other major actions of insulin such as protein synthesis and anti-lipolysis were normal. This defect corresponded to a reduction in the maximum response to insulin. The pattern of change observed for phosphorylation in the Akt pathway was inconsistent with a simple defect at the level of Akt. The only Akt substrate that showed consistently reduced phosphorylation was the RabGAP AS160 that regulates GLUT4 translocation. We conclude that insulin resistance in adipose tissue is highly selective for glucose metabolism and likely involves a defect in one of the components regulating GLUT4 translocation to the cell surface in response to insulin. PMID:25720492

  11. Adipocyte lipolysis and insulin resistance.

    PubMed

    Morigny, Pauline; Houssier, Marianne; Mouisel, Etienne; Langin, Dominique

    2016-06-01

    Obesity-induced insulin resistance is a major risk factor for the development of type 2 diabetes. Basal fat cell lipolysis (i.e., fat cell triacylglycerol breakdown into fatty acids and glycerol in the absence of stimulatory factors) is elevated during obesity and is closely associated with insulin resistance. Inhibition of adipocyte lipolysis may therefore be a promising therapeutic strategy for treating insulin resistance and preventing obesity-associated type 2 diabetes. In this review, we explore the relationship between adipose lipolysis and insulin sensitivity. After providing an overview of the components of fat cell lipolytic machinery, we describe the hypotheses that may support the causality between lipolysis and insulin resistance. Excessive circulating fatty acids may ectopically accumulate in insulin-sensitive tissues and impair insulin action. Increased basal lipolysis may also modify the secretory profile of adipose tissue, influencing whole body insulin sensitivity. Finally, excessive fatty acid release may also worsen adipose tissue inflammation, a well-known parameter contributing to insulin resistance. Partial genetic or pharmacologic inhibition of fat cell lipases in mice as well as short term clinical trials using antilipolytic drugs in humans support the benefit of fat cell lipolysis inhibition on systemic insulin sensitivity and glucose metabolism, which occurs without an increase of fat mass. Modulation of fatty acid fluxes and, putatively, of fat cell secretory pattern may explain the amelioration of insulin sensitivity whereas changes in adipose tissue immune response do not seem involved. PMID:26542285

  12. Problems in diabetes mellitus management. Insulin resistance.

    PubMed

    Wolfsheimer, K J

    1990-12-01

    Insulin resistance is a cause for morning hyperglycemia seen in diabetic patients. Other reasons for morning hyperglycemia should be eliminated by performing an insulin response test. Once insulin resistance has been established as the cause of hyperglycemia, a step-by-step process should be used to establish the cause of the insulin resistance. Common causes of insulin resistance include hyperadrenocorticism, acromegaly, hyperthyroidism, and obesity. Hepatic disease, renal insufficiency, and sepsis are other causes of insulin resistance in practice. Less common causes include insulin antibodies, pregnancy, neoplasia, hyperandrogenism, and pheochromocytoma. If the underlying cause cannot be found or resolved, then increased doses of insulin are required to manage the hyperglycemia. PMID:2134077

  13. Lipid signals and insulin resistance.

    PubMed

    Zhang, Chongben; Klett, Eric L; Coleman, Rosalind A

    2013-12-01

    The metabolic syndrome, a cluster of metabolic derangements that include obesity, glucose intolerance, dyslipidemia and hypertension, is a major risk factor for cardiovascular disease. Insulin resistance has been proposed to be the common feature that links obesity to the metabolic syndrome, but the mechanism remains obscure. Although the excess content of triacylglycerol in muscle and liver is highly associated with insulin resistance in these tissues, triacylglycerol itself is not causal but merely a marker. Thus, attention has turned to the accumulation of cellular lipids known to have signaling roles. This review will discuss recent progress in understanding how glycerolipids and related lipid intermediates may impair insulin signaling. PMID:24533033

  14. Oxidative Stress and Insulin Resistance

    PubMed Central

    Park, Kyong; Gross, Myron; Lee, Duk-Hee; Holvoet, Paul; Himes, John H.; Shikany, James M.; Jacobs, David R.

    2009-01-01

    OBJECTIVE Although cumulative evidence suggests that increased oxidative stress may lead to insulin resistance in vivo or in vitro, community-based studies are scarce. This study examined the longitudinal relationships of oxidative stress biomarkers with the development of insulin resistance and whether these relationships were independent of obesity in nondiabetic young adults. RESEARCH DESIGN AND METHODS Biomarkers of oxidative stress (F2-isoprostanes [F2Isop] and oxidized LDL [oxLDL]), insulin resistance (the homeostasis model assessment of insulin resistance [HOMA-IR]), and various fatness measures (BMI, waist circumference, and estimated percent fat) were obtained in a population-based observational study (Coronary Artery Risk Development in Young Adults) and its ancillary study (Young Adult Longitudinal Trends in Antioxidants) during 2000–2006. RESULTS There were substantial increases in estimated mean HOMA-IR over time. OxLDL and F2Isop showed little association with each other. Mean evolving HOMA-IR increased with increasing levels of oxidative stress markers (P < 0.001 for oxLDL and P = 0.06 for F2Isop), measured in 2000–2001. After additional adjustment for adiposity, a positive association between oxLDL and HOMA-IR was strongly evident, whereas the association between F2Isop and HOMA-IR was not. CONCLUSIONS We observed positive associations between each of two oxidative stress markers and insulin resistance. The association with oxidized LDL was independent of obesity, but that with F2Isop was not. PMID:19389821

  15. Insulin Resistance and Prediabetes

    MedlinePlus

    ... to be used in most health care providers' offices. The clamp is a research tool used by scientists to learn more about glucose metabolism. Research has shown that if blood tests indicate prediabetes, insulin ... care provider's office or commercial facility and sending the sample to ...

  16. Treatment of insulin resistance in uremia.

    PubMed

    Stefanović, V; Nesić, V; Stojimirović, B

    2003-02-01

    Insulin resistance is a characteristic feature of uremia. As long as the hyperinsulinemia adequate to overcome the insulin resistance, glucose tolerance remains normal. In patients destined to develop type 2 diabetes, the beta cell compensatory response declines, and relative, or absolute, insulin deficiency develops. At this point glucose intolerance and eventually frank type 2 diabetes occur. Insulin resistance and concomitant hyperinsulinemia are present irrespective of the type of renal disease. Several studies have confirmed that hemodialysis (HD) treatment significantly improves insulin resistance. Both CAPD and CCPD are shown to improve insulin resistance in uremic patients. Comparing the effect of PD and HD treatment, it was found that the CCPD group has significantly higher insulin sensitivity than the HD group with the CAPD group similar to HD. Treatment of calcium and phosphate disturbances, including vitamin D therapy, significantly reduces insulin resistance in uremia. Treatment with recombinant human erythropoietin (EPO) is an efficient way to increase hematocrit, to reverse cardiovascular problems and to improve insulin sensitivity. Angiotensin-converting enzyme inhibitors have been shown to improve insulin resistance, hyperinsulinemia and glucose intolerance in uremic patients. Thiazolidinediones (TZDs), the new insulin-sensitizing drugs, provide the proof that pharmacologic treatment of insulin resistance can be of enormous clinical benefit. The great potential of insulin resistance therapy illuminated by the TZDs will continue to catalyze research in this area directed toward the discovery of new insulin-sensitizing agents that work through other mechanisms. PMID:12653342

  17. Nutritional Modulation of Insulin Resistance

    PubMed Central

    Weickert, Martin O.

    2012-01-01

    Insulin resistance has been proposed as the strongest single predictor for the development of Type 2 Diabetes (T2DM). Chronic oversupply of energy from food, together with inadequate physical activity, have been recognized as the most relevant factors leading to overweight, abdominal adiposity, insulin resistance, and finally T2DM. Conversely, energy reduced diets almost invariably to facilitate weight loss and reduce abdominal fat mass and insulin resistance. However, sustained weight loss is generally difficult to achieve, and distinct metabolic characteristics in patients with T2DM further compromise success. Therefore, investigating the effects of modulating the macronutrient composition of isoenergetic diets is an interesting concept that may lead to additional important insights. Metabolic effects of various different dietary concepts and strategies have been claimed, but results from randomized controlled studies and particularly from longer-term-controlled interventions in humans are often lacking. However, some of these concepts are supported by recent research, at least in animal models and short-term studies in humans. This paper provides an update of the current literature regarding the role of nutrition in the modulation of insulin resistance, which includes the discussion of weight-loss-independent metabolic effects of commonly used dietary concepts. PMID:24278690

  18. Insulin resistance in the liver: Deficiency or excess of insulin?

    PubMed Central

    Bazotte, Roberto B; Silva, Lorena G; Schiavon, Fabiana PM

    2014-01-01

    In insulin-resistant states (obesity, pre-diabetes, and type 2 diabetes), hepatic production of glucose and lipid synthesis are heightened in concert, implying that insulin deficiency and insulin excess coexists in this setting. The fact that insulin may be inadequate or excessive at any one point in differing organs and tissues has many biologic ramifications. In this context the concept of metabolic compartmentalization in the liver is offered herein as one perspective of this paradox. In particular, we focus on the hypothesis that insulin resistance accentuates differences in periportal and perivenous hepatocytes, namely periportal glucose production and perivenous lipid synthesis. Subsequently, excessive production of glucose and accumulation of lipids could be expected in the livers of patients with obesity and insulin resistance. Overall, in this review, we provide our integrative perspective regarding how excessive production of glucose in periportal hepatocytes and accumulation of lipids in perivenous hepatocytes interact in insulin resistant states. PMID:25486190

  19. Mitochondrial efficiency and insulin resistance.

    PubMed

    Crescenzo, Raffaella; Bianco, Francesca; Mazzoli, Arianna; Giacco, Antonia; Liverini, Giovanna; Iossa, Susanna

    2014-01-01

    Insulin resistance, "a relative impairment in the ability of insulin to exert its effects on glucose, protein and lipid metabolism in target tissues," has many detrimental effects on metabolism and is strongly correlated to deposition of lipids in non-adipose tissues. Mitochondria are the main cellular sites devoted to ATP production and fatty acid oxidation. Therefore, a role for mitochondrial dysfunction in the onset of skeletal muscle insulin resistance has been proposed and many studies have dealt with possible alteration in mitochondrial function in obesity and diabetes, both in humans and animal models. Data reporting evidence of mitochondrial dysfunction in type two diabetes mellitus are numerous, even though the issue that this reduced mitochondrial function is causal in the development of the disease is not yet solved, also because a variety of parameters have been used in the studies carried out on this subject. By assessing the alterations in mitochondrial efficiency as well as the impact of this parameter on metabolic homeostasis of skeletal muscle cells, we have obtained results that allow us to suggest that an increase in mitochondrial efficiency precedes and therefore can contribute to the development of high-fat-induced insulin resistance in skeletal muscle. PMID:25601841

  20. Metabolic inflammation: connecting obesity and insulin resistance.

    PubMed

    Dali-Youcef, Nassim; Mecili, Mustapha; Ricci, Roméo; Andrès, Emmanuel

    2013-05-01

    Insulin resistance is a pathological condition that arises when insulin signaling is impaired, forcing β-cells to produce more insulin in order to cope with body demands and to maintain glucose homeostasis. When the pancreas is no more able to support an appropriate insulin secretion, insulin resistance becomes decompensated and hyperglycemia is detected. One of the mechanisms leading to insulin resistance is low-grade inflammation that involves a number of protagonists such as inflammatory cytokines, lipids and their metabolites, reactive oxygen species (ROS), hypoxia and endoplasmic reticulum stress, and changes in gut microbiota profiles. We review here the molecular aspects of metabolic inflammation converging to insulin resistance and secondarily to type 2 diabetes. We also discuss the place of high-sensitivity C-reactive protein (hsCRP) in the assessment of metabolic inflammation and potential therapeutic interventions aimed to impede inflammation and therefore prevent insulin resistance. PMID:22834949

  1. Insulin Resistance and Skin Diseases

    PubMed Central

    Napolitano, Maddalena; Megna, Matteo; Monfrecola, Giuseppe

    2015-01-01

    In medical practice, almost every clinician may encounter patients with skin disease. However, it is not always easy for physicians of all specialties to face the daily task of determining the nature and clinical implication of dermatologic manifestations. Are they confined to the skin, representing a pure dermatologic event? Or are they also markers of internal conditions relating to the patient's overall health? In this review, we will discuss the principal cutaneous conditions which have been linked to metabolic alterations. Particularly, since insulin has an important role in homeostasis and physiology of the skin, we will focus on the relationships between insulin resistance (IR) and skin diseases, analyzing strongly IR-associated conditions such as acanthosis nigricans, acne, and psoriasis, without neglecting emerging and potential scenarios as the ones represented by hidradenitis suppurativa, androgenetic alopecia, and hirsutism. PMID:25977937

  2. Aggravation of post-ischemic liver injury by overexpression of insulin-like growth factor binding protein 3

    PubMed Central

    Zhou, Lu; Koh, Hyoung-Won; Bae, Ui-Jin; Park, Byung-Hyun

    2015-01-01

    Insulin-like growth factor-1 (IGF-1) is known to inhibit reperfusion-induced apoptosis. IGF-binding protein-3 (IGFBP-3) is the major circulating carrier protein for IGF-1 and induces apoptosis. In this study, we determined if IGFBP-3 was important in the hepatic response to I/R. To deliver IGFBP-3, we used an adenovirus containing IGFBP-3 cDNA (AdIGFBP-3) or an IGFBP-3 mutant devoid of IGF binding affinity but retaining IGFBP-3 receptor binding ability (AdIGFBP-3GGG). Mice subjected to I/R injury showed typical patterns of hepatocellular damage. Protein levels of IGFBP-3 were increased after reperfusion and showed a positive correlation with the extent of liver injury. Prior injection with AdIGFBP-3 aggravated liver injury: serum aminotransferases, prothrombin time, proinflammatory cytokines, hepatocellular necrosis and apoptosis, and neutrophil infiltration were markedly increased compared to control mice. A decrease in antioxidant potential and an upregulation of NADPH oxidase might have caused these aggravating effects of IGFBP-3. Experiments using HepG2 cells and N-acetylcysteine-pretreated mice showed a discernible effect of IGFBP-3 on reactive oxygen species generation. Lastly, AdIGFBP-3 abolished the beneficial effects of ischemic preconditioning and hypothermia. Mice treated with AdIGFBP-3GGG exhibited effects similar to those of AdIGFBP-3, suggesting a ligand-independent effect of IGFBP-3. Our results suggest IGFBP-3 as an aggravating factor during hepatic I/R injury. PMID:26073647

  3. SIRT2 regulates insulin sensitivity in insulin resistant neuronal cells.

    PubMed

    Arora, Amita; Dey, Chinmoy Sankar

    2016-06-10

    Insulin resistance in brain is well-associated with pathophysiology of deficits in whole-body energy metabolism, neurodegenerative diseases etc. Among the seven sirtuins, SIRT2 is the major deacetylase expressed in brain. Inhibition of SIRT2 confers neuroprotection in case of Parkinson's disease (PD) and Huntington's disease (HD). However, the role of this sirtuin in neuronal insulin resistance is not known. In this study, we report the role of SIRT2 in regulating insulin-sensitivity in neuronal cells in vitro. Using approaches like pharmacological inhibition of SIRT2, siRNA mediated SIRT2 knockdown and over-expression of wild-type and catalytically-mutated SIRT2, we observed that downregulation of SIRT2 ameliorated the reduced activity of AKT and increased insulin-stimulated glucose uptake in insulin resistant neuro-2a cells. The data was supported by over expression of catalytically-inactive SIRT2 in insulin-resistant human SH-SY5Y neuronal cells. Data highlights a crucial role of SIRT2 in regulation of neuronal insulin sensitivity under insulin resistant condition. PMID:27163642

  4. [Resistance to the action of insulin].

    PubMed

    Azevedo, M da S

    1993-06-01

    The author analyses the insulin and glucagon effect on glycaemia regulation. The structure of glucose transporters and insulin receptors is described in some detail. Finally the author attempts to explain the insulin resistance mechanism based on a post receptor alteration that would be advantageous in traditional nutrition, but is noxious in a western type society, due to excessive caloric intake. PMID:8368096

  5. Selective Insulin Resistance in the Kidney

    PubMed Central

    Horita, Shoko; Nakamura, Motonobu; Suzuki, Masashi; Satoh, Nobuhiko; Suzuki, Atsushi; Seki, George

    2016-01-01

    Insulin resistance has been characterized as attenuation of insulin sensitivity at target organs and tissues, such as muscle and fat tissues and the liver. The insulin signaling cascade is divided into major pathways such as the PI3K/Akt pathway and the MAPK/MEK pathway. In insulin resistance, however, these pathways are not equally impaired. For example, in the liver, inhibition of gluconeogenesis by the insulin receptor substrate (IRS) 2 pathway is impaired, while lipogenesis by the IRS1 pathway is preserved, thus causing hyperglycemia and hyperlipidemia. It has been recently suggested that selective impairment of insulin signaling cascades in insulin resistance also occurs in the kidney. In the renal proximal tubule, insulin signaling via IRS1 is inhibited, while insulin signaling via IRS2 is preserved. Insulin signaling via IRS2 continues to stimulate sodium reabsorption in the proximal tubule and causes sodium retention, edema, and hypertension. IRS1 signaling deficiency in the proximal tubule may impair IRS1-mediated inhibition of gluconeogenesis, which could induce hyperglycemia by preserving glucose production. In the glomerulus, the impairment of IRS1 signaling deteriorates the structure and function of podocyte and endothelial cells, possibly causing diabetic nephropathy. This paper mainly describes selective insulin resistance in the kidney, focusing on the proximal tubule. PMID:27247938

  6. Angiotensin and insulin resistance: conspiracy theory.

    PubMed

    Townsend, Raymond R

    2003-04-01

    Resistance to the metabolic effects of insulin is a contender for the short list of major cardiovascular risk factors. Since the elements of the syndrome of insulin resistance were first articulated together in 1988, numerous epidemiologic investigations and treatment endeavors have established a relationship between the metabolic disarray of impaired insulin action and cardiovascular disease. Angiotensin II, the primary effector of the renin-angiotensin system, has also achieved a place in the chronicles of cardiovascular risk factors. Conspiracy mechanisms by which angiotensin II and insulin resistance interact in the pathogenesis of cardiovascular disease are reviewed, with particular attention to recent developments in this engaging area of human research. PMID:12642009

  7. Treatment Approach to Patients With Severe Insulin Resistance.

    PubMed

    Church, Timothy J; Haines, Stuart T

    2016-04-01

    In Brief Patients with severe insulin resistance require >2 units/kg of body weight or 200 units/day of insulin. Yet, many patients do not achieve glycemic targets despite using very high doses of insulin. Insulin can cause weight gain, which further contributes to worsening insulin resistance. This article describes the pharmacological options for managing patients with severe insulin resistance, including the use of U-500 insulin and newer agents in combination with insulin. PMID:27092020

  8. Insulin Resistance and Heart Failure: Molecular Mechanisms

    PubMed Central

    Aroor, Annayya R.; Mandavia, Chirag H.; Sowers, James R.

    2012-01-01

    Insulin resistance and associated reductions in cardiac insulin metabolic signaling is emerging as a major factor for the development of heart failure and assumes more importance because of an epidemic increase in obesity and the cardiorenal metabolic syndrome and our aging population. Major factors contributing to the development of cardiac insulin resistance are oxidative stress, hyperglycemia, hyperlipidemia, dysregulated secretion of adipokines/cytokines and inappropriate activation of renin-angiotensin II-aldosterone system (RAAS) and the sympathetic nervous system. The effects of cardiac insulin resistance are exacerbated by metabolic, endocrine and cytokine alterations associated with systemic insulin resistance. The aggregate of these various alterations leads to an insulin resistant phenotype with metabolic inflexibility, impaired calcium handling, mitochondrial dysfunction and oxidative stress, dysregulated myocardial-endothelial interactions resulting in energy deficiency, impaired diastolic dysfunction, myocardial cell death and cardiac fibrosis. Therefore, understanding the molecular mechanisms linking insulin resistance and heart failure may help to design new and more effective mechanism-based drugs to improve myocardial and systemic insulin resistance. PMID:22999243

  9. A gene expression signature for insulin resistance.

    PubMed

    Konstantopoulos, Nicky; Foletta, Victoria C; Segal, David H; Shields, Katherine A; Sanigorski, Andrew; Windmill, Kelly; Swinton, Courtney; Connor, Tim; Wanyonyi, Stephen; Dyer, Thomas D; Fahey, Richard P; Watt, Rose A; Curran, Joanne E; Molero, Juan-Carlos; Krippner, Guy; Collier, Greg R; James, David E; Blangero, John; Jowett, Jeremy B; Walder, Ken R

    2011-02-11

    Insulin resistance is a heterogeneous disorder caused by a range of genetic and environmental factors, and we hypothesize that its etiology varies considerably between individuals. This heterogeneity provides significant challenges to the development of effective therapeutic regimes for long-term management of type 2 diabetes. We describe a novel strategy, using large-scale gene expression profiling, to develop a gene expression signature (GES) that reflects the overall state of insulin resistance in cells and patients. The GES was developed from 3T3-L1 adipocytes that were made "insulin resistant" by treatment with tumor necrosis factor-α (TNF-α) and then reversed with aspirin and troglitazone ("resensitized"). The GES consisted of five genes whose expression levels best discriminated between the insulin-resistant and insulin-resensitized states. We then used this GES to screen a compound library for agents that affected the GES genes in 3T3-L1 adipocytes in a way that most closely resembled the changes seen when insulin resistance was successfully reversed with aspirin and troglitazone. This screen identified both known and new insulin-sensitizing compounds including nonsteroidal anti-inflammatory agents, β-adrenergic antagonists, β-lactams, and sodium channel blockers. We tested the biological relevance of this GES in participants in the San Antonio Family Heart Study (n = 1,240) and showed that patients with the lowest GES scores were more insulin resistant (according to HOMA_IR and fasting plasma insulin levels; P < 0.001). These findings show that GES technology can be used for both the discovery of insulin-sensitizing compounds and the characterization of patients into subtypes of insulin resistance according to GES scores, opening the possibility of developing a personalized medicine approach to type 2 diabetes. PMID:21081660

  10. Insulin resistance and diabetes in HIV infection.

    PubMed

    Das, Satyajit

    2011-09-01

    Insulin resistance is an important and under recognized consequence of HIV treatment. Different studies have yielded widely varying estimates of the prevalence of impaired glucose metabolism in people on highly active antiretroviral therapy (HAART). The risk increases further with hepatitis C co infection. Although Protease inhibitors (PIs) are the main drug class implicated in insulin resistance, some studies have shown an association of increased risk of diabetes with cumulative exposure of nucleoside reverse transcriptase inhibitors (NRTIs). The effect of switching to other antiretrovirals has not been fully determined and the long-term consequences of insulin resistance in this population are not known. Treatment of established diabetes mellitus should generally follow existing guidelines. It is therefore reasonable to recommend general measures to increase insulin sensitivity in all patients infected with HIV, such as regular aerobic exercise and weight reduction for overweight persons. The present review article has the information of some recent patents regarding the insulin resistance in HIV infection. PMID:21824074

  11. Insulin resistance and muscle insulin receptor substrate‐1 serine hyperphosphorylation

    PubMed Central

    Stuart, Charles A.; Howell, Mary E. A.; Cartwright, Brian M.; McCurry, Melanie P.; Lee, Michelle L.; Ramsey, Michael W.; Stone, Michael H.

    2014-01-01

    Abstract Insulin resistance in metabolic syndrome subjects is profound in spite of muscle insulin receptor and insulin‐responsive glucose transporter (GLUT4) expression being nearly normal. Insulin receptor tyrosine kinase phosphorylation of insulin receptor substrate‐1 (IRS‐1) at Tyr896 is a necessary step in insulin stimulation of translocation of GLUT4 to the cell surface. Serine phosphorylation of IRS‐1 by some kinases diminishes insulin action in mice. We evaluated the phosphorylation status of muscle IRS‐1 in 33 subjects with the metabolic syndrome and seventeen lean controls. Each underwent euglycemic insulin clamps and a thigh muscle biopsy before and after 8 weeks of either strength or endurance training. Muscle IRS‐1 phosphorylation at six sites was quantified by immunoblots. Metabolic syndrome muscle IRS‐1 had excess phosphorylation at Ser337 and Ser636 but not at Ser307, Ser789, or Ser1101. Ser337 is a target for phosphorylation by glycogen synthase kinase 3 (GSK3) and Ser636 is phosphorylated by c‐Jun N‐terminal kinase 1 (JNK1). Exercise training without weight loss did not change the IRS‐1 serine phosphorylation. These data suggest that baseline hyperphosphorylation of at least two key serines within muscle IRS‐1 diminishes the transmission of the insulin signal and thereby decreases the insulin‐stimulated translocation of GLUT4. Excess fasting phosphorylation of muscle IRS‐1 at Ser636 may be a major cause of the insulin resistance seen in obesity and might prevent improvement in insulin responsiveness when exercise training is not accompanied by weight loss. PMID:25472611

  12. Insulin Receptor Signaling in Normal and Insulin-Resistant States

    PubMed Central

    Boucher, Jérémie; Kleinridders, André; Kahn, C. Ronald

    2014-01-01

    In the wake of the worldwide increase in type-2 diabetes, a major focus of research is understanding the signaling pathways impacting this disease. Insulin signaling regulates glucose, lipid, and energy homeostasis, predominantly via action on liver, skeletal muscle, and adipose tissue. Precise modulation of this pathway is vital for adaption as the individual moves from the fed to the fasted state. The positive and negative modulators acting on different steps of the signaling pathway, as well as the diversity of protein isoform interaction, ensure a proper and coordinated biological response to insulin in different tissues. Whereas genetic mutations are causes of rare and severe insulin resistance, obesity can lead to insulin resistance through a variety of mechanisms. Understanding these pathways is essential for development of new drugs to treat diabetes, metabolic syndrome, and their complications. PMID:24384568

  13. Selective insulin resistance in hepatocyte senescence

    SciTech Connect

    Aravinthan, Aloysious; Challis, Benjamin; Shannon, Nicholas; Hoare, Matthew; Heaney, Judith; Alexander, Graeme J.M.

    2015-02-01

    Insulin resistance has been described in association with chronic liver disease for decades. Hepatocyte senescence has been demonstrated in chronic liver disease and as many as 80% of hepatocytes show a senescent phenotype in advanced liver disease. The aim of this study was to understand the role of hepatocyte senescence in the development of insulin resistance. Senescence was induced in HepG2 cells via oxidative stress. The insulin metabolic pathway was studied in control and senescent cells following insulin stimulation. GLUT2 and GLUT4 expressions were studied in HepG2 cells and human liver tissue. Further, GLUT2 and GLUT4 expressions were studied in three independent chronic liver disease cohorts. Signalling impairment distal to Akt in phosphorylation of AS160 and FoxO1 was evident in senescent HepG2 cells. Persistent nuclear localisation of FoxO1 was demonstrated in senescent cells despite insulin stimulation. Increased GLUT4 and decreased GLUT2 expressions were evident in senescent cells, human cirrhotic liver tissue and publically available liver disease datasets. Changes in GLUT expressions were associated with a poor clinical prognosis. In conclusion, selective insulin resistance is evident in senescent HepG2 cells and changes in GLUT expressions can be used as surrogate markers of hepatocyte senescence. - Highlights: • Senescent hepatocytes demonstrate selective insulin resistance. • GLUT changes act as markers of hepatocyte senescence and have prognostic value. • Study offers insight into long noticed intimacy of cirrhosis and insulin resistance.

  14. Role of mitochondrial function in insulin resistance.

    PubMed

    Brands, Myrte; Verhoeven, Arthur J; Serlie, Mireille J

    2012-01-01

    The obesity pandemic increases the prevalence of type 2 diabetes (DM2).DM2 develops when pancreatic β-cells fail and cannot compensate for the decrease in insulin sensitivity. How excessive caloric intake and weight gain cause insulin resistance has not completely been elucidated.Skeletal muscle is responsible for a major part of insulin stimulated whole-body glucose disposal and, hence, plays an important role in the pathogenesis of insulin resistance.It has been hypothesized that skeletal muscle mitochondrial dysfunction is involved in the accumulation of intramyocellular lipid metabolites leading to lipotoxicity and insulin resistance. However, findings on skeletal muscle mitochondrial function in relation to insulin resistance in human subjects are inconclusive. Differences in mitochondrial activity can be the result of several factors, including a reduced mitochondrial density, differences in insulin stimulated mitochondrial respiration, lower energy demand or reduced skeletal muscle perfusion, besides an intrinsic mitochondrial defect. The inconclusive results may be explained by the use of different techniques and study populations. Also, mitochondrial capacity is in far excess to meet energy requirements and therefore it may be questioned whether a reduced mitochondrial capacity limits mitochondrial fatty acid oxidation. Whether reduced mitochondrial function is causally related to insulin resistance or rather a consequence of the sedentary lifestyle remains to be elucidated. PMID:22399424

  15. [Insulin resistance - its causes and therapy possibilities].

    PubMed

    Pelikánová, Terezie

    2014-09-01

    Insulin resistance (IR) is defined as a condition where normal plasma free insuconcentrations induce a reduced response of the body. In the narrower sense we understand IR as the impairment of insulin action in the target structure which may arise at any level of the insulin signalling cascade. In the clinical conditions we usually define it as the impairment of insulin action in glucose metabolism, although it is true that the impairment may concern different effects of insulin and different cell structures. The characteristic feature of IR linked to the metabolic syndrome or Type 2 diabetes is defective signalling which affects PI3-kinase branch of insulin signalling cascade. Other insulin actions depending on the signalling through the Ras complex and MAP-kinase, may not be affected. Due to compensatory hyperinsulinemia they may be even increased. The article summarizes some recent findings regarding the structure and regulation of insulin signalling cascade and analyses selected primary and secondary causes of IR which include genetic and epigenetic factors, the microRNA regulation role, metabolic, humoral and immunological factors. The detailed knowledge of the causes of IR opens possibilities of its rational treatment. This is currently based on the treatment of curable causes of IR, i.e. consistent compensation of diabetes, weight reduction, regimen arrangements (diet, physical activity), re-assessment of the need to use corticosteroids in therapy, treatment of coexisting conditions and possibly administration of metformin or pioglitazone.Key words: cytokines - insulin resistance - insulin signalling cascade. PMID:25294764

  16. [The polycystic ovary syndrome and insulin resistance].

    PubMed

    Kreze, A; Hrnciar, J; Dobáková, M; Pekarová, E

    1997-10-01

    The insulin resistance syndrome and the polycystic ovary syndrome (PCOS) appear to have some following coincidences: the existence of subclinical acanthosis nigricans in PCOS hyperinsulinemic women, correlation of insulin levels and free testosterone, insulin-like growth factor I binding protein (IGFIBP), and sex-hormone binding globulin. Insulin and IGFI act synergically with luteinizing hormone increasing the activity of cytochrome P450c17 and its enzymatic activity in the adrenals. The decrease in IGFI level and IGFI receptors in the ovarian granulosa cells reduce the steroids aromatisation. The increased expression of IGFI receptors in the theca cells favours the androgens' synthesis. Long-term insulin therapy results in an increase in ovary volume and the blood androgens levels. The deterioration of insulin resistance in PSOC women progresses also by the reduction of type I of skeletal muscle fibres which are sensitive to insulin, and the increase of type II fibres which are resistant to insulin in hyperandrogenemia. Testosterone deteriorates the skeletal as well as hepatic insulin sensitivity by both its facilitating effect on lipolysis and the increase of free fatty acids. Abdominal obesity seen in PCOS and insulin resistance is composed by adipocytes with glucocorticoid receptors, which after cortisol stimulation activate the lipoprotein lipase and fat accumulation. Gynoid obesity with the preferential aromatisation of steroids is not evolved because of the low estrogens and progesterone levels in PCOS. Low progesterone levels (with anticortisol effect) support the development of abdominal obesity. Ultimately, the early peak of insulin secretion (4-8 min) in PCOS is higher. This fact should testify a certain diabetic disposition. (Ref. 37.) PMID:9490171

  17. Mechanisms Linking Inflammation to Insulin Resistance

    PubMed Central

    Chen, Li; Wang, Hua

    2015-01-01

    Obesity is now widespread around the world. Obesity-associated chronic low-grade inflammation is responsible for the decrease of insulin sensitivity, which makes obesity a major risk factor for insulin resistance and related diseases such as type 2 diabetes mellitus and metabolic syndromes. The state of low-grade inflammation is caused by overnutrition which leads to lipid accumulation in adipocytes. Obesity might increase the expression of some inflammatory cytokines and activate several signaling pathways, both of which are involved in the pathogenesis of insulin resistance by interfering with insulin signaling and action. It has been suggested that specific factors and signaling pathways are often correlated with each other; therefore, both of the fluctuation of cytokines and the status of relevant signaling pathways should be considered during studies analyzing inflammation-related insulin resistance. In this paper, we discuss how these factors and signaling pathways contribute to insulin resistance and the therapeutic promise targeting inflammation in insulin resistance based on the latest experimental studies. PMID:26136779

  18. Mechanisms Linking Inflammation to Insulin Resistance.

    PubMed

    Chen, Li; Chen, Rui; Wang, Hua; Liang, Fengxia

    2015-01-01

    Obesity is now widespread around the world. Obesity-associated chronic low-grade inflammation is responsible for the decrease of insulin sensitivity, which makes obesity a major risk factor for insulin resistance and related diseases such as type 2 diabetes mellitus and metabolic syndromes. The state of low-grade inflammation is caused by overnutrition which leads to lipid accumulation in adipocytes. Obesity might increase the expression of some inflammatory cytokines and activate several signaling pathways, both of which are involved in the pathogenesis of insulin resistance by interfering with insulin signaling and action. It has been suggested that specific factors and signaling pathways are often correlated with each other; therefore, both of the fluctuation of cytokines and the status of relevant signaling pathways should be considered during studies analyzing inflammation-related insulin resistance. In this paper, we discuss how these factors and signaling pathways contribute to insulin resistance and the therapeutic promise targeting inflammation in insulin resistance based on the latest experimental studies. PMID:26136779

  19. Insulin resistance: regression and clustering.

    PubMed

    Yoon, Sangho; Assimes, Themistocles L; Quertermous, Thomas; Hsiao, Chin-Fu; Chuang, Lee-Ming; Hwu, Chii-Min; Rajaratnam, Bala; Olshen, Richard A

    2014-01-01

    In this paper we try to define insulin resistance (IR) precisely for a group of Chinese women. Our definition deliberately does not depend upon body mass index (BMI) or age, although in other studies, with particular random effects models quite different from models used here, BMI accounts for a large part of the variability in IR. We accomplish our goal through application of Gauss mixture vector quantization (GMVQ), a technique for clustering that was developed for application to lossy data compression. Defining data come from measurements that play major roles in medical practice. A precise statement of what the data are is in Section 1. Their family structures are described in detail. They concern levels of lipids and the results of an oral glucose tolerance test (OGTT). We apply GMVQ to residuals obtained from regressions of outcomes of an OGTT and lipids on functions of age and BMI that are inferred from the data. A bootstrap procedure developed for our family data supplemented by insights from other approaches leads us to believe that two clusters are appropriate for defining IR precisely. One cluster consists of women who are IR, and the other of women who seem not to be. Genes and other features are used to predict cluster membership. We argue that prediction with "main effects" is not satisfactory, but prediction that includes interactions may be. PMID:24887437

  20. Anthropometric indicators of insulin resistance.

    PubMed

    Vasques, Ana Carolina; Rosado, Lina; Rosado, Gilberto; Ribeiro, Rita de Cassia; Franceschini, Sylvia; Geloneze, Bruno

    2010-07-01

    Some studies have analyzed the efficacy of anthropometric indicators in predicting insulin resistance (IR), for they are more economic and accessible. In this study, the objective was to discuss the measures and anthropometric indices that have been associated with IR. A bibliographic review was done, based on Scielo, Science Direct and Pubmed. Among these studies, waist and sagittal abdominal diameter presented better predictive capacity for IR, with more consistent results. The waist-to-thigh, waist-to-size, neck-to-thigh ratios, the conicity and the sagittal index have showed positive results; nevertheless, more studies are necessary to consolidate them as predictors to IR. The obtained results, with the use of body mass index and of the waist-to-hip ratio, were inconsistent. In the Brazilian population, the realization of studies evaluating the performance of these indicators in predicting IR is suggested, since the results of the studies conducted in other populations are not always applicable to ours, due to ethnic differences resulting from the great miscegenation in the country. PMID:20694396

  1. Silymarin Induces Insulin Resistance through an Increase of Phosphatase and Tensin Homolog in Wistar Rats

    PubMed Central

    Cheng, Kai-Chun; Asakawa, Akihiro; Li, Ying-Xiao; Chung, Hsien-Hui; Amitani, Haruka; Ueki, Takatoshi; Cheng, Juei-Tang; Inui, Akio

    2014-01-01

    Background and aims Phosphatase and tensin homolog (PTEN) is a phosphoinositide phosphatase that regulates crucial cellular functions, including insulin signaling, lipid and glucose metabolism, as well as survival and apoptosis. Silymarin is the active ingredient in milk thistle and exerts numerous effects through the activation of PTEN. However, the effect of silymarin on the development of insulin resistance remains unknown. Methods Wistar rats fed fructose-rich chow or normal chow were administered oral silymarin to identify the development of insulin resistance using the homeostasis model assessment of insulin resistance and hyperinsulinemic- euglycemic clamping. Changes in PTEN expression in skeletal muscle and liver were compared using western blotting analysis. Further investigation was performed in L6 cells to check the expression of PTEN and insulin-related signals. PTEN deletion in L6 cells was achieved by small interfering ribonucleic acid transfection. Results Oral administration of silymarin at a dose of 200 mg/kg once daily induced insulin resistance in normal rats and enhanced insulin resistance in fructose-rich chow-fed rats. An increase of PTEN expression was observed in the skeletal muscle and liver of rats with insulin resistance. A decrease in the phosphorylation of Akt in L6 myotube cells, which was maintained in a high-glucose condition, was also observed. Treatment with silymarin aggravated high-glucose-induced insulin resistance. Deletion of PTEN in L6 cells reversed silymarin-induced impaired insulin signaling and glucose uptake. Conclusions Silymarin has the ability to disrupt insulin signaling through increased PTEN expression. Therefore, silymarin should be used carefully in type-2 diabetic patients. PMID:24404172

  2. The Extracellular Matrix and Insulin Resistance

    PubMed Central

    Williams, Ashley S.; Kang, Li; Wasserman, David H.

    2015-01-01

    The extracellular matrix (ECM) is a highly dynamic compartment that undergoes remodeling as a result of injury and repair. Over the past decade, mounting evidence in humans and rodents suggest that ECM remodeling is associated with diet-induced insulin resistance in several metabolic tissues. Additionally, integrin receptors for the ECM have also been implicated in the regulation of insulin action. This review will address what is currently known about the ECM, integrins and insulin action in the muscle, liver and adipose tissue. Understanding how ECM remodeling and integrin signaling regulates insulin action may aid in the development of new therapeutic targets for the treatment of insulin resistance and type 2 diabetes. PMID:26059707

  3. Myeloid lineage cell-restricted insulin resistance protects apolipoproteinE-deficient mice against atherosclerosis

    PubMed Central

    Baumgartl, Julia; Baudler, Stephanie; Scherner, Maximilian; Babaev, Vladimir; Makowski, Liza; Suttles, Jill; McDuffie, Marcia; Fazio, Sergio; Kahn, C. Ronald; Hotamisligil, Gökhan S.; Krone, Wilhelm; Linton, MacRae; Brüning, Jens C.

    2014-01-01

    Summary Inflammatory processes play an important role in the pathogenesis of vascular diseases, and insulin-resistant diabetes mellitus type 2 represents an important risk factor for the development of atherosclerosis. To directly address the role of insulin resistance in myeloid lineage cells in the development of atherosclerosis, we have created mice with myeloid lineagespecific inactivation of the insulin receptor gene. On an ApoE-deficient background, MphIRKO mice developed smaller atherosclerotic lesions. There was a dramatic decrease in LPS-stimulated IL-6 and IL-1β expression in the presence of macrophage autonomous insulin resistance. Consistently, while insulin-resistant IRS-2-deficient mice on an ApoE-deficient background display aggravated atherosclerosis, fetal liver cell transplantation of IRS-2–/–ApoE–/– cells ameliorated atherosclerosis in Apo-E-deficient mice. Thus, systemic versus myeloid cell-restricted insulin resistance has opposing effects on the development of atherosclerosis, providing direct evidence that myeloid lineage autonomous insulin signaling provides proinflammatory signals predisposing to the development of atherosclerosis. PMID:16581002

  4. Insulin resistance causes human gallbladder dysmotility.

    PubMed

    Nakeeb, Attila; Comuzzie, Anthony G; Al-Azzawi, Hayder; Sonnenberg, Gabriele E; Kissebah, Ahmed H; Pitt, Henry A

    2006-01-01

    Obesity, diabetes, and hyperlipidemia are known risk factors for the development of gallstones. A growing body of animal and human data has correlated insulin resistance with organ dysfunction. The relationship among obesity, diabetes, hyperlipidemia, and abnormal gallbladder motility remains unclear. Therefore, we designed a study to investigate the association among obesity, insulin resistance, hyperlipidemia, and gallbladder dysmotility. One hundred ninety-two healthy adult nondiabetic volunteers were studied. Gallbladder ultrasounds were performed before and after a standardized fatty meal. A gallbladder ejection fraction (EF) was calculated, and an EF of < 25% was considered abnormal. Serum was analyzed for cholesterol, triglycerides, cholecystokinin, leptin, glucose, and insulin. The homeostasis assessment model (HOMA) was used to determine insulin resistance. The volunteers had a mean age of 38 years (range, 18-77), and 55% were female. Thirty subjects (15%) had gallstones and were excluded from the study. Thirty subjects (19%) had abnormal gallbladder motility (EF < 25%). In lean subjects (n = 96) fasting glucose was significantly increased in the 16 subjects with gallbladder EF < 25% versus the 80 subjects with gallbladder EF > 25% (109 +/- 20 mg/dl versus 78 +/- 2 mg/dl, P < 0.05). Similarly, the HOMA index was significantly greater in subjects with gallbladder EF < 25% versus gallbladder EF >25% (3.3 +/- 1.2 versus 2.0 +/- 0.2, P < 0.05). In obese subjects (n = 66), fasting glucose, insulin, and insulin resistance were not associated with a gallbladder EF < 25%. These data suggest that in lean, nondiabetic volunteers without gallstones, gallbladder dysmotility is associated with an elevated fasting glucose as well as a high index of insulin resistance. We conclude that insulin resistance alone may be responsible for gallbladder dysmotility that may result in acalculous cholecystitis or gallstone formation. PMID:16843864

  5. Insulin resistance, metabolic stress, and atherosclerosis

    PubMed Central

    Pansuria, Meghana; Xi, Hang; Li, Le; Yang, Xiao-Feng; Wang, Hong

    2012-01-01

    Atherosclerosis, a pathological process that underlies the development of cardiovascular disease, is the primary cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). T2DM is characterized by hyperglycemia and insulin resistance (IR), in which target tissues fail to respond to insulin. Systemic IR is associated with impaired insulin signaling in the metabolic tissues and vasculature. Insulin receptor is highly expressed in the liver, muscle, pancreas, and adipose tissue. It is also expressed in vascular cells. It has been suggested that insulin signaling in vascular cells regulates cell proliferation and vascular function. In this review, we discuss the association between IR, metabolic stress, and atherosclerosis with focus on 1) tissue and cell distribution of insulin receptor and its differential signaling transduction and 2) potential mechanism of insulin signaling impairment and its role in the development of atherosclerosis and vascular function in metabolic disorders including hyperglycemia, hypertension, dyslipidemia, and hyperhomocysteinemia. We propose that insulin signaling impairment is the foremost biochemical mechanism underlying increased cardiovascular morbidity and mortality in atherosclerosis, T2DM, and metabolic syndrome. PMID:22202099

  6. Endothelin-1 exacerbates development of hypertension and atherosclerosis in modest insulin resistant syndrome

    SciTech Connect

    Lin, Yan-Jie; Juan, Chi-Chang; Kwok, Ching-Fai; Hsu, Yung-Pei; Shih, Kuang-Chung; Chen, Chin-Chang; Ho, Low-Tone

    2015-05-08

    Endothelin-1 (ET-1) is known as potent vasoconstrictor, by virtue of its mitogenic effects, and may deteriorate the process of hypertension and atherosclerosis by aggravating hyperplasia and migration in VSMCs. Our previous study demonstrated that insulin infusion caused sequential induction of hyperinsulinemia, hyperendothelinemia, insulin resistance, and then hypertension in rats. However, the underlying mechanism of ET-1 interfere insulin signaling in VSMCs remains unclear. To characterize insulin signaling during modest insulin resistant syndrome, we established and monitored rats by feeding high fructose-diet (HFD) until high blood pressure and modest insulin resistance occurred. To explore the role of ET-1/ET{sub A}R during insulin resistance, ET{sub A}R expression, ET-1 binding, and insulin signaling were investigated in the HFD-fed rats and cultured A-10 VSMCs. Results showed that high blood pressure, tunica medial wall thickening, plasma ET-1 and insulin, and accompanied with modest insulin resistance without overweight and hyperglycemia occurred in early-stage HFD-fed rats. In the endothelium-denuded aorta from HFD-fed rats, ET{sub A}R expression, but not ET{sub B}R, and ET-1 binding in aorta were increased. Moreover, decreasing of insulin-induced Akt phosphorylation and increasing of insulin-induced ERK phosphorylation were observed in aorta during modest insulin resistance. Interestingly, in ET-1 pretreated VSMCs, the increment of insulin-induced Akt phosphorylation was decreased whereas the increment of insulin-induced ERK phosphorylation was increased. In addition, insulin potentiated ET-1-induced VSMCs migration and proliferation due to increasing ET-1 binding. ETAR antagonist reversed effects of ET-1 on insulin-induced signaling and VSMCs migration and proliferation. In summary, modest insulin resistance syndrome accompanied with hyperinsulinemia leading to the potentiation on ET-1-induced actions in aortic VSMCs. ET-1 via ET{sub A}R pathway

  7. The role of fatty acids in insulin resistance.

    PubMed

    Sears, Barry; Perry, Mary

    2015-01-01

    Insulin resistance is a multi-faceted disruption of the communication between insulin and the interior of a target cell. The underlying cause of insulin appears to be inflammation that can either be increased or decreased by the fatty acid composition of the diet. However, the molecular basis for insulin resistance can be quite different in various organs. This review deals with various types of inflammatory inputs mediated by fatty acids, which affect the extent of insulin resistance in various organs. PMID:26415887

  8. B-1a Lymphocytes Attenuate Insulin Resistance

    PubMed Central

    Shen, Lei; Chng, MH; Alonso, Michael N.; Yuan, Robert

    2015-01-01

    Obesity-associated insulin resistance, a common precursor of type 2 diabetes, is characterized by chronic inflammation of tissues, including visceral adipose tissue (VAT). Here we show that B-1a cells, a subpopulation of B lymphocytes, are novel and important regulators of this process. B-1a cells are reduced in frequency in obese high-fat diet (HFD)-fed mice, and EGFP interleukin-10 (IL-10) reporter mice show marked reductions in anti-inflammatory IL-10 production by B cells in vivo during obesity. In VAT, B-1a cells are the dominant producers of B cell–derived IL-10, contributing nearly half of the expressed IL-10 in vivo. Adoptive transfer of B-1a cells into HFD-fed B cell–deficient mice rapidly improves insulin resistance and glucose tolerance through IL-10 and polyclonal IgM-dependent mechanisms, whereas transfer of B-2 cells worsens metabolic disease. Genetic knockdown of B cell–activating factor (BAFF) in HFD-fed mice or treatment with a B-2 cell–depleting, B-1a cell–sparing anti-BAFF antibody attenuates insulin resistance. These findings establish B-1a cells as a new class of immune regulators that maintain metabolic homeostasis and suggest manipulation of these cells as a potential therapy for insulin resistance. PMID:25249575

  9. Polyunsaturated fatty acids and insulin resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have reviewed results from published studies regarding the effects of polyunsaturated fatty acids (PUFA) intake on insulin resistance (IR) in human subjects. Evidence has been gathered from epidemiological, cross-sectional and interventions studies. Increased intake of trans fatty acids (TFA) inc...

  10. Acrolein metabolites, diabetes and insulin resistance.

    PubMed

    Feroe, Aliya G; Attanasio, Roberta; Scinicariello, Franco

    2016-07-01

    Acrolein is a dietary and environmental pollutant that has been associated in vitro to dysregulate glucose transport. We investigated the association of urinary acrolein metabolites N-acetyl-S-(3-hydroxypropyl)-l-cysteine (3-HPMA) and N-acetyl-S-(carboxyethyl)-l-cysteine (CEMA) and their molar sum (∑acrolein) with diabetes using data from investigated 2027 adults who participated in the 2005-2006 National Health and Nutrition Examination Survey (NHANES). After excluding participants taking insulin or other diabetes medication we, further, investigated the association of the compounds with insulin resistance (n=850), as a categorical outcome expressed by the homeostatic model assessment (HOMA-IR>2.6). As secondary analyses, we investigated the association of the compounds with HOMA-IR, HOMA-β, fasting insulin and fasting plasma glucose. The analyses were performed using urinary creatinine as independent variable in the models, and, as sensitivity analyses, the compounds were used as creatinine corrected variables. Diabetes as well as insulin resistance (defined as HOMA-IR>2.6) were positively associated with the 3-HPMA, CEMA and ∑Acrolein with evidence of a dose-response relationship (p<0.05). The highest 3rd and 4th quartiles of CEMA compared to the lowest quartile were significantly associated with higher HOMA-IR, HOMA-β and fasting insulin with a dose-response relationship. The highest 3rd quartile of 3-HPMA and ∑Acrolein were positively and significantly associated with HOMA-IR, HOMA-β and fasting insulin. These results suggest a need of further studies to fully understand the implications of acrolein with type 2 diabetes and insulin. PMID:26991531

  11. Insulin resistance and cancer: epidemiological evidence.

    PubMed

    Tsugane, Shoichiro; Inoue, Manami

    2010-05-01

    Over the last 60 years, Japanese people have experienced a rapid and drastic change in lifestyle, including diet. Suspicions have been raised that so-called 'Westernization', characterized by a high-calorie diet and physical inactivity, is associated with increasing trends in the incidence of cancer of the colon, liver, pancreas, prostate, and breast, as well as type 2 diabetes. Epidemiological evidence from our prospective study, the Japan Public Health Center-based Prospective (JPHC) study, and systematic literature reviews generally support the idea that factors related to diabetes or insulin resistance are associated with an increased risk of colon (mostly in men), liver, and pancreatic cancers. These cancers are inversely associated with physical activity and coffee consumption, which are known to decrease the risk of type 2 diabetes. The suggested mechanism of these effects is that insulin resistance and the resulting chronic hyperinsulinemia and increase in bioavailable insulin-like growth factor 1 (IGF1) stimulate tumor growth. In contrast, associations with diabetes are less clear for cancer of the colon in women, and breast and prostate, which are known to be related to sex hormones. The effect of insulin resistance or body fat on sex-hormone production and bioavailability may modify their carcinogenic effect differently from cancers of the colon in men, and liver and pancreas. In conclusion, there is substantial evidence to show that cancers of the colon, liver, and pancreas are associated with insulin resistance, and that these cancers can be prevented by increasing physical activity, and possibly coffee consumption. PMID:20345478

  12. Insulin-induced cytokine production in macrophages causes insulin resistance in hepatocytes.

    PubMed

    Manowsky, Julia; Camargo, Rodolfo Gonzalez; Kipp, Anna P; Henkel, Janin; Püschel, Gerhard P

    2016-06-01

    Overweight and obesity are associated with hyperinsulinemia, insulin resistance, and a low-grade inflammation. Although hyperinsulinemia is generally thought to result from an attempt of the β-cell to compensate for insulin resistance, there is evidence that hyperinsulinaemia itself may contribute to the development of insulin resistance and possibly the low-grade inflammation. To test this hypothesis, U937 macrophages were exposed to insulin. In these cells, insulin induced expression of the proinflammatory cytokines IL-1β, IL-8, CCL2, and OSM. The insulin-elicited induction of IL-1β was independent of the presence of endotoxin and most likely mediated by an insulin-dependent activation of NF-κB. Supernatants of the insulin-treated U937 macrophages rendered primary cultures of rat hepatocytes insulin resistant; they attenuated the insulin-dependent induction of glucokinase by 50%. The cytokines contained in the supernatants of insulin-treated U937 macrophages activated ERK1/2 and IKKβ, resulting in an inhibitory serine phosphorylation of the insulin receptor substrate. In addition, STAT3 was activated and SOCS3 induced, further contributing to the interruption of the insulin receptor signal chain in hepatocytes. These results indicate that hyperinsulinemia per se might contribute to the low-grade inflammation prevailing in overweight and obese patients and thereby promote the development of insulin resistance particularly in the liver, because the insulin concentration in the portal circulation is much higher than in all other tissues. PMID:27094035

  13. Mitochondrial dysfunction and insulin resistance: an update

    PubMed Central

    Montgomery, Magdalene K; Turner, Nigel

    2014-01-01

    Mitochondrial dysfunction has been implicated in the development of insulin resistance (IR); however, a large variety of association and intervention studies as well as genetic manipulations in rodents have reported contrasting results. Indeed, even 39 years after the first publication describing a relationship between IR and diminished mitochondrial function, it is still unclear whether a direct relationship exists, and more importantly if changes in mitochondrial capacity are a cause or consequence of IR. This review will take a journey through the past and summarise the debate about the occurrence of mitochondrial dysfunction and its possible role in causing decreased insulin action in obesity and type 2 diabetes. Evidence is presented from studies in various human populations, as well as rodents with genetic manipulations of pathways known to affect mitochondrial function and insulin action. Finally, we have discussed whether mitochondria are a potential target for the treatment of IR. PMID:25385852

  14. Role of insulin resistance and diet in acne.

    PubMed

    Kumari, Rashmi; Thappa, Devinder Mohan

    2013-01-01

    There is increasing evidence in support of the interplay of growth hormone (GH), insulin, and insulin-like growth factor-1 (IGF-1) signaling during puberty, which have a causal role in pathogenesis of acne by influencing adrenal and gonadal androgen metabolism. Milk consumption and hyperglycemic diets can induce insulin and IGF-1-mediated PI3K ⁄ Akt-activation inducing sebaceous lipogenesis, sebocyte, and keratinocyte proliferation, which can aggravate acne. Occurence of acne as part of various syndromes also provides evidence in favor of correlation between IGF-1 and acne. PMID:23619434

  15. History of gestational diabetes, insulin resistance and coronary risk.

    PubMed

    Davis, C L; Gutt, M; Llabre, M M; Marks, J B; O'Sullivan, M J; Potter, J E; Landel, J L; Kumar, M; Schneiderman, N; Gellman, M; Skyler, J S

    1999-01-01

    The purpose of this study was to examine characteristics associated with the insulin metabolic syndrome, including insulin resistance, abnormal glucose tolerance, dyslipidemia, obesity, and elevated blood pressure, among women who have experienced gestational diabetes. 39 nondiabetic, young (20-42 years), postpartum (3-18 months) white women were recruited from obstetrical clinics. Twenty-one women had a history of gestational diabetes; 18 had uncomplicated pregnancies. Multivariate analyses revealed a significant difference between groups in insulin resistance (M, measured by euglycemic clamp) and insulin levels (from an oral glucose tolerance test), with insulin resistance showing a statistically stronger difference than insulin levels. Groups also differed significantly when compared on a set of variables associated with insulin metabolic syndrome: glucose tolerance, triglycerides, blood pressure, and body-mass index. Using insulin resistance as a covariate eliminated these group differences, suggesting that insulin resistance is the key factor underlying insulin metabolic syndrome. The higher risk of later developing type 2 diabetes and hypertension in women who have a history of gestational diabetes is explicable by their poorer profile on variables associated with insulin metabolic syndrome, and appears to be attributable to insulin resistance. Thus, insulin resistance appears to distinguish young women at risk for cardiovascular disease. PMID:10616862

  16. Vascular stiffness in insulin resistance and obesity

    PubMed Central

    Jia, Guanghong; Aroor, Annayya R.; DeMarco, Vincent G.; Martinez-Lemus, Luis A.; Meininger, Gerald A.; Sowers, James R.

    2015-01-01

    Obesity, insulin resistance, and type 2 diabetes are associated with a substantially increased prevalence of vascular fibrosis and stiffness, with attendant increased risk of cardiovascular and chronic kidney disease. Although the underlying mechanisms and mediators of vascular stiffness are not well understood, accumulating evidence supports the role of metabolic and immune dysregulation related to increased adiposity, activation of the renin angiotensin aldosterone system, reduced bioavailable nitric oxide, increased vascular extracellular matrix (ECM) and ECM remodeling in the pathogenesis of vascular stiffness. This review will give a brief overview of the relationship between obesity, insulin resistance and increased vascular stiffness to provide a contemporary understanding of the proposed underlying mechanisms and potential therapeutic strategies. PMID:26321962

  17. Genetics Home Reference: type A insulin resistance syndrome

    MedlinePlus

    ... Ovarian Cysts Health Topic: Blood Sugar Health Topic: Diabetes Genetic and Rare Diseases Information Center (1 link) Insulin- ... List from the University of Kansas Medical Center: Diabetes Genetic Testing Registry (1 link) Insulin-resistant diabetes mellitus ...

  18. Adrenocortical tumors and insulin resistance: What is the first step?

    PubMed

    Altieri, Barbara; Tirabassi, Giacomo; Casa, Silvia Della; Ronchi, Cristina L; Balercia, Giancarlo; Orio, Francesco; Pontecorvi, Alfredo; Colao, Annamaria; Muscogiuri, Giovanna

    2016-06-15

    The pathogenetic mechanisms underlying the onset of adrenocortical tumors (ACTs) are still largely unknown. Recently, more attention has been paid to the role of insulin and insulin-like growth factor (IGF) system on general tumor development and progression. Increased levels of insulin, IGF-1 and IGF-2 are associated with tumor cell growth and increased risk of cancer promotion and progression in patients with type 2 diabetes. Insulin resistance and compensatory hyperinsulinemia may play a role in adrenal tumor growth through the activation of insulin and IGF-1 receptors. Interestingly, apparently non-functioning ACTs are often associated with a high prevalence of insulin resistance and metabolic syndrome. However, it is unclear if ACT develops from a primary insulin resistance and compensatory hyperinsulinemia or if insulin resistance is only secondary to the slight cortisol hypersecretion by ACT. The aim of this review is to summarize the current evidence regarding the relationship between hyperinsulinemia and adrenocortical tumors. PMID:26637955

  19. Macrophage TCF-4 co-activates p65 to potentiate chronic inflammation and insulin resistance in mice.

    PubMed

    Kang, Xia; Hou, Along; Wang, Rui; Liu, Da; Xiang, Wei; Xie, Qingyun; Zhang, Bo; Gan, Lixia; Zheng, Wei; Miao, Hongming

    2016-07-01

    Transcription factor 4 (TCF-4) was recently identified as a candidate gene for the cause of type 2 diabetes, although the mechanisms have not been fully elucidated. In the present study, we demonstrated that the TCF-4 transgene in macrophages aggravated high-fat diet (HFD)-induced insulin resistance and chronic inflammation, characterized by the elevation of proinflammatory cytokines in the blood, liver and white adipose tissue, as well as a proinflammatory profile of immune cells in visceral fats in mice. Mechanistically, TCF-4 functioned as a co-activator of p65 to amplify the saturated free fatty acid (FFA)-stimulated promoter activity, mRNA transcription and secretion of proinflammatory cytokines in primary macrophages. Blockage of p65 with a specific interfering RNA or inhibitor could prevent TCF-4-enhanced expression of proinflammatory cytokines in FFA/lipopolysaccharide-treated primary macrophages. The p65 inhibitor could abolish macrophage TCF-4 transgene-aggravated systemic inflammation, glucose intolerance and insulin resistance in HFD-treated mice. In addition, we demonstrated that the mRNA expression of TCF-4 in the peripheral blood monocytes from humans was positively correlated to the levels of interleukin (IL)-1β, tumour necrosis factor α, IL-6 and fasting plasma glucose. In summary, we identified TCF-4 as a co-activator of p65 in the potentiation of proinflammatory cytokine production in macrophages and aggravation of HFD-induced chronic inflammation and insulin resistance in mice. PMID:27129186

  20. Globular adiponectin ameliorates metabolic insulin resistance via AMPK-mediated restoration of microvascular insulin responses.

    PubMed

    Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W; Barrett, Eugene J; Cao, Wenhong; Liu, Zhenqi

    2015-09-01

    Adiponectin is an adipokine with anti-inflammatory and anti-diabetic properties. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance in obesity and diabetes. Insulin resistance is present in muscle microvasculature and this may contribute to decreased insulin delivery to, and action in, muscle. In this study we examined whether adiponectin ameliorates metabolic insulin resistance by affecting muscle microvascular recruitment. We demonstrated that a high-fat diet induces vascular adiponectin and insulin resistance but globular adiponectin administration can restore vascular insulin responses and improve insulin's metabolic action via an AMPK- and nitric oxide-dependent mechanism. This suggests that globular adiponectin might have a therapeutic potential for improving insulin resistance and preventing cardiovascular complications in patients with diabetes via modulation of microvascular insulin responses. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance, and microvasculature plays a critical role in the regulation of insulin action in muscle. Here we tested whether adiponectin replenishment could improve metabolic insulin sensitivity in male rats fed a high-fat diet (HFD) via the modulation of microvascular insulin responses. Male Sprague-Dawley rats were fed either a HFD or low-fat diet (LFD) for 4 weeks. Small resistance artery myograph changes in tension, muscle microvascular recruitment and metabolic response to insulin were determined. Compared with rats fed a LFD, HFD feeding abolished the vasodilatory actions of globular adiponectin (gAd) and insulin on pre-constricted distal saphenous arteries. Pretreatment with gAd improved insulin responses in arterioles isolated from HFD rats, which was blocked by AMP-activated protein kinase (AMPK) inhibition. Similarly, HFD abolished microvascular responses to either gAd or insulin and decreased insulin-stimulated glucose disposal by

  1. An Integrated View of Insulin Resistance and Endothelial Dysfunction

    PubMed Central

    Muniyappa, Ranganath; Iantorno, Micaela; Quon, Michael J.

    2008-01-01

    Synopsis Endothelial dysfunction and insulin resistance are frequently co-morbid states. Vasodilator actions of insulin are mediated by phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathways that stimulate production of nitric oxide from vascular endothelium. This helps to couple metabolic and hemodynamic homeostasis under healthy conditions. In pathological states, shared causal factors including glucotoxicity, lipotoxicity, and inflammation selectively impair PI3K-dependent insulin signaling pathways that contribute to reciprocal relationships between insulin resistance and endothelial dysfunction. We discuss implications of pathway-selective insulin resistance in vascular endothelium, interactions between endothelial dysfunction and insulin resistance, and therapeutic interventions that may simultaneously improve both metabolic and cardiovascular physiology in insulin-resistant conditions. PMID:18775359

  2. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy

    PubMed Central

    Jia, Guanghong; DeMarco, Vincent G.; Sowers, James R.

    2016-01-01

    Insulin resistance, type 2 diabetes mellitus and associated hyperinsulinaemia can promote the development of a specific form of cardiomyopathy that is independent of coronary artery disease and hypertension. Termed diabetic cardiomyopathy, this form of cardiomyopathy is a major cause of morbidity and mortality in developed nations, and the prevalence of this condition is rising in parallel with increases in the incidence of obesity and type 2 diabetes mellitus. Of note, female patients seem to be particularly susceptible to the development of this complication of metabolic disease. The diabetic cardiomyopathy observed in insulin-resistant or hyperinsulinaemic states is characterized by impaired myocardial insulin signalling, mitochondrial dysfunction, endoplasmic reticulum stress, impaired calcium homeostasis, abnormal coronary microcirculation, activation of the sympathetic nervous system, activation of the renin–angiotensin–aldosterone system and maladaptive immune responses. These pathophysiological changes result in oxidative stress, fibrosis, hypertrophy, cardiac diastolic dysfunction and eventually systolic heart failure. This Review highlights a surge in diabetic cardiomyopathy research, summarizes current understanding of the molecular mechanisms underpinning this condition and explores potential preventive and therapeutic strategies. PMID:26678809

  3. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy.

    PubMed

    Jia, Guanghong; DeMarco, Vincent G; Sowers, James R

    2016-03-01

    Insulin resistance, type 2 diabetes mellitus and associated hyperinsulinaemia can promote the development of a specific form of cardiomyopathy that is independent of coronary artery disease and hypertension. Termed diabetic cardiomyopathy, this form of cardiomyopathy is a major cause of morbidity and mortality in developed nations, and the prevalence of this condition is rising in parallel with increases in the incidence of obesity and type 2 diabetes mellitus. Of note, female patients seem to be particularly susceptible to the development of this complication of metabolic disease. The diabetic cardiomyopathy observed in insulin- resistant or hyperinsulinaemic states is characterized by impaired myocardial insulin signalling, mitochondrial dysfunction, endoplasmic reticulum stress, impaired calcium homeostasis, abnormal coronary microcirculation, activation of the sympathetic nervous system, activation of the renin-angiotensin-aldosterone system and maladaptive immune responses. These pathophysiological changes result in oxidative stress, fibrosis, hypertrophy, cardiac diastolic dysfunction and eventually systolic heart failure. This Review highlights a surge in diabetic cardiomyopathy research, summarizes current understanding of the molecular mechanisms underpinning this condition and explores potential preventive and therapeutic strategies. PMID:26678809

  4. Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance.

    PubMed

    Aroor, Annayya R; McKarns, Susan; Demarco, Vincent G; Jia, Guanghong; Sowers, James R

    2013-11-01

    Insulin resistance is a hallmark of obesity, the cardiorenal metabolic syndrome and type 2 diabetes mellitus (T2DM). The progression of insulin resistance increases the risk for cardiovascular disease (CVD). The significance of insulin resistance is underscored by the alarming rise in the prevalence of obesity and its associated comorbidities in the Unites States and worldwide over the last 40-50 years. The incidence of obesity is also on the rise in adolescents. Furthermore, premenopausal women have lower CVD risk compared to men, but this protection is lost in the setting of obesity and insulin resistance. Although systemic and cardiovascular insulin resistance is associated with impaired insulin metabolic signaling and cardiovascular dysfunction, the mechanisms underlying insulin resistance and cardiovascular dysfunction remain poorly understood. Recent studies show that insulin resistance in obesity and diabetes is linked to a metabolic inflammatory response, a state of systemic and tissue specific chronic low grade inflammation. Evidence is also emerging that there is polarization of macrophages and lymphocytes towards a pro-inflammatory phenotype that contributes to progression of insulin resistance in obesity, cardiorenal metabolic syndrome and diabetes. In this review, we provide new insights into factors, such as, the renin-angiotensin-aldosterone system, sympathetic activation and incretin modulators (e.g., DPP-4) and immune responses that mediate this inflammatory state in obesity and other conditions characterized by insulin resistance. PMID:23932846

  5. Insulin resistance in severe acne vulgaris

    PubMed Central

    Cengiz, Fatma Pelin; Kemeriz, Funda

    2015-01-01

    Introduction Acne vulgaris is a pilosebaceous gland disease that usually affects people from puberty to young adulthood. It is seen especially on the face, neck, trunk and arms. Its severity differs from patient to patient and its pathogenesis is multifactorial. The main pathogenic factors of acne are high sebaceous gland secretion, follicular hyperproliferation, high androgen effects, propionibacterium acnes colonization and inflammation. Diet is always thought a probable reason for acne and many studies are done about acne and diet. Aim To determine the effect of insulin resistance in severe acne vulgaris. Material and methods Two hundred and forty-three acne vulgaris patients and 156 healthy controls were enrolled into the study. The blood levels of insulin and glucose were measured. Homeostasis Model Assessment (HOMA) Index was calculated. The values were compared with the control group. Results All of the patients were in the severe acne group according to their scores on the global acne scoring scale. While fasting blood glucose levels were not different between the groups (p > 0.05, 82.91 ±9.76 vs. 80.26 ±8.33), the fasting insulin levels were significantly higher in the patient group than in the control group (p < 0.001, 14.01 ±11.94 vs. 9.12 ±3.53). Additionally, there was a highly significant difference between the patient and control groups in terms of HOMA values (p < 0.001, 2.87 ±2.56 vs. 1.63 ±0.65). Conclusions These results suggest that insulin resistance may have a role in the pathogenesis of acne. PMID:26366152

  6. Pioglitazone Increases Whole Body Insulin Sensitivity in Obese, Insulin-Resistant Rhesus Monkeys

    PubMed Central

    Tozzo, Effie; Bhat, Gowri; Cheon, Kyeongmi; Camacho, Raul C.

    2015-01-01

    Hyperinsulinemic-euglycemic clamps are considered the "gold standard" for assessing whole body insulin sensitivity. When used in combination with tracer dilution techniques and physiological insulin concentrations, insulin sensitization can be dissected and attributed to hepatic and peripheral (primarily muscle) effects. Non-human primates (NHPs), such as rhesus monkeys, are the closest pre-clinical species to humans, and thus serve as an ideal model for testing of compound efficacy to support translation to human efficacy. We determined insulin infusion rates that resulted in high physiological insulin concentrations that elicited maximal pharmacodynamic responses during hyperinsulinemic-euglycemic clamps. These rates were then used with [U-13C]-D-glucose, to assess and document the degrees of hepatic and peripheral insulin resistance between healthy and insulin-resistant, dysmetabolic NHPs. Next, dysmetabolic NHPs were treated for 28 days with pioglitazone (3 mg/kg) and again had their insulin sensitivity assessed, illustrating a significant improvement in hepatic and peripheral insulin sensitivity. This coincided with a significant increase in insulin clearance, and normalization of circulating adiponectin. In conclusion, we have determined a physiological clamp paradigm (similar to humans) for assessing glucose turnover in NHPs. We have also demonstrated that insulin-resistant, dysmetabolic NHPs respond to the established insulin sensitizer, pioglitazone, thus confirming their use as an ideal pre-clinical translational model to assess insulin sensitizing compounds. PMID:25954816

  7. Role of sialic acid in insulin action and the insulin resistance of diabetes mellitus

    SciTech Connect

    Salhanick, A.I.; Amatruda, J.M. )

    1988-08-01

    Adipocytes treated with neuraminidase show markedly reduced responsiveness to insulin without any alteration in insulin binding. In addition, several studies have separately demonstrated both insulin resistance and decreases in membrane sialic acid content and associated biosynthetic enzymes in diabetes mellitus. In the present study, the authors investigated the role that sialic acid residues may play in insulin action and in the hepatic insulin resistance associated with nonketotic diabetes. Primary cultures of hepatocytes from normal rats treated with neuraminidase demonstrated a dose-dependent decrease in insulin-stimulated lipogenesis. At a concentration of neuraminidase that decreases insulin action by 50%, 23% of total cellular sialic acid content was released. Neuraminidase-releasable sialic acid was significantly decreased in hepatocytes from diabetic rats and this was associated with significant insulin resistance. Treatment of hepatocytes from diabetic rats with cytidine 5{prime}-monophospho-N-acetylneuraminic acid (CMP-NANA) enhanced insulin responsiveness 39%. The enhanced insulin responsiveness induced by CMP-NANA was blocked by cytidine 5{prime}-monophosphate (CMP) suggesting that the CMP-NANA effect was catalyzed by a cell surface sialyl-transferase. CMP reduced neuraminidase-releasable ({sup 14}C)sialic acid incorporation into hepatocytes by 43%. The data demonstrate a role for cell surface sialic acid residues in hepatic insulin action and support a role for decreased cell surface sialic acid residues in the insulin resistance of diabetes mellitus.

  8. Skeletal Muscle Insulin Resistance and Absence of Inflammation Characterize Insulin-Resistant Grade I Obese Women

    PubMed Central

    Bourret, Annick; Lambert, Karen; Birot, Olivier; Fédou, Christine; Dupuy, Anne-Marie; Cristol, Jean-Paul; Sutra, Thibault; Molinari, Nicolas; Maimoun, Laurent; Mariano-Goulart, Denis; Galtier, Florence; Avignon, Antoine; Stanke-Labesque, Françoise; Mercier, Jacques; Sultan, Ariane; Bisbal, Catherine

    2016-01-01

    Context Obesity is associated with insulin-resistance (IR), the key feature of type 2 diabetes. Although chronic low-grade inflammation has been identified as a central effector of IR development, it has never been investigated simultaneously at systemic level and locally in skeletal muscle and adipose tissue in obese humans characterized for their insulin sensitivity. Objectives We compared metabolic parameters and inflammation at systemic and tissue levels in normal-weight and obese subjects with different insulin sensitivity to better understand the mechanisms involved in IR development. Methods 30 post-menopausal women were classified as normal-weight insulin-sensitive (controls, CT) and obese (grade I) insulin-sensitive (OIS) or insulin-resistant (OIR) according to their body mass index and homeostasis model assessment of IR index. They underwent a hyperinsulinemic-euglycemic clamp, blood sampling, skeletal muscle and subcutaneous adipose tissue biopsies, an activity questionnaire and a self-administrated dietary recall. We analyzed insulin sensitivity, inflammation and IR-related parameters at the systemic level. In tissues, insulin response was assessed by P-Akt/Akt expression and inflammation by macrophage infiltration as well as cytokines and IκBα expression. Results Systemic levels of lipids, adipokines, inflammatory cytokines, and lipopolysaccharides were equivalent between OIS and OIR subjects. In subcutaneous adipose tissue, the number of anti-inflammatory macrophages was higher in OIR than in CT and OIS and was associated with higher IL-6 level. Insulin induced Akt phosphorylation to the same extent in CT, OIS and OIR. In skeletal muscle, we could not detect any inflammation even though IκBα expression was lower in OIR compared to CT. However, while P-Akt/Akt level increased following insulin stimulation in CT and OIS, it remained unchanged in OIR. Conclusion Our results show that systemic IR occurs without any change in systemic and tissues

  9. Molecular Mechanisms of Chromium in Alleviating Insulin Resistance

    PubMed Central

    Hua, Yinan; Clark, Suzanne; Ren, Jun; Sreejayan, Nair

    2011-01-01

    Type 2 diabetes is often associated with obesity, dyslipidemia, and cardiovascular anomalies and is a major health problem approaching global epidemic proportions. Insulin resistance, a prediabetic condition, precedes the onset of frank type 2 diabetes and offers potential avenues for early intervention to treat the disease. Although lifestyle modifications and exercise can reduce the incidence of diabetes, compliance has proved to be difficult, warranting pharmacological interventions. However, most of the currently available drugs that improve insulin sensitivity have adverse effects. Therefore, attractive strategies to alleviate insulin resistance include dietary supplements. One such supplement is chromium, which has been shown reduce insulin resistance in some, but not all, studies. Furthermore, the molecular mechanisms of chromium in alleviating insulin resistance remain elusive. This review examines emerging reports on the effect of chromium, as well as molecular and cellular mechanisms by which chromium may provide beneficial effects in alleviating insulin resistance. PMID:22423897

  10. Obesity and Insulin Resistance: An Abridged Molecular Correlation

    PubMed Central

    Mukherjee, Biswajit; Hossain, Chowdhury M; Mondal, Laboni; Paul, Paramita; Ghosh, Miltu K

    2013-01-01

    A relationship between obesity and type 2 diabetes is now generally well accepted. This relationship represents several major health hazards including morbid obesity and cardiovascular complications worldwide. Diabetes mellitus is a complex metabolic disorder characterized by impaired insulin release and insulin resistance. Lipids play an important physiological role in skeletal muscle, heart, liver and pancreas. Deregulation of fatty acid metabolism is the main culprit for developing insulin resistance and type 2 diabetes. A predominant predisposing factor to developing obesity, insulin resistance and type 2 diabetes is the permanent elevation of free fatty acids in plasma followed by impaired utilization of lipids by muscle. Diabetes-induced inflammation and oxidative stress have also vital role for development of insulin resistance in diabetic patients. The present review is intended to describe the correlation between lipids, obesity and insulin resistance based on current literature, in order to elucidate involved molecular mechanisms in depth. PMID:25278764

  11. Effects of sleeve gastrectomy on insulin resistance

    PubMed Central

    CĂTOI, ADRIANA FLORINELA; PÂRVU, ALINA; MIRONIUC, AUREL; GALEA, ROMEO FLORIN; MUREŞAN, ADRIANA; BIDIAN, CRISTINA; POP, IOANA

    2016-01-01

    Background and aim Obesity is a major risk factor for the onset of insulin resistance (IR), hyperinsulinemia and type 2 diabetes mellitus (T2DM) Evidence data has proven that beyond important weight loss bariatric surgery especially Roux-en-Y gastric bypass (RYGB) and bilio-pancreatic diversion (BPD) leads to significant early reduction of insulinemia and of IR calculated through the homeostatic model assessment (HOMA-IR), independently of fat mass decrease. Sleeve gastrectomy (SG) is now used as a sole weight loss operation with good results. Therefore, the aim of the present study was to investigate the early changes of fasting blood glucose, insulin and HOMA-IR in a group of morbidly obese (MO) patients i.e. at 7, 30 and 90 days after SG. Methods The study included 20 MO patients (7 male and 13 female) submitted to SG. Anthropometrical (weight, body mass index –BMI, percent excess BMI loss -%EBMIL) and biochemical (plasma glucose, insulin and calculated HOMA-IR ) evaluation were performed before and at 7, 30 and 90 days after SG. In addition, a second group of 10 normal weight healthy subjects with a BMI ranging form 19 kg/m2 to 23.14 kg/m2, matched for age and gender was investigated. Results Plasma glucose (p=0.018), insulin (p=0.004) and HOMA-IR (p=0.006) values were statistically different between the studied groups. After surgery, at every follow-up point, there were statistically different weight and BMI mean values relative to the operation day (p<0.003). BMI, decreased at 7 days (estimated reduction=2.79; 95% CI:[2.12;3.45]), at 30 days (estimated reduction=5.65; 95% CI:[3.57;7.73]) and at 90 days (estimated reduction=10.88; 95% CI:[7.35;14.41]) respectively after SG. We noted a tendency toward statistical significant change of mean insulin values at 7 days after surgery (corrected p=0.075), no statistical change at 30 days (corrected p=0.327) and a significant change at 90 days (corrected p=0.027) after SG as compared to baseline. There was a

  12. Divergent role of sphingosine 1-phosphate on insulin resistance.

    PubMed

    Fayyaz, Susann; Japtok, Lukasz; Kleuser, Burkhard

    2014-01-01

    Insulin resistance is a complex metabolic disorder in which insulin-sensitive tissues fail to respond to the physiological action of insulin. There is a strong correlation of insulin resistance and the development of type 2 diabetes both reaching epidemic proportions. Dysfunctional lipid metabolism is a hallmark of insulin resistance and a risk factor for several cardiovascular and metabolic disorders. Numerous studies in humans and rodents have shown that insulin resistance is associated with elevations of non-esterified fatty acids (NEFA) in the plasma. Moreover, bioactive lipid intermediates such as diacylglycerol (DAG) and ceramides appear to accumulate in response to NEFA, which may interact with insulin signaling. However, recent work has also indicated that sphingosine 1-phosphate (S1P), a breakdown product of ceramide, modulate insulin signaling in different cell types. In this review, we summarize the current state of knowledge about S1P and insulin signaling in insulin sensitive cells. A specific focus is put on the action of S1P on hepatocytes, pancreatic β-cells and skeletal muscle cells. In particular, modulation of S1P-signaling can be considered as a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes. PMID:24977487

  13. The effect of oxytetracycline on insulin resistance in obese mice

    PubMed Central

    Bégin-Heick, Nicole; Bourassa, Michel; Heick, H. M. C.

    1974-01-01

    1. Chronic oxytetracycline treatment was found to improve the insulin resistance of the obese–hyperglycaemic mouse. 2. The improved response to insulin was accompanied by decreased concentrations of circulating insulin and glucose, by a decrease in the lipid content of the liver and by an increase in the insulin-receptor sites of the liver and adipose tissue. 3. The increase in insulin-receptor sites preceded the fall in blood glucose. 4. Comparable studies done on food-restricted animals indicated that although chronic food restriction corrected the hyperinsulinaemia it did not restore the insulin-receptor sites or the hyperglycaemia. PMID:4464837

  14. Insulin Resistance Alters Islet Morphology in Nondiabetic Humans

    PubMed Central

    Mezza, Teresa; Muscogiuri, Giovanna; Sorice, Gian Pio; Clemente, Gennaro; Hu, Jiang; Pontecorvi, Alfredo; Holst, Jens J.; Giaccari, Andrea; Kulkarni, Rohit N.

    2014-01-01

    Type 2 diabetes is characterized by poor glucose uptake in metabolic tissues and manifests when insulin secretion fails to cope with worsening insulin resistance. In addition to its effects on skeletal muscle, liver, and adipose tissue metabolism, it is evident that insulin resistance also affects pancreatic β-cells. To directly examine the alterations that occur in islet morphology as part of an adaptive mechanism to insulin resistance, we evaluated pancreas samples obtained during pancreatoduodenectomy from nondiabetic subjects who were insulin-resistant or insulin-sensitive. We also compared insulin sensitivity, insulin secretion, and incretin levels between the two groups. We report an increased islet size and an elevated number of β- and α-cells that resulted in an altered β-cell–to–α-cell area in the insulin- resistant group. Our data in this series of studies suggest that neogenesis from duct cells and transdifferentiation of α-cells are potential contributors to the β-cell compensatory response to insulin resistance in the absence of overt diabetes. PMID:24215793

  15. Metabolic syndrome and insulin resistance in obese adolescents

    PubMed Central

    Gobato, Amanda Oliva; Vasques, Ana Carolina J.; Zambon, Mariana Porto; Barros, Antonio de Azevedo; Hessel, Gabriel

    2014-01-01

    Objective: To verify the prevalence of metabolic syndrome and insulin resistance in obese adolescents and its relationship with different body composition indicators. Methods: A cross-sectional study comprising 79 adolescents aged ten to 18 years old. The assessed body composition indicators were: body mass index (BMI), body fat percentage, abdominal circumference, and subcutaneous fat. The metabolic syndrome was diagnosed according to the criteria proposed by Cook et al. The insulin resistance was determined by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) index for values above 3.16. The analysis of ROC curves was used to assess the BMI and the abdominal circumference, aiming to identify the subjects with metabolic syndrome and insulin resistance. The cutoff point corresponded to the percentage above the reference value used to diagnose obesity. Results: The metabolic syndrome was diagnosed in 45.5% of the patients and insulin resistance, in 29.1%. Insulin resistance showed association with HDL-cholesterol (p=0.032) and with metabolic syndrome (p=0.006). All body composition indicators were correlated with insulin resistance (p<0.01). In relation to the cutoff point evaluation, the values of 23.5 and 36.3% above the BMI reference point allowed the identification of insulin resistance and metabolic syndrome. The best cutoff point for abdominal circumference to identify insulin resistance was 40%. Conclusions: All body composition indicators, HDL-cholesterol and metabolic syndrome showed correlation with insulin resistance. The BMI was the most effective anthropometric indicator to identify insulin resistance. PMID:24676191

  16. Cerebral blood flow links insulin resistance and baroreflex sensitivity.

    PubMed

    Ryan, John P; Sheu, Lei K; Verstynen, Timothy D; Onyewuenyi, Ikechukwu C; Gianaros, Peter J

    2013-01-01

    Insulin resistance confers risk for diabetes mellitus and associates with a reduced capacity of the arterial baroreflex to regulate blood pressure. Importantly, several brain regions that comprise the central autonomic network, which controls the baroreflex, are also sensitive to the neuromodulatory effects of insulin. However, it is unknown whether peripheral insulin resistance relates to activity within central autonomic network regions, which may in turn relate to reduced baroreflex regulation. Accordingly, we tested whether resting cerebral blood flow within central autonomic regions statistically mediated the relationship between insulin resistance and an indirect indicator of baroreflex regulation; namely, baroreflex sensitivity. Subjects were 92 community-dwelling adults free of confounding medical illnesses (48 men, 30-50 years old) who completed protocols to assess fasting insulin and glucose levels, resting baroreflex sensitivity, and resting cerebral blood flow. Baroreflex sensitivity was quantified by measuring the magnitude of spontaneous and sequential associations between beat-by-beat systolic blood pressure and heart rate changes. Individuals with greater insulin resistance, as measured by the homeostatic model assessment, exhibited reduced baroreflex sensitivity (b = -0.16, p < .05). Moreover, the relationship between insulin resistance and baroreflex sensitivity was statistically mediated by cerebral blood flow in central autonomic regions, including the insula and cingulate cortex (mediation coefficients < -0.06, p-values < .01). Activity within the central autonomic network may link insulin resistance to reduced baroreflex sensitivity. Our observations may help to characterize the neural pathways by which insulin resistance, and possibly diabetes mellitus, relates to adverse cardiovascular outcomes. PMID:24358272

  17. Integrating Mechanisms for Insulin Resistance: Common Threads and Missing Links

    PubMed Central

    Samuel, Varman T.; Shulman, Gerald I.

    2012-01-01

    Insulin resistance is a complex metabolic disorder that defies a single etiological pathway. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response (UPR) pathway and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. However, these pathways are also closely linked to changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition. Ultimately, accumulation of specific lipid metabolites (diacylglycerols and/or ceramides) in liver and skeletal muscle, may be a common pathway leading to impaired insulin signaling and insulin resistance. PMID:22385956

  18. Arginine supplementation improves insulin resistance in obese adolescents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Arginine through a NO mediated mechanism improves insulin resistance in type 2 diabetes. To assess the effect of a short-term (1 week) dietary arginine supplementation on insulin resistance in glucose intolerant obese adolescents, we conducted a randomized, cross-over study in 12 subjects (16 +/- 1 ...

  19. Acylcarnitines: potential implications for skeletal muscle insulin resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Insulin resistance is linked to increased acylcarnitine species in a number of tissues including skeletal muscle, due to incomplete fatty acid oxidation (FAO). It is not known if acylcarnitines participate in muscle insulin resistance or simply reflect dysregulated metabolism. The aim of this stud...

  20. Severe Insulin Resistance Improves Immediately After Sleeve Gastrectomy.

    PubMed

    Sharma, Rahul; Hassan, Chandra; Chaiban, Joumana T

    2016-01-01

    Introduction. Obese individuals exhibit insulin resistance often leading to adverse health outcomes. When compared with intensive medical therapy, bariatric surgery has shown better outcomes mainly in terms of insulin resistance and glycemic control. Using the Homeostasis Model Assessment of insulin resistance (HOMA-IR), we report herein a case illustrating a drastic improvement in severe insulin resistance after sleeve gastrectomy in the immediate postoperative period. Case Report. A patient with long-standing history of morbid obesity, type 2 diabetes, obstructive sleep apnea, hypertension, and severe insulin resistance (requiring approximately 2 units of insulin per kg per day) was enrolled in the medical weight management program for 6 months during which he lost 40 lbs and his insulin requirements decreased. He then underwent a sleeve gastrectomy and did not require insulin therapy as of postoperative day 1. His HOMA-IR improved by about 76% between day 1 and day 14 postoperatively. Conclusion. Sleeve gastrectomy leads to a drastic improvement in severe insulin resistance as early as the first postoperative day. PMID:26788532

  1. Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization

    PubMed Central

    Sears, D. D.; Hsiao, G.; Hsiao, A.; Yu, J. G.; Courtney, C. H.; Ofrecio, J. M.; Chapman, J.; Subramaniam, S.

    2009-01-01

    Cellular and tissue defects associated with insulin resistance are coincident with transcriptional abnormalities and are improved after insulin sensitization with thiazolidinedione (TZD) PPARγ ligands. We characterized 72 human subjects by relating their clinical phenotypes with functional pathway alterations. We transcriptionally profiled 364 biopsies harvested before and after hyperinsulinemic-euglycemic clamp studies, at baseline and after 3-month TZD treatment. We have identified molecular and functional characteristics of insulin resistant subjects and distinctions between TZD treatment responder and nonresponder subjects. Insulin resistant subjects exhibited alterations in skeletal muscle (e.g., glycolytic flux and intramuscular adipocytes) and adipose tissue (e.g., mitochondrial metabolism and inflammation) that improved relative to TZD-induced insulin sensitization. Pre-TZD treatment expression of MLXIP in muscle and HLA-DRB1 in adipose tissue from insulin resistant subjects was linearly predictive of post-TZD insulin sensitization. We have uniquely characterized coordinated cellular and tissue functional pathways that are characteristic of insulin resistance, TZD-induced insulin sensitization, and potential TZD responsiveness. PMID:19841271

  2. Postreceptor defects causing insulin resistance in normoinsulinemic non-insulin-dependent diabetes mellitus

    SciTech Connect

    Bolinder, J.; Ostman, J.; Arner, P.

    1982-10-01

    The mechanisms of the diminished hypoglycemic response to insulin in non-insulin-dependent diabetes mellitus (NIDDM) with normal levels of circulating plasma insulin were investigated. Specific binding of mono-/sup 125/I (Tyr A14)-insulin to isolated adipocytes and effects of insulin (5--10,000 microunits/ml) on glucose oxidation and lipolysis were determined simultaneously in subcutaneous adipose tissue of seven healthy subjects of normal weight and seven untreated NIDDM patients with normal plasma insulin levels. The two groups were matched for age, sex, and body weight. Insulin binding, measured in terms of receptor number and affinity, was normal in NIDDM, the total number of receptors averaging 350,000 per cell. Neither sensitivity nor the maximum antilipolytic effect of insulin was altered in NIDDM patients as compared with control subjects; the insulin concentration producing half the maximum effect (ED50) was 10 microunits/ml. As regards the effect of insulin on glucose oxidation, for the control subjects ED50 was 30 microunits/ml, whereas in NIDDM patients, insulin exerted no stimulatory effect. The results obtained suggest that the effect of insulin on glucose utilization in normoinsulinemic NIDDM may be diminished in spite of normal insulin binding to receptors. The resistance may be due solely to postreceptor defects, and does not involve antilipolysis.

  3. Linking Gut Microbiota and Inflammation to Obesity and Insulin Resistance.

    PubMed

    Saad, M J A; Santos, A; Prada, P O

    2016-07-01

    Obesity and insulin resistance are the major predisposing factors to comorbidities, such as Type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular and neurodegenerative diseases, and several types of cancer. The prevalence of obesity is still increasing worldwide and now affects a large number of individuals. Here, we review the role of the gut microbiota in the pathophysiology of insulin resistance/obesity. The human intestine is colonized by ∼100 trillion bacteria, which constitute the gut microbiota. Studies have shown that lean and overweight rodents and humans may present differences in the composition of their intestinal flora. Over the past 10 years, data from different sources have established a causal link between the intestinal microbiota and obesity/insulin resistance. It is important to emphasize that diet-induced obesity promotes insulin resistance by mechanisms independent and dependent on gut microbiota. In this review, we present several mechanisms that contribute to explaining the link between intestinal flora and insulin resistance/obesity. The LPS from intestinal flora bacteria can induce a chronic subclinical inflammatory process and obesity, leading to insulin resistance through activation of TLR4. The reduction in circulating SCFA may also have an essential role in the installation of reduced insulin sensitivity and obesity. Other mechanisms include effects of bile acids, branched-chain amino acids (BCAA), and some other lesser-known factors. In the near future, this area should open new therapeutic avenues for obesity/insulin resistance and its comorbidities. PMID:27252163

  4. Hepatitis C Virus, Insulin Resistance, and Steatosis

    PubMed Central

    Kralj, Dominik; Jukić, Lucija Virović; Stojsavljević, Sanja; Duvnjak, Marko; Smolić, Martina; Čurčić, Ines Bilić

    2016-01-01

    Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide. Liver steatosis is a common finding in many hepatic and extrahepatic disorders, the most common being metabolic syndrome (MS). Over time, it has been shown that the frequent coexistence of these two conditions is not coincidental, since many epidemiological, clinical, and experimental studies have indicated HCV to be strongly associated with liver steatosis and numerous metabolic derangements. Here, we present an overview of publications that provide clinical evidence of the metabolic effects of HCV and summarize the available data on the pathogenetic mechanisms of this association. It has been shown that HCV infection can induce insulin resistance (IR) in the liver and peripheral tissues through multiple mechanisms. Substantial research has suggested that HCV interferes with insulin signaling both directly and indirectly, inducing the production of several proinflammatory cytokines. HCV replication, assembly, and release from hepatocytes require close interactions with lipid droplets and host lipoproteins. This modulation of lipid metabolism in host cells can induce hepatic steatosis, which is more pronounced in patients with HCV genotype 3. The risk of steatosis depends on several viral factors (including genotype, viral load, and gene mutations) and host features (visceral obesity, type 2 diabetes mellitus, genetic predisposition, medication use, and alcohol consumption). HCV-related IR and steatosis have been shown to have a remarkable clinical impact on the prognosis of HCV infection and quality of life, due to their association with resistance to antiviral therapy, progression of hepatic fibrosis, and development of hepatocellular carcinoma. Finally, HCV-induced IR, oxidative stress, and changes in lipid and iron metabolism lead to glucose intolerance, arterial hypertension, hyperuricemia, and atherosclerosis, resulting in increased cardiovascular mortality. PMID:27047774

  5. Insulin resistance and breast-cancer risk.

    PubMed

    Bruning, P F; Bonfrèr, J M; van Noord, P A; Hart, A A; de Jong-Bakker, M; Nooijen, W J

    1992-10-21

    Life-style has a major influence on the incidence of breast cancer. To evaluate the effects of life-style related metabolic-endocrine factors on breast cancer risk we conducted a case-control study comparing 223 women aged 38 to 75 years presenting with operable (stage I or II) breast cancer and 441 women of the same age having no breast cancer, who participated in a population-based breast cancer screening program. Women reporting diabetes mellitus were excluded. Sera from 110 women of the same age group presenting with early stage melanoma, lymphoma or cervical cancer were used as a second 'other-cancer control group'. Serum levels of C-peptide were significantly higher in early breast cancer cases compared to controls. The same was found for the ratios C-peptide to glucose or C-peptide to fructosamine, indicating insulin resistance. Sex hormone binding globulin was inversely, triglycerides and available estradiol were positively related to C-peptide. Serum C-peptide levels were related to body mass index (BMI), and to waist/hip ratio (WHR), in particular in controls. However, the relative increase of C-peptide, C-peptide to glucose or C-peptide to fructosamine in cases was independent of BMI or WHR. The log relative risk was linearly related to the log C-peptide levels. Relative risk according to quintiles, and adjusted for age, family history, BMI and WHR, for women at the 80% level was 2.9 as compared with those at the 20% level for C-peptide. Elevated C-peptide or C-peptide to fructosamine values were not observed in the sera from women belonging to the 'other-cancer control group'. This study suggests that hyperinsulinemia with insulin resistance is a significant risk factor for breast cancer independent of general adiposity or body fat distribution. PMID:1399128

  6. Hepatitis C Virus, Insulin Resistance, and Steatosis.

    PubMed

    Kralj, Dominik; Virović Jukić, Lucija; Stojsavljević, Sanja; Duvnjak, Marko; Smolić, Martina; Čurčić, Ines Bilić

    2016-03-28

    Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide. Liver steatosis is a common finding in many hepatic and extrahepatic disorders, the most common being metabolic syndrome (MS). Over time, it has been shown that the frequent coexistence of these two conditions is not coincidental, since many epidemiological, clinical, and experimental studies have indicated HCV to be strongly associated with liver steatosis and numerous metabolic derangements. Here, we present an overview of publications that provide clinical evidence of the metabolic effects of HCV and summarize the available data on the pathogenetic mechanisms of this association. It has been shown that HCV infection can induce insulin resistance (IR) in the liver and peripheral tissues through multiple mechanisms. Substantial research has suggested that HCV interferes with insulin signaling both directly and indirectly, inducing the production of several proinflammatory cytokines. HCV replication, assembly, and release from hepatocytes require close interactions with lipid droplets and host lipoproteins. This modulation of lipid metabolism in host cells can induce hepatic steatosis, which is more pronounced in patients with HCV genotype 3. The risk of steatosis depends on several viral factors (including genotype, viral load, and gene mutations) and host features (visceral obesity, type 2 diabetes mellitus, genetic predisposition, medication use, and alcohol consumption). HCV-related IR and steatosis have been shown to have a remarkable clinical impact on the prognosis of HCV infection and quality of life, due to their association with resistance to antiviral therapy, progression of hepatic fibrosis, and development of hepatocellular carcinoma. Finally, HCV-induced IR, oxidative stress, and changes in lipid and iron metabolism lead to glucose intolerance, arterial hypertension, hyperuricemia, and atherosclerosis, resulting in increased cardiovascular mortality. PMID:27047774

  7. Acne: risk indicator for increased body mass index and insulin resistance.

    PubMed

    Melnik, Bodo C; John, Swen Malte; Plewig, Gerd

    2013-11-01

    Acne appears to represent a visible indicator disease of over-activated mTORC1 signalling, an unfavour-able metabolic deviation on the road to serious common Western diseases of civilisation associated with increased body mass index and insulin resistance. Exaggerated mTORC1 signalling by Western diet explains the association of acne with increased body mass index, insulin resistance, and early onset of menarche. Both, a high glycaemic load and increased consumption of milk and milk products, staples of Western diet, aggravate mammalian target of rapamycin complex 1 signalling. This review of the literature summarises present evidence for an association between acne, increased body mass index, insulin resistance and Western diet. By dietary intervention with a Palaeolithic-type diet, the dermatologist has the chance to attenuate patients' increased mTORC1 signalling by reducing glycaemic load and milk consumption, which may not only improve acne but may delay the march to more serious mTORC1-driven diseases of civilisation. PMID:23975508

  8. Leptin, skeletal muscle lipids, and lipid-induced insulin resistance.

    PubMed

    Dube, John J; Bhatt, Bankim A; Dedousis, Nikolas; Bonen, Arend; O'Doherty, Robert M

    2007-08-01

    Leptin-induced increases in insulin sensitivity are well established and may be related to the effects of leptin on lipid metabolism. However, the effects of leptin on the levels of lipid metabolites implicated in pathogenesis of insulin resistance and the effects of leptin on lipid-induced insulin resistance are unknown. The current study addressed in rats the effects of hyperleptinemia (HL) on insulin action and markers of skeletal muscle (SkM) lipid metabolism in the absence or presence of acute hyperlipidemia induced by an infusion of a lipid emulsion. Compared with controls (CONT), HL increased insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp ( approximately 15%), and increased SkM Akt ( approximately 30%) and glycogen synthase kinase 3 alpha ( approximately 52%) phosphorylation. These improvements in insulin action were associated with decreased SkM triglycerides (TG; approximately 61%), elevated ceramides ( approximately 50%), and similar diacylglycerol (DAG) levels in HL compared with CONT. Acute hyperlipidemia in CONT decreased insulin sensitivity ( approximately 25%) and increased SkM DAG ( approximately 33%) and ceramide ( approximately 60%) levels. However, hyperlipidemia did not induce insulin resistance or SkM DAG and ceramide accumulation in HL. SkM total fatty acid transporter CD36, plasma membrane fatty acid binding protein, acetyl Co-A carboxylase phosphorylation, and fatty acid oxidation were similar in HL compared with CONT. However, HL decreased SkM protein kinase C theta (PKC theta), a kinase implicated in mediating the detrimental effects of lipids on insulin action. We conclude that increases in insulin sensitivity induced by HL are associated with decreased levels of SkM TG and PKC theta and increased SkM insulin signaling, but not with decreases in other lipid metabolites implicated in altering SkM insulin sensitivity (DAG and ceramide). Furthermore, insulin resistance induced by an acute lipid infusion is prevented by

  9. New insights into insulin action and resistance in the vasculature

    PubMed Central

    Manrique, Camila; Lastra, Guido; Sowers, James R.

    2014-01-01

    Two-thirds of adults in the United States are overweight or obese, and another 26 million have type 2 diabetes. Decreased insulin sensitivity in cardiovascular tissue is an underlying abnormality in these individuals. Insulin metabolic signaling increases endothelial cell nitric oxide production. Impaired vascular insulin sensitivity is an early defect leading to impaired vascular relaxation. In overweight and obese persons, as well as in those with hypertension, systemic and vascular insulin resistance often occurs in conjunction with activation of the cardiovascular tissue renin–angiotensin–aldosterone system (RAAS). Activated angiotensin II type 1 receptor and mineralocorticoid receptor signaling promote the development of vascular insulin resistance and impaired endothelial nitric oxide–mediated relaxation. Research in this area has implicated excessive serine phosphorylation and proteasomal degradation of the docking protein insulin receptor substrate and enhanced signaling through hybrid insulin/insulin-like growth factor (IGF-1) receptor as important mechanisms underlying RAAS impediment of downstream vascular insulin metabolic signaling. This review will present recent evidence supporting the notion that RAAS signaling represents a potential pathway for the development of vascular insulin resistance and impaired endothelial-mediated vasodilation. PMID:24650277

  10. Is insulin resistance the principal cause of type 2 diabetes?

    PubMed

    Gerich, J E

    1999-09-01

    The data presented from these recent studies raise serious doubt concerning the commonly held view that insulin resistance is the principal cause of type 2 diabetes: first of all they provide evidence that insulin resistance may not be the primary genetic factor for type 2 diabetes; secondly, they demonstrate that at least under certain circumstances insulin resistance is not essential for diabetes to occur, and then finally, they indicate that insulin resistance may not be the predominant factor determining the degree of hyperglycaemia. Although these studies suggest that the role of insulin resistance relative to that of beta-cell dysfunction in the pathogenesis of type 2 diabetes has been generally overestimated, one should not be left with the impression that insulin resistance is not important. It is certainly an important factor in determining the degree of hyperglycaemia or glucose intolerance present at a given level of beta-cell function. The improvement in glycaemic control after weight loss which lessens insulin resistance or after the administration of pharmacologic agents that improve insulin sensitivity clearly argue that insulin resistance is important in this regard. In addition to influencing the severity of glucose intolerance, insulin resistance is probably also important in determining the time of onset of diabetes. It may do this simply by altering the balance between the body's demand for insulin and the ability of the pancreas to provide insulin. It might adversely affect beta-cell function in addition to increasing the demand for insulin. This concept is schematically represented in figure 3. It is well established that beta-cell function normally deteriorates as a function of age [41]. Although the prevalence of type 2 diabetes increases as a function of age, this by itself obviously does not result in diabetes in the great majority of people. In such individuals their insulin sensitivity is sufficient to maintain the balance between the

  11. Hypertension Management and Microvascular Insulin Resistance in Diabetes

    PubMed Central

    Ko, Seung-Hyun; Cao, Wenhong; Liu, Zhenqi

    2011-01-01

    Type 2 diabetes is in essence a vascular disease and is frequently associated with hypertension, macrovascular events, and microvascular complications. Microvascular dysfunction, including impaired recruitment and capillary rarefaction, has been implicated in the pathogenesis of diabetic complications. Microvascular insulin resistance and renin-angiotensin system upregulation are present in diabetes, and each contributes to the development of hypertension and microvascular dysfunction. In the insulin-sensitive state, insulin increases microvascular perfusion by increasing endothelial nitric oxide production, but this effect is abolished by insulin resistance. Angiotensin II, acting via the type 1 receptors, induces inflammation and oxidative stress, leading to impaired insulin signaling, reduced nitric oxide availability, and vasoconstriction. Conversely, it acts on the type 2 receptors to cause vasodilatation. Because substrate and hormonal exchanges occur in the microvasculature, antihypertensive agents targeted to improve microvascular insulin sensitivity and function may have beneficial effects beyond their capacity to lower blood pressure in patients with diabetes. PMID:20582734

  12. Alteration of local adipose tissue trace element homeostasis as a possible mechanism of obesity-related insulin resistance.

    PubMed

    Tinkov, Alexey A; Sinitskii, Anton I; Popova, Elizaveta V; Nemereshina, Olga N; Gatiatulina, Evgenia R; Skalnaya, Margarita G; Skalny, Anatoly V; Nikonorov, Alexandr A

    2015-09-01

    The mechanisms of association between obesity and the related metabolic disturbances in general and insulin resistance in particular are extensively studied. Taking into account a key role of adipose tissue insulin resistance in the development of systemic obesity-related insulin resistance, the estimation of mechanisms linking increased adiposity and impaired insulin signaling in adipocytes will allow to develop novel prophylactic and therapeutic approaches to treatment of these states. A number of trace elements like chromium, zinc, and vanadium have been shown to take part in insulin signaling via various mechanisms. Taking into account a key role of adipocyte in systemic carbohydrate homeostasis it can be asked if trace element homeostasis in adipose tissue may influence regulatory mechanisms of glucose metabolism. We hypothesize that caloric excess through currently unknown mechanisms results in decreased chromium, vanadium, and zinc content in adipocytes. Decreased content of trace elements in the adipose tissue causes impairment of intra-adipocyte insulin signaling subsequently leading to adipose tissue insulin resistance. The latter significantly contributes to systemic insulin resistance and further metabolic disruption in obesity. It is also possible that decreased adipose tissue trace element content is associated with dysregulation of insulin-sensitizing and proinflammatory adipokines also leading to insulin resistance. We hypothesize that insulin resistance and adipokine dysbalance increase the severity of obesity subsequently aggravating alteration of adipose tissue trace element balance. Single indications of high relative adipose tissue trace element content, decreased Cr, V, and Zn content in obese adipose tissue, and tight association between fat tissue chromium, vanadium, and zinc levels and metabolic parameters in obesity may be useful for hypothesis validation. If our hypothesis will be confirmed by later studies, adipose tissue chromium

  13. Autophagy downregulation contributes to insulin resistance mediated injury in insulin receptor knockout podocytes in vitro

    PubMed Central

    Xin, Wei; Li, Zhaoping; Chen, Liyong

    2016-01-01

    It is unknown whether autophagy activity is altered in insulin resistant podocytes and whether autophagy could be a therapeutic target for diabetic nephropathy (DN). Here we used shRNA transfection to knockdown the insulin receptor (IR) gene in cultured human immortalized podocytes as an in vitro insulin resistant model. Autophagy related proteins LC3, Beclin, and p62 as well as nephrin, a podocyte injury marker, were assessed using western blot and immunofluorescence staining. Our results show that autophagy is suppressed when podocytes lose insulin sensitivity and that treatment of rapamycin, an mTOR specific inhibitor, could attenuate insulin resistance induced podocytes injury via autophagy activation. The present study deepens our understanding of the role of autophagy in the pathogenesis of DN. PMID:27077005

  14. [Childhhood obesity, insulin resistance and increased cardiovascular risk].

    PubMed

    Carlone, Angela; Venditti, Chiara; Cipolloni, Laura; Zampetti, Simona; Spoletini, Marialuisa; Capizzi, Marco; Leto, Gaetano; Buzzetti, Raffaella

    2012-10-01

    Excess fat is one of the major risk factors for insulin resistance predisposing to the development of cardiovascular diseases in western countries. We know that obese patients are strongly at risk of cardiovascular diseases, like myocardial infarction or stroke. These diseases are the most frequent cause of death in the adult population, representing a social and economic problem. Today there are not available and useful markers for screening and diagnosis of insulin- resistance in young people. "Easy-to-detect" clinical markers must be found to identify young subjects at risk of cardiovascular diseases. Very interesting the relationship between wrist circumference, its bone composition and insulin resistance. PMID:23114400

  15. Role of insulin resistance in uric acid nephrolithiasis

    PubMed Central

    Li, Hanhan; Klett, Dane E; Littleton, Raymond; Elder, Jack S; Sammon, Jesse D

    2014-01-01

    Metabolic syndrome has been implicated in the pathogenesis of uric acid stones. Although not completely understood, its role is supported by many studies demonstrating increased prevalence of uric acid stones in patients with metabolic syndrome and in particular insulin resistance, a major component of metabolic syndrome. This review presents epidemiologic studies demonstrating the association between metabolic syndrome and nephrolithiasis in general as well as the relationship between insulin resistance and uric acid stone formation, in particular. We also review studies that explore the pathophysiologic relationship between insulin resistance and uric acid nephrolithiasis. PMID:25374817

  16. [Severe type A insulin resistance syndrome due to a mutation in the insulin receptor gene].

    PubMed

    Ros, P; Colino-Alcol, E; Grasso, V; Barbetti, F; Argente, J

    2015-01-01

    Insulin resistance syndromes without lipodystrophy are an infrequent and heterogeneous group of disorders with variable clinical phenotypes, associated with hyperglycemia and hyperinsulinemia. The three conditions related to mutations in the insulin receptor gene are leprechaunism or Donohue syndrome, Rabson-Mendenhall syndrome, and Type A syndrome. A case is presented on a patient diagnosed with type A insulin resistance, defined by the triad of extreme insulin resistance, acanthosis nigricans, and hyperandrogenism, carrying a heterozygous mutation in exon 19 of the insulin receptor gene coding for its tyrosine kinase domain that is crucial for the catalytic activity of the receptor. The molecular basis of the syndrome is reviewed, focusing on the structure-function relationships of the insulin receptor, knowing that the criteria for survival are linked to residual insulin receptor function. It is also pointed out that, although type A insulin resistance appears to represent a somewhat less severe condition, these patients have a high morbidity and their treatment is still unsatisfactory. PMID:25027621

  17. Cognitively impaired elderly exhibit insulin resistance and no memory improvement with infused insulin.

    PubMed

    Morris, Jill K; Vidoni, Eric D; Mahnken, Jonathan D; Montgomery, Robert N; Johnson, David K; Thyfault, John P; Burns, Jeffrey M

    2016-03-01

    Insulin resistance is a risk factor for Alzheimer's disease (AD), although its role in AD etiology is unclear. We assessed insulin resistance using fasting and insulin-stimulated measures in 51 elderly subjects with no dementia (ND; n = 37) and with cognitive impairment (CI; n = 14). CI subjects exhibited either mild CI or AD. Fasting insulin resistance was measured using the homeostatic model assessment of insulin resistance (HOMA-IR). Insulin-stimulated glucose disposal was assessed using the hyperinsulinemic-euglycemic clamp to calculate glucose disposal rate into lean mass, the primary site of insulin-stimulated glucose disposal. Because insulin crosses the blood-brain barrier, we also assessed whether insulin infusion would improve verbal episodic memory compared to baseline. Different but equivalent versions of cognitive tests were administered in counterbalanced order in the basal and insulin-stimulated state. Groups did not differ in age or body mass index. Cognitively impaired subjects exhibited greater insulin resistance as measured at fasting (HOMA-IR; ND: 1.09 [1.1] vs. CI: 2.01 [2.3], p = 0.028) and during the hyperinsulinemic clamp (glucose disposal rate into lean mass; ND: 9.9 (4.5) vs. AD 7.2 (3.2), p = 0.040). Cognitively impaired subjects also exhibited higher fasting insulin compared to ND subjects, (CI: 8.7 [7.8] vs. ND: 4.2 [3.8] μU/mL; p = 0.023) and higher fasting amylin (CI: 24.1 [39.1] vs. 8.37 [14.2]; p = 0.050) with no difference in fasting glucose. Insulin infusion elicited a detrimental effect on one test of verbal episodic memory (Free and Cued Selective Reminding Test) in both groups (p < 0.0001) and no change in performance on an additional task (delayed logical memory). In this study, although insulin resistance was observed in cognitively impaired subjects compared to ND controls, insulin infusion did not improve memory. Furthermore, a significant correlation between HOMA-IR and glucose disposal rate was present only in ND

  18. Metabolic Acidosis-Induced Insulin Resistance and Cardiovascular Risk

    PubMed Central

    Souto, Gema; Donapetry, Cristóbal; Calviño, Jesús

    2011-01-01

    Abstract Microalbuminuria has been conclusively established as an independent cardiovascular risk factor, and there is evidence of an association between insulin resistance and microalbuminuria, the former preceding the latter in prospective studies. It has been demonstrated that even the slightest degree of metabolic acidosis produces insulin resistance in healthy humans. Many recent epidemiological studies link metabolic acidosis indicators with insulin resistance and systemic hypertension. The strongly acidogenic diet consumed in developed countries produces a lifetime acidotic state, exacerbated by excess body weight and aging, which may result in insulin resistance, metabolic syndrome, and type 2 diabetes, contributing to cardiovascular risk, along with genetic causes, lack of physical exercise, and other factors. Elevated fruits and vegetables consumption has been associated with lower diabetes incidence. Diseases featuring severe atheromatosis and elevated cardiovascular risk, such as diabetes mellitus and chronic kidney failure, are typically characterized by a chronic state of metabolic acidosis. Diabetic patients consume particularly acidogenic diets, and deficiency of insulin action generates ketone bodies, creating a baseline state of metabolic acidosisworsened by inadequate metabolic control, which creates a vicious circle by inducing insulin resistance. Even very slight levels of chronic kidney insufficiency are associated with increased cardiovascular risk, which may be explained at least in part by deficient acid excretory capacity of the kidney and consequent metabolic acidosis-induced insulin resistance. PMID:21352078

  19. p-Cresyl sulfate promotes insulin resistance associated with CKD.

    PubMed

    Koppe, Laetitia; Pillon, Nicolas J; Vella, Roxane E; Croze, Marine L; Pelletier, Caroline C; Chambert, Stéphane; Massy, Ziad; Glorieux, Griet; Vanholder, Raymond; Dugenet, Yann; Soula, Hédi A; Fouque, Denis; Soulage, Christophe O

    2013-01-01

    The mechanisms underlying the insulin resistance that frequently accompanies CKD are poorly understood, but the retention of renally excreted compounds may play a role. One such compound is p-cresyl sulfate (PCS), a protein-bound uremic toxin that originates from tyrosine metabolism by intestinal microbes. Here, we sought to determine whether PCS contributes to CKD-associated insulin resistance. Administering PCS to mice with normal kidney function for 4 weeks triggered insulin resistance, loss of fat mass, and ectopic redistribution of lipid in muscle and liver, mimicking features associated with CKD. Mice treated with PCS exhibited altered insulin signaling in skeletal muscle through ERK1/2 activation. In addition, exposing C2C12 myotubes to concentrations of PCS observed in CKD caused insulin resistance through direct activation of ERK1/2. Subtotal nephrectomy led to insulin resistance and dyslipidemia in mice, and treatment with the prebiotic arabino-xylo-oligosaccharide, which reduced serum PCS by decreasing intestinal production of p-cresol, prevented these metabolic derangements. Taken together, these data suggest that PCS contributes to insulin resistance and that targeting PCS may be a therapeutic strategy in CKD. PMID:23274953

  20. Metabolic acidosis-induced insulin resistance and cardiovascular risk.

    PubMed

    Souto, Gema; Donapetry, Cristóbal; Calviño, Jesús; Adeva, Maria M

    2011-08-01

    Microalbuminuria has been conclusively established as an independent cardiovascular risk factor, and there is evidence of an association between insulin resistance and microalbuminuria, the former preceding the latter in prospective studies. It has been demonstrated that even the slightest degree of metabolic acidosis produces insulin resistance in healthy humans. Many recent epidemiological studies link metabolic acidosis indicators with insulin resistance and systemic hypertension. The strongly acidogenic diet consumed in developed countries produces a lifetime acidotic state, exacerbated by excess body weight and aging, which may result in insulin resistance, metabolic syndrome, and type 2 diabetes, contributing to cardiovascular risk, along with genetic causes, lack of physical exercise, and other factors. Elevated fruits and vegetables consumption has been associated with lower diabetes incidence. Diseases featuring severe atheromatosis and elevated cardiovascular risk, such as diabetes mellitus and chronic kidney failure, are typically characterized by a chronic state of metabolic acidosis. Diabetic patients consume particularly acidogenic diets, and deficiency of insulin action generates ketone bodies, creating a baseline state of metabolic acidosis worsened by inadequate metabolic control, which creates a vicious circle by inducing insulin resistance. Even very slight levels of chronic kidney insufficiency are associated with increased cardiovascular risk, which may be explained at least in part by deficient acid excretory capacity of the kidney and consequent metabolic acidosis-induced insulin resistance. PMID:21352078

  1. Acylcarnitines: potential implications for skeletal muscle insulin resistance

    PubMed Central

    Aguer, Céline; McCoin, Colin S.; Knotts, Trina A.; Thrush, A. Brianne; Ono-Moore, Kikumi; McPherson, Ruth; Dent, Robert; Hwang, Daniel H.; Adams, Sean H.; Harper, Mary-Ellen

    2015-01-01

    Insulin resistance may be linked to incomplete fatty acid β-oxidation and the subsequent increase in acylcarnitine species in different tissues including skeletal muscle. It is not known if acylcarnitines participate in muscle insulin resistance or simply reflect dysregulated metabolism. The aims of this study were to determine whether acylcarnitines can elicit muscle insulin resistance and to better understand the link between incomplete muscle fatty acid β-oxidation, oxidative stress, inflammation, and insulin-resistance development. Differentiated C2C12, primary mouse, and human myotubes were treated with acylcarnitines (C4:0, C14:0, C16:0) or with palmitate with or without carnitine acyltransferase inhibition by mildronate. Treatment with C4:0, C14:0, and C16:0 acylcarnitines resulted in 20–30% decrease in insulin response at the level of Akt phosphorylation and/or glucose uptake. Mildronate reversed palmitate-induced insulin resistance concomitant with an ∼25% decrease in short-chain acylcarnitine and acetylcarnitine secretion. Although proinflammatory cytokines were not affected under these conditions, oxidative stress was increased by 2–3 times by short- or long-chain acylcarnitines. Acylcarnitine-induced oxidative stress and insulin resistance were reversed by treatment with antioxidants. Results are consistent with the conclusion that incomplete muscle fatty acid β-oxidation causes acylcarnitine accumulation and associated oxidative stress, raising the possibility that these metabolites play a role in muscle insulin resistance.—Aguer, C., McCoin, C. S., Knotts, T. A., Thrush, A. B., Ono-Moore, K., McPherson, R., Dent, R., Hwang, D. H., Adams, S. H., Harper, M.-E. Acylcarnitines: potential implications for skeletal muscle insulin resistance. PMID:25342132

  2. Adipokines, Insulin Resistance and Coronary Artery Calcification

    PubMed Central

    Qasim, Atif; Mehta, Nehal N.; Tadesse, Mahlet G.; Wolfe, Megan L.; Rhodes, Thomas; Girman, Cynthia; Reilly, Muredach P

    2008-01-01

    Objectives We evaluated the hypothesis that plasma levels of adiponectin and leptin are independently but oppositely associated with coronary calcification (CAC), a measure of subclinical atherosclerosis. In addition, we assessed which biomarkers of adiposity and insulin resistance are the strongest predictors of CAC beyond traditional risk factors, the metabolic syndrome and plasma C-reactive protein (CRP). Background Adipokines are fat-secreted biomolecules with pleiotropic actions that converge in diabetes and cardiovascular disease. Methods We examined the association of plasma adipocytokines with CAC in 860 asymptomatic, non-diabetic participants in the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA). Results Plasma adiponectin and leptin levels had opposite and distinct associations with adiposity, insulin resistance and inflammation. Plasma leptin was positively (top vs. bottom quartile) associated with higher CAC after adjusting for age, gender, traditional risk factors and Framingham Risk Scores (FRS) [tobit regression ratio 2.42 (95% CI 1.48–3.95, p=0.002)] and further adjusting for metabolic syndrome and CRP [ratio 2.31 (95% CI 1.36–3.94, p=0.002)]. In contrast, adiponectin levels were not associated with CAC. Comparative analyses suggested that levels of leptin, IL-6 and sol-TNFR2 as well as HOMA-IR predicted CAC scores but only leptin and HOMA-IR provided value beyond risk factors, the metabolic syndrome and CRP. Conclusion In SIRCA, while both leptin and adiponectin levels were associated with metabolic and inflammatory markers, only leptin was a significant independent predictor of CAC. Of several metabolic markers, leptin and the HOMA-IR index had the most robust, independent associations with CAC. Condensed Abstract Adipokines are fat-secreted biomolecules with pleiotropic actions and represent novel markers for cardiovascular risk. We examined the association of plasma adipocytokines with CAC in 860 asymptomatic, non

  3. Xylitol prevents NEFA-induced insulin resistance in rats

    PubMed Central

    Kishore, P.; Kehlenbrink, S.; Hu, M.; Zhang, K.; Gutierrez-Juarez, R.; Koppaka, S.; El-Maghrabi, M. R.

    2013-01-01

    Aims/hypothesis Increased NEFA levels, characteristic of type 2 diabetes mellitus, contribute to skeletal muscle insulin resistance. While NEFA-induced insulin resistance was formerly attributed to decreased glycolysis, it is likely that glucose transport is the rate-limiting defect. Recently, the plant-derived sugar alcohol xylitol has been shown to have favourable metabolic effects in various animal models. Furthermore, its derivative xylulose 5-phosphate may prevent NEFA-induced suppression of glycolysis. We therefore examined whether and how xylitol might prevent NEFA-induced insulin resistance. Methods We examined the ability of xylitol to prevent NEFA-induced insulin resistance. Sustained ~1.5-fold elevations in NEFA levels were induced with Intralipid/heparin infusions during 5 h euglycaemic–hyperinsulinaemic clamp studies in 24 conscious non-diabetic Sprague-Dawley rats, with or without infusion of xylitol. Results Intralipid infusion reduced peripheral glucose uptake by ~25%, predominantly through suppression of glycogen synthesis. Co-infusion of xylitol prevented the NEFA-induced decreases in both glucose uptake and glycogen synthesis. Although glycolysis was increased by xylitol infusion alone, there was minimal NEFA-induced suppression of glycolysis, which was not affected by co-infusion of xylitol. Conclusions/interpretation We conclude that xylitol prevented NEFA-induced insulin resistance, with favourable effects on glycogen synthesis accompanying the improved insulin-mediated glucose uptake. This suggests that this pentose sweetener has beneficial insulin-sensitising effects. PMID:22460760

  4. B lymphocytes as emerging mediators of insulin resistance

    PubMed Central

    Winer, D A; Winer, S; Shen, L; Chng, M H Y; Engleman, E G

    2012-01-01

    Obesity is associated with chronic inflammation of various tissues including visceral adipose tissue (VAT), which contributes to insulin resistance. T cells and macrophages infiltrate VAT in obesity and orchestrate this inflammation. Recently, we made the surprising discovery that B cells are important contributors to this process. Thus, some B cells and the antibodies they produce can promote VAT-associated and systemic inflammation, leading to insulin resistance. This report will focus on the properties of these B cells, and how they contribute to insulin resistance through T-cell modulation and production of pathogenic autoantibodies. Understanding the mechanisms by which B cells contribute to insulin resistance should lead to new antibody-based diagnostics and B-cell modulating therapeutics to manage this increasingly prevalent disease. PMID:25089193

  5. Genetics of Insulin Resistance and the Metabolic Syndrome.

    PubMed

    Brown, Audrey E; Walker, Mark

    2016-08-01

    Insulin resistance and the metabolic syndrome are complex metabolic traits and key risk factors for the development of cardiovascular disease. They result from the interplay of environmental and genetic factors but the full extent of the genetic background to these conditions remains incomplete. Large-scale genome-wide association studies have helped advance the identification of common genetic variation associated with insulin resistance and the metabolic syndrome, and more recently, exome sequencing has allowed the identification of rare variants associated with the pathogenesis of these conditions. Many variants associated with insulin resistance are directly involved in glucose metabolism; however, functional studies are required to assess the contribution of other variants to the development of insulin resistance. Many genetic variants involved in the pathogenesis of the metabolic syndrome are associated with lipid metabolism. PMID:27312935

  6. Metabolic Syndrome: Insulin Resistance and Prediabetes.

    PubMed

    Mayans, Laura

    2015-08-01

    Metabolic syndrome is a cluster of conditions that synergistically increase the risk of cardiovascular disease, type 2 diabetes, and premature mortality. The components are abdominal obesity, impaired glucose metabolism, dyslipidemia, and hypertension. Prediabetes, which is a combination of excess body fat and insulin resistance, is considered an underlying etiology of metabolic syndrome. Prediabetes manifests as impaired fasting glucose and/or impaired glucose tolerance. Impaired fasting glucose is defined as a fasting blood glucose level of 100 to 125 mg/dL; impaired glucose tolerance requires a blood glucose level of 140 to 199 mg/dL 2 hours after a 75-g oral intake of glucose. In patients with prediabetes, the rate of progression to diabetes within 3 years can be decreased by approximately 58% with lifestyle modifications. These include weight loss through exercise (30 minutes or more of moderate physical activity on most, preferably all, days of the week) and dietary modifications. Recommended diets are high in fruits, vegetables, whole grains, and fish. Consumption of sweetened beverages, including diet soda, should be avoided. For patients who do not achieve goals with lifestyle modifications, metformin can be considered. Weight loss drugs and bariatric surgery are appropriate for select patients. Hypertension and dyslipidemia should be managed according to current guidelines. PMID:26280340

  7. Disruption of Adipose Rab10-Dependent Insulin Signaling Causes Hepatic Insulin Resistance.

    PubMed

    Vazirani, Reema P; Verma, Akanksha; Sadacca, L Amanda; Buckman, Melanie S; Picatoste, Belen; Beg, Muheeb; Torsitano, Christopher; Bruno, Joanne H; Patel, Rajesh T; Simonyte, Kotryna; Camporez, Joao P; Moreira, Gabriela; Falcone, Domenick J; Accili, Domenico; Elemento, Olivier; Shulman, Gerald I; Kahn, Barbara B; McGraw, Timothy E

    2016-06-01

    Insulin controls glucose uptake into adipose and muscle cells by regulating the amount of GLUT4 in the plasma membrane. The effect of insulin is to promote the translocation of intracellular GLUT4 to the plasma membrane. The small Rab GTPase, Rab10, is required for insulin-stimulated GLUT4 translocation in cultured 3T3-L1 adipocytes. Here we demonstrate that both insulin-stimulated glucose uptake and GLUT4 translocation to the plasma membrane are reduced by about half in adipocytes from adipose-specific Rab10 knockout (KO) mice. These data demonstrate that the full effect of insulin on adipose glucose uptake is the integrated effect of Rab10-dependent and Rab10-independent pathways, establishing a divergence in insulin signal transduction to the regulation of GLUT4 trafficking. In adipose-specific Rab10 KO female mice, the partial inhibition of stimulated glucose uptake in adipocytes induces insulin resistance independent of diet challenge. During euglycemic-hyperinsulinemic clamp, there is no suppression of hepatic glucose production despite normal insulin suppression of plasma free fatty acids. The impact of incomplete disruption of stimulated adipocyte GLUT4 translocation on whole-body glucose homeostasis is driven by a near complete failure of insulin to suppress hepatic glucose production rather than a significant inhibition in muscle glucose uptake. These data underscore the physiological significance of the precise control of insulin-regulated trafficking in adipocytes. PMID:27207531

  8. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance

    PubMed Central

    McNay, Ewan C.; Ong, Cecilia T.; McCrimmon, Rory J.; Cresswell, James; Bogan, Jonathan S.; Sherwin, Robert S

    2010-01-01

    Insulin regulates glucose uptake and storage in peripheral tissues, and has been shown to act within the hypothalamus to acutely regulate food intake and metabolism. The machinery for transduction of insulin signaling is also present in other brain areas, particularly in the hippocampus, but a physiological role for brain insulin outside the hypothalamus has not been established. Recent studies suggest that insulin may be able to modulate cognitive functions including memory. Here we report that local delivery of insulin to the rat hippocampus enhances spatial memory, in a PI-3-kinase dependent manner, and that intrahippocampal insulin also increases local glycolytic metabolism. Selective blockade of endogenous intrahippocampal insulin signaling impairs memory performance. Further, a rodent model of type 2 diabetes mellitus produced by a high-fat diet impairs basal cognitive function and attenuates both cognitive and metabolic responses to hippocampal insulin administration. Our data demonstrate that insulin is required for optimal hippocampal memory processing. Insulin resistance within the telencephalon may underlie the cognitive deficits commonly reported to accompany type 2 diabetes. PMID:20176121

  9. [Obesity and fatty acids in the etiology of insulin resistance].

    PubMed

    Galgani, J; Díaz, E

    2000-12-01

    Fatty acids, obesity and insulin resistance relationship are discussed. In the last decades fatty acids (FA) have been implicated in the etiology of insulin resistance. Initially, this process was related to FA inhibitory effects on glucose uptake mediated by the FA oxidation metabolites. This mechanism known as the Randle cycle has been presently discarded based on recent evidence for FA effects on glucose metabolism. Now is known that cytosolic lipid content and FA molecular structure determines higher or lower storage and oxidation capacity. Another factor is given by Tumor Necrosis Factor-alpha, which is overexpressed in animal and human obesity, producing insulin signaling and glucose uptake inhibition. This paper discuss the role played by FA and obesity on insulin resistance, mainly in relation to FA effects on glucose metabolism in the liver, muscle and adipose tissues. In the obesity condition adipose tissue releases higher levels of free FA which in turn stimulates hepatic glucose production. Adipose tissue also, increase TNF-alpha secretion impairing glucose utilization and insulin signaling. In muscle, cytosolic lipid content activate a Protein Kinase that inhibits the insulin signaling and reduce GLUT-4 translocation. The study of cellular and metabolic changes associated to weight gain and its relationship with insulin resistance etiology are encouraged. PMID:11227245

  10. Insulin resistance: The linchpin between prediabetes and cardiovascular disease.

    PubMed

    Salazar, Martin R; Carbajal, Horacio A; Espeche, Walter G; Aizpurúa, Marcelo; Leiva Sisnieguez, Carlos E; Leiva Sisnieguez, Betty C; Stavile, Rodolfo N; March, Carlos E; Reaven, Gerald M

    2016-03-01

    The aim of this study was to test the hypothesis that cardiovascular disease occurs to the greatest extent in persons with prediabetes mellitus who are also insulin resistant. In 2003, 664 non-diabetic women (n = 457) and men (n = 207), aged 52 ± 16 and 53 ± 15 years, were surveyed during a programme for cardiovascular disease prevention. Fasting plasma glucose concentrations defined participants as having normal fasting plasma glucose (fasting plasma glucose <5.6 mmol/L) or prediabetes mellitus (fasting plasma glucose ⩾5.6 and <7.0 mmol/L). The tertile of prediabetes mellitus subjects with the highest fasting plasma insulin concentration was classified as insulin resistant. Baseline cardiovascular disease risk factors were accentuated in prediabetes mellitus versus normal fasting glucose, particularly in prediabetes mellitus/insulin resistant. In 2012, 86% of the sample were surveyed again, and the crude incidence for cardiovascular disease was higher in subjects with prediabetes mellitus versus normal fasting glucose (13.7 vs 6.0/100 persons/10 years; age- and sex-adjusted hazard ratio = 1.88, p = 0.052). In prediabetes mellitus, the crude incidences were 22.9 versus 9.6/100 persons/10 years in insulin resistant versus non-insulin resistant persons (age- and sex-adjusted hazard ratio = 2.36, p = 0.040). In conclusion, cardiovascular disease risk was accentuated in prediabetes mellitus/insulin resistant individuals, with a relative risk approximately twice as high compared to prediabetes mellitus/non-insulin resistant subjects. PMID:26802220

  11. Role of nutrition in preventing insulin resistance in children.

    PubMed

    Blasetti, Annalisa; Franchini, Simone; Comegna, Laura; Prezioso, Giovanni; Chiarelli, Francesco

    2016-03-01

    Nutrition during prenatal, early postnatal and pubertal period is crucial for the development of insulin resistance and its consequences. During prenatal period fetal environment and nutrition seems to interfere with metabolism programming later in life. The type of dietary carbohydrates, glycemic index, protein, fat and micronutrient content in maternal nutrition could influence insulin sensitivity in the newborn. The effects of lactation on metabolism and nutritional behavior later in life have been studied. Dietary habits and quality of diet during puberty could prevent the onset of a pathological insulin resistance through an adequate distribution of macro- and micronutrients, a diet rich in fibers and vegetables and poor in saturated fats, proteins and sugars. We want to overview the latest evidences on the risk of insulin resistance later in life due to both nutritional behaviors and components during the aforementioned periods of life, following a chronological outline from fetal development to adolescence. PMID:26630690

  12. Insulin resistance and lipid alterations in subclinical hypothyroidism

    PubMed Central

    Sridevi, Atluri; Vivekanand, B.; Giridhar, G.; Mythili, A.; Subrahmanyan, K. A. V.

    2012-01-01

    Introduction: It is known that dyslipidemia and increased insulin resistance were associated with overt hypothyroidism, but their association with subclinical hypothyroidism is conflicting. Aim was to evaluate insulin resistance and lipid alterations in subclinical hypothyroidism. Methods: Fifty consecutive cases of subclinical hypothyroidism are the subjects of the study. The cases are compared with age, gender and BMI matched controls. Lipid profile, insulin levels, FPG are assessed after overnight fast. Insulin resistance is calculated using HOMA-IR. The correlation between TSH& lipid prolife, TSH & IR was assessed. Results: Total cholesterol (169.37±32.83 vs. 154.5±18.71, p= 0.031) & low density lipoprotein cholesterol (105.76±26.92vs 93.80±16.67, p=0.037) were significantly higher in cases compared to controls. High density lipoprotein cholesterol (44.23±4.65 vs 42.26±3.20, p=0.0507) was lower in cases which showed a trend towards significance. Triglycerides (97.64±39.44 vs. 92.96±43.49,p=0.65) , fasting insulin levels (11.74±7.16 vs 9.77±5.54,p=0.211) and Insulin resistance (2.30±1.49 vs. 1.78±1.09, p=0.11) were elevated but did not differ significantly between the two groups. Conclusion: Subclinical hypothyroidism is associated with elevation of TC, LDL-C and non significant increase in TG and insulin resistance. Both lipid profile and insulin resistance did not correlate with severity of hypothyroidism. PMID:23565422

  13. Insulin Resistance and Impaired Mitochondrial Function in Obese Adolescent Girls

    PubMed Central

    Bredella, Miriam A.; Thakur, Hena; Torriani, Martin; Misra, Madhusmita

    2014-01-01

    Abstract Background: Mitochondrial dysfunction plays a role in the development of muscle insulin resistance (IR) and the accumulation of intramyocellular lipid (IMCL) in skeletal muscle that can, in turn, interfere with insulin signaling. The purpose of this study was to assess mitochondrial function (MF) and IMCL in obese adolescent girls with and without IR to determine whether: (1) Girls with IR have impaired MF, and (2) impaired MF in girls with IR is related to higher IMCL. Methods: We examined 22 obese girls aged 13–21 years old for IR [defined as a homeostasis model assessment of insulin resistance (HOMA-IR) value >4. Phosphorus magnetic resonance spectroscopy (31P-MRS) and proton magnetic resonance spectroscopy (1H-MRS), respectively, were used to determine MF and IMCL of the soleus muscle along with magnetic resonance imaging (MRI) measures of visceral, subcutaneous, and total adipose tissue (VAT, SAT, and TAT) in girls with HOMA-IR >4 (insulin-resistant group) versus HOMA-IR ≤4 (insulin-sensitive group). Serum lipids and waist-to-hip ratio (W/H) were also measured. Results: Girls with IR (n=8) did not differ from the insulin-sensitive group (n=14) for age, bone age, weight, VAT, SAT, TAT, or IMCL. However, the insulin-resistant group had higher W/H. Additionally the insulin-resistance group had a lower log rate of postexercise phosphocreatine (PCr) recovery (ViPCr) and a higher log PCr recovery constant (tau), indicative of impaired MF. Conclusions: Obese girls with increased IR have impaired mitochondrial function. This association is not mediated by alterations in IMCL or adipose tissue. Further studies are necessary to determine whether there is a causal relation between impaired mitochondrial function and IR in obesity and mediators of such a relationship. PMID:24251951

  14. Insulin resistance is a cellular antioxidant defense mechanism.

    PubMed

    Hoehn, Kyle L; Salmon, Adam B; Hohnen-Behrens, Cordula; Turner, Nigel; Hoy, Andrew J; Maghzal, Ghassan J; Stocker, Roland; Van Remmen, Holly; Kraegen, Edward W; Cooney, Greg J; Richardson, Arlan R; James, David E

    2009-10-20

    We know a great deal about the cellular response to starvation via AMPK, but less is known about the reaction to nutrient excess. Insulin resistance may be an appropriate response to nutrient excess, but the cellular sensors that link these parameters remain poorly defined. In the present study we provide evidence that mitochondrial superoxide production is a common feature of many different models of insulin resistance in adipocytes, myotubes, and mice. In particular, insulin resistance was rapidly reversible upon exposure to agents that act as mitochondrial uncouplers, ETC inhibitors, or mitochondrial superoxide dismutase (MnSOD) mimetics. Similar effects were observed with overexpression of mitochondrial MnSOD. Furthermore, acute induction of mitochondrial superoxide production using the complex III antagonist antimycin A caused rapid attenuation of insulin action independently of changes in the canonical PI3K/Akt pathway. These results were validated in vivo in that MnSOD transgenic mice were partially protected against HFD induced insulin resistance and MnSOD+/- mice were glucose intolerant on a standard chow diet. These data place mitochondrial superoxide at the nexus between intracellular metabolism and the control of insulin action potentially defining this as a metabolic sensor of energy excess. PMID:19805130

  15. Insulin resistance is a cellular antioxidant defense mechanism

    PubMed Central

    Hoehn, Kyle L.; Salmon, Adam B.; Hohnen-Behrens, Cordula; Turner, Nigel; Hoy, Andrew J.; Maghzal, Ghassan J.; Stocker, Roland; Van Remmen, Holly; Kraegen, Edward W.; Cooney, Greg J.; Richardson, Arlan R.; James, David E.

    2009-01-01

    We know a great deal about the cellular response to starvation via AMPK, but less is known about the reaction to nutrient excess. Insulin resistance may be an appropriate response to nutrient excess, but the cellular sensors that link these parameters remain poorly defined. In the present study we provide evidence that mitochondrial superoxide production is a common feature of many different models of insulin resistance in adipocytes, myotubes, and mice. In particular, insulin resistance was rapidly reversible upon exposure to agents that act as mitochondrial uncouplers, ETC inhibitors, or mitochondrial superoxide dismutase (MnSOD) mimetics. Similar effects were observed with overexpression of mitochondrial MnSOD. Furthermore, acute induction of mitochondrial superoxide production using the complex III antagonist antimycin A caused rapid attenuation of insulin action independently of changes in the canonical PI3K/Akt pathway. These results were validated in vivo in that MnSOD transgenic mice were partially protected against HFD induced insulin resistance and MnSOD+/− mice were glucose intolerant on a standard chow diet. These data place mitochondrial superoxide at the nexus between intracellular metabolism and the control of insulin action potentially defining this as a metabolic sensor of energy excess. PMID:19805130

  16. Zataria multiflora increases insulin sensitivity and PPARγ gene expression in high fructose fed insulin resistant rats

    PubMed Central

    Mohammadi, Abbas; Gholamhoseinian, Ahmad; Fallah, Hossein

    2014-01-01

    Objective(s): In insulin resistance, the insulin action in liver, muscles and adipocytes decreases and result in hyperglycemia, dyslipidemia and hyperinsulinemia. In this study we evaluate the effect of Zataria multiflora extract on insulin sensitivity in high fructose fed insulin resistant rats, since this extract was shown antihyperglycemic effect in streptozotocin induced diabetes in rats. Materials and Methods: Experimental rats were fed with high fructose diet for 6 weeks and then were treated with Z. multiflora extract or a pioglitazone solution for 2 weeks. Blood and tissue samples were collected for analysis at the end of two weeks. Blood glucose, serum level of triglyceride and cholesterol were measured by auto analyzer. Insulin and adiponectin levels were assayed by enzyme-linked immunosorbent assay (ELISA) method. Plasma free fatty acids profile was studied by gas chromatography. Peroxisome proliferator activated receptor (PPAR.γ) and Glucose transporter type 4 (GLUT.4) gene expressions were assessed by real time polymerase chain reaction (PCR) and western blotting. Results: Animals were treated by Z. multiflora extract showed insulin (43±11pmol/l), adiponectin (5.3±0.5 μg/ml), glucose (144±9.8 mg/dl), and triglyceride (120±10 mg/dl) levels significantly improved as compare with the control group [insulin (137±34 pmol/l), adiponectin (3.9±0.15 μg/ml), glucose (187±15mg/dl), and triglycerides (217±18 mg/dl)]. PPARγ protein level, also significantly increased in Zataria multiflora treated group. Conclusion: This study demonstrates the beneficial effects of Zataria multiflora extract on insulin resistance in rats fed with a high-fructose diet through at least three mechanisms including direct insulin like effect, increasing in adiponectin and of PPARγ protein expression. PMID:24904719

  17. Insulin receptor mutation results in insulin resistance and hyperinsulinemia but does not exacerbate Alzheimer's-like phenotypes in mice.

    PubMed

    Murakami, Kazuma; Yokoyama, Shin-ichi; Murata, Nakaba; Ozawa, Yusuke; Irie, Kazuhiro; Shirasawa, Takuji; Shimizu, Takahiko

    2011-05-27

    Obesity is a risk factor for Alzheimer's disease (AD), which is characterized by amyloid β depositions and cognitive dysfunction. Although insulin resistance is one of the phenotypes of obesity, its deleterious effects on AD progression remain to be fully elucidated. We previously reported that the suppression of insulin signaling in a mouse with a heterozygous mutation (P1195L) in the gene for the insulin receptor showed insulin resistance and hyperinsulinemia but did not develop diabetes mellitus [15]. Here, we generated a novel AD mouse model carrying the same insulin receptor mutation and showed that the combination of insulin resistance and hyperinsulinemia did not accelerate plaque formation or memory abnormalities in these mice. Interestingly, the insulin receptor mutation reduced oxidative damage in the brains of the AD mice. These findings suggest that insulin resistance is not always involved in the pathogenesis of AD. PMID:21549686

  18. Adipose Tissue Hypoxia, Inflammation, and Fibrosis in Obese Insulin-Sensitive and Obese Insulin-Resistant Subjects.

    PubMed

    Lawler, Helen M; Underkofler, Chantal M; Kern, Philip A; Erickson, Christopher; Bredbeck, Brooke; Rasouli, Neda

    2016-04-01

    We confirmed fat hypoxia in obese as compared to lean subjects. However, fat oxygenation was similar in obese insulin sensitive and insulin resistant subjects suggesting fat hypoxia may be simply a consequence of fat expansion. PMID:26871994

  19. Gender Differences in Insulin Resistance, Body Composition, and Energy Balance

    PubMed Central

    Geer, Eliza B.; Shen, Wei

    2010-01-01

    Background Men and women differ substantially in regard to degrees of insulin resistance, body composition, and energy balance. Adipose tissue distribution, in particular the presence of elevated visceral and hepatic adiposity, plays a central role in the development of insulin resistance and obesity-related complications. Objective This review summarizes published data on gender differences in insulin resistance, body composition, and energy balance, to provide insight into novel gender-specific avenues of research as well as gender-tailored treatments of insulin resistance, visceral adiposity, and obesity. Methods English-language articles were identified from searches of the PubMed database through November 2008, and by reviewing the references cited in these reports. Searches included combinations of the following terms: gender, sex, insulin resistance, body composition, energy balance, and hepatic adipose tissue. Results For a given body mass index, men were reported to have more lean mass, women to have higher adiposity. Men were also found to have more visceral and hepatic adipose tissue, whereas women had more peripheral or subcutaneous adipose tissue. These differences, as well as differences in sex hormones and adipokines, may contribute to a more insulin-sensitive environment in women than in men. When normalized to kilograms of lean body mass, men and women had similar resting energy expenditure, but physical energy expenditure was more closely related to percent body fat in men than in women. Conclusion Greater amounts of visceral and hepatic adipose tissue, in conjunction with the lack of a possible protective effect of estrogen, may be related to higher insulin resistance in men compared with women. PMID:19318219

  20. Insulin and Insulin-Like Growth Factor Resistance in Alcoholic Neurodegeneration

    PubMed Central

    de la Monte, Suzanne M.; Tong, Ming; Cohen, Ariel C.; Sheedy, Donna; Harper, Clive; Wands, Jack R.

    2012-01-01

    Background Chronic alcohol feeding of adult Long Evans rats causes major central nervous system abnormalities that link neuronal loss and impaired acetylcholine homeostasis to ethanol inhibition of insulin and insulin-like growth factor (IGF) signaling and increased oxidative stress. Objectives We now characterize the integrity of insulin and IGF signaling mechanisms and assess molecular indices of neurodegeneration in the cerebellar vermis and anterior cingulate gyrus of human alcoholics. Results Alcoholic cerebella had increased neuronal loss, gliosis, lipid peroxidation, and DNA damage relative to control. Quantitative RT-PCR studies demonstrated reduced expression of insulin, insulin receptor and IGF-II receptor in the anterior cingulate, and reduced expression of insulin, IGF-I, and their corresponding receptors in the vermis. Competitive equilibrium binding assays revealed significantly reduced specific binding to the insulin, IGF-I, and IGF-II receptors in both the anterior cingulate and vermis of alcoholic brains. These effects of chronic alcohol abuse were associated with significantly reduced expression of choline acetyltransferase, which is needed for acetylcholine biosynthesis. Conclusions The results suggest that alcoholic neurodegeneration in humans is associated with insulin and IGF resistance with attendant impairment of neuronal survival mechanisms and acetylcholine homeostasis. PMID:18616667

  1. Insulin Signaling in Insulin Resistance States and Cancer: A Modeling Analysis

    PubMed Central

    Bertuzzi, Alessandro; Conte, Federica; Mingrone, Geltrude; Papa, Federico; Salinari, Serenella

    2016-01-01

    Insulin resistance is the common denominator of several diseases including type 2 diabetes and cancer, and investigating the mechanisms responsible for insulin signaling impairment is of primary importance. A mathematical model of the insulin signaling network (ISN) is proposed and used to investigate the dose-response curves of components of this network. Experimental data of C2C12 myoblasts with phosphatase and tensin homologue (PTEN) suppressed and data of L6 myotubes with induced insulin resistance have been analyzed by the model. We focused particularly on single and double Akt phosphorylation and pointed out insulin signaling changes related to insulin resistance. Moreover, a new characterization of the upstream signaling of the mammalian target of rapamycin complex 2 (mTORC2) is presented. As it is widely recognized that ISN proteins have a crucial role also in cell proliferation and death, the ISN model was linked to a cell population model and applied to data of a cell line of acute myeloid leukemia treated with a mammalian target of rapamycin inhibitor with antitumor activity. The analysis revealed simple relationships among the concentrations of ISN proteins and the parameters of the cell population model that characterize cell cycle progression and cell death. PMID:27149630

  2. Treatment of insulin resistance: straight from the gut.

    PubMed

    Zhang, Xueli; Zheng, Xiao; Yuan, Yang

    2016-08-01

    Insulin resistance (IR) is a key pathological hallmark of obesity and type 2 diabetes. Emerging evidence has uncovered the gastrointestinal (GI) system as a previously overlooked player in fine-tuning systemic glucose homeostasis and insulin responses, which involved a complex inter-organ crosstalk through metabolic, endocrine, immune and neural mechanisms. These facts raise the intriguing possibility to explore the GI system as a new territory for IR intervention and glycemic control. Here we provide an overview of recent findings illustrating GI signals in the control of systemic insulin sensitivity and glucose homeostasis, and discuss the therapeutic prospects of exploiting the GI mechanisms to reverse IR and treat metabolic diseases. PMID:27326909

  3. Macrophage-secreted factors induce adipocyte inflammation and insulin resistance

    SciTech Connect

    Permana, Paska A. . E-mail: Paska.Permana@med.va.gov; Menge, Christopher; Reaven, Peter D.

    2006-03-10

    Macrophage infiltration into adipose tissue increases with obesity, a condition associated with low-grade inflammation and insulin resistance. We investigated the direct effects of macrophage-secreted factors on adipocyte inflammation and insulin resistance. 3T3-L1 adipocytes incubated with media conditioned by RAW264.7 macrophages (RAW-CM) showed dramatically increased transcription of several inflammation-related genes, greater nuclear factor kappa B (NF-{kappa}B) activity, and enhanced binding of U937 monocytes. All of these effects were prevented by co-incubation with pyrrolidinedithiocarbamate, an NF-{kappa}B inhibitor. Adipocytes incubated with RAW-CM also released more non-esterified fatty acids and this increased lipolysis was not suppressed by insulin. In addition, RAW-CM treatment decreased insulin-stimulated glucose uptake in adipocytes. Taken together, these results indicate that macrophage-secreted factors induce inflammatory responses and reduce insulin responsiveness in adipocytes. These effects of macrophage-secreted factors on adipocytes may contribute significantly to the systemic inflammation and insulin resistance associated with obesity.

  4. Atorvastatin ameliorates endothelium-specific insulin resistance induced by high glucose combined with high insulin.

    PubMed

    Yang, Ou; Li, Jinliang; Chen, Haiyan; Li, Jie; Kong, Jian

    2016-09-01

    The aim of the present study was to establish an endothelial cell model of endothelium-specific insulin resistance to evaluate the effect of atorvastatin on insulin resistance-associated endothelial dysfunction and to identify the potential pathway responsible for its action. Cultured human umbilical vein endothelial cells (HUVECs) were pretreated with different concentrations of glucose with, or without, 10‑5 M insulin for 24 h, following which the cells were treated with atorvastatin. The tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate-1 (IRS‑1), the production of nitric oxide (NO), the activity and phosphorylation level of endothelial NO synthase (eNOS) on serine1177, and the mRNA levels of endothelin‑1 (ET‑1) were assessed during the experimental procedure. Treatment of the HUVECs with 30 mM glucose and 10‑5 M insulin for 24 h impaired insulin signaling, with reductions in the tyrosine phosphorylation of IR and protein expression of IRS‑1 by almost 75 and 65%, respectively. This, in turn, decreased the activity and phosphorylation of eNOS on serine1177, and reduced the production of NO by almost 80%. By contrast, the mRNA levels of ET‑1 were upregulated. All these changes were ameliorated by atorvastatin. Taken together, these results demonstrated that high concentrations of glucose and insulin impaired insulin signaling leading to endothelial dysfunction, and that atorvastatin ameliorated these changes, acting primarily through the phosphatidylinositol 3-kinase/Akt/eNOS signaling pathway. PMID:27484094

  5. Changing Clinical Characteristics according to Insulin Resistance and Insulin Secretion in Newly Diagnosed Type 2 Diabetic Patients in Korea

    PubMed Central

    Son, Jang Won; Park, Cheol-Young; Lee, Han-Kyu; Lee, Yil-Seob

    2015-01-01

    Background The role of increased insulin resistance in the pathogenesis of type 2 diabetes has been emphasized in Asian populations. Thus, we evaluated the proportion of insulin resistance and the insulin secretory capacity in patients with early phase type 2 diabetes in Korea. Methods We performed a cross-sectional analysis of 1,314 drug-naive patients with newly diagnosed diabetes from primary care clinics nationwide. The homeostasis model assessment of insulin resistance (HOMA-IR) was used as an index to measure insulin resistance, which was defined as a HOMA-IR ≥2.5. Insulin secretory defects were classified based on fasting plasma C-peptide levels: severe (<1.1 ng/mL), moderate (1.1 to 1.7 ng/mL) and mild to non-insulin secretory defect (≥1.7 ng/mL). Results The mean body mass index (BMI) was 25.2 kg/m2; 77% of patients had BMIs >23.0 kg/m2. Up to 50% of patients had central obesity based on their waist circumference (≥90 cm in men and 85 cm in women), and 70.6% had metabolic syndrome. Overall, 59.5% of subjects had insulin resistance, and 20.2% demonstrated a moderate to severe insulin secretory defect. Among those with insulin resistance, a high proportion of subjects (79.0%) had a mild or no insulin secretory defect. Only 2.6% of the men and 1.9% of the women had both insulin resistance and a moderate to severe insulin secretory defect. Conclusion In this study, patients with early phase type 2 diabetes demonstrated increased insulin resistance, but preserved insulin secretion, with a high prevalence of obesity and metabolic syndrome. PMID:26566496

  6. [Insulin receptor defect as a cause of Rabson-Mendenhall syndrome and other rare genetic insulin resistance syndromes].

    PubMed

    Rojek, Aleksandra; Niedziela, Marek

    2010-01-01

    Insulin plays a very important role in maintaining homeostasis of the whole organism. It regulates glucose metabolism, glycogen synthesis, lipid and protein metabolism. Insulin receptors are present in virtually all cells, which is reflected by the diversity of regulatory processes in which this hormone is involved. Any dysfunction of insulin signalling pathway as a result of insulin receptor gene mutations is linked with various forms of insulin resistance, including insulin resistance type A, Donohue or Rabson-Mendenhall syndrome, which differ in the level of severity. Molecular analysis of insulin receptor gene may lead to a better understanding of molecular mechanisms underlying various types of insulin resistance and help to develop a more efficient treatment. They may also be used as a powerful tool in prenatal diagnostics as well as in pregnancy planning. PMID:21092701

  7. Glucagon-like peptide 1 recruits muscle microvasculature and improves insulin's metabolic action in the presence of insulin resistance.

    PubMed

    Chai, Weidong; Zhang, Xingxing; Barrett, Eugene J; Liu, Zhenqi

    2014-08-01

    Glucagon-like peptide 1 (GLP-1) acutely recruits muscle microvasculature, increases muscle delivery of insulin, and enhances muscle use of glucose, independent of its effect on insulin secretion. To examine whether GLP-1 modulates muscle microvascular and metabolic insulin responses in the setting of insulin resistance, we assessed muscle microvascular blood volume (MBV), flow velocity, and blood flow in control insulin-sensitive rats and rats made insulin-resistant acutely (systemic lipid infusion) or chronically (high-fat diet [HFD]) before and after a euglycemic-hyperinsulinemic clamp (3 mU/kg/min) with or without superimposed systemic GLP-1 infusion. Insulin significantly recruited muscle microvasculature and addition of GLP-1 further expanded muscle MBV and increased insulin-mediated glucose disposal. GLP-1 infusion potently recruited muscle microvasculature in the presence of either acute or chronic insulin resistance by increasing muscle MBV. This was associated with an increased muscle delivery of insulin and muscle interstitial oxygen saturation. Muscle insulin sensitivity was completely restored in the presence of systemic lipid infusion and significantly improved in rats fed an HFD. We conclude that GLP-1 infusion potently expands muscle microvascular surface area and improves insulin's metabolic action in the insulin-resistant states. This may contribute to improved glycemic control seen in diabetic patients receiving incretin-based therapy. PMID:24658303

  8. Immunometabolism of AMPK in insulin resistance and atherosclerosis.

    PubMed

    Fullerton, Morgan D; Steinberg, Gregory R; Schertzer, Jonathan D

    2013-02-25

    Obesity leads to insulin resistance and atherosclerosis, which precede Type 2 diabetes and cardiovascular disease. Immunometabolism addresses how metabolic and inflammatory pathways converge to maintain health and a contemporary problem is determining how obesity-induced inflammation precipitates chronic diseases such as insulin resistance and atherosclerosis. AMP-activated protein kinase (AMPK) is an important serine/threonine kinase well known for regulating metabolic processes and maintaining energy homeostasis. However, both metabolic and immunological AMPK-mediated effects play a role in disease. Pro-inflammatory mediators suppress AMPK activity and hinder lipid oxidation. In addition, AMPK activation curbs inflammation by directly inhibiting pro-inflammatory signaling pathways and limiting the build-up of specific lipid intermediates that elicit immune responses. In the context of obesity and chronic disease, these reciprocal responses involve both immune and metabolic cells. Therefore, the immunometabolism of AMPK-mediated processes and therapeutics should be considered in atherosclerosis and insulin resistance. PMID:22361321

  9. Insulin resistance in young, lean male subjects with essential hypertension.

    PubMed

    Penesova, A; Cizmarova, E; Belan, V; Blazicek, P; Imrich, R; Vlcek, M; Vigas, M; Selko, D; Koska, J; Radikova, Z

    2011-06-01

    Impaired insulin action, frequently found in essential hypertension (HT), is modified by other factors, such as higher age, accumulation of body fat, dyslipidaemia, impaired glucose metabolism and endothelial dysfunction. In addition, antihypertensive and insulin-sensitizing medication itself may significantly affect cardiovascular and metabolic milieu. The aim of this study was to assess insulin sensitivity, acute insulin response, lipidaemic status and the adipokines' concentrations with regard to abdominal fat distribution in young, lean male subjects with treatment-naïve essential HT and in matched healthy normotensive (NT) subjects. We studied 27 HT patients (age: 19.9±0.6 years; body mass index (BMI): 22.9±0.5 kg m(-2)) and 15 NT controls (age: 22.3±1.0 years; BMI: 23.7±0.6 kg m(-2)). The subjects underwent an oral and an intravenous glucose tolerance test (OGTT, IVGTT) on separate days in random order. Higher fasting insulin (P<0.001), non-esterified fatty acids (P<0.05) and plasminogen activator inhibitor factor 1 concentrations (P<0.05) were found in HT patients when compared with NT patients. Despite comparable anthropometric parameters and body fat distribution assessed by magnetic resonance imaging in both groups, newly diagnosed untreated young hypertensive male subjects showed decreased insulin sensitivity, augmented insulin response to both oral and intravenous glucose load (P<0.01; P<0.05 respectively) and 'higher still normal' 2-h plasma glucose levels during OGTT. Untreated, young, lean hypertensive male subjects, with distribution of abdominal adipose tissue and lipid profile comparable with their healthy NT matched counterparts, showed considerable signs of insulin resistance and hyperinsulinaemia. We hypothesize that insulin resistance is the initial feature, which is influenced by several environmental factors, and HT is one of their common consequences. PMID:20631738

  10. A Model of Insulin Resistance and Nonalcoholic Steatohepatitis in Rats

    PubMed Central

    Svegliati-Baroni, Gianluca; Candelaresi, Cinzia; Saccomanno, Stefania; Ferretti, Gianna; Bachetti, Tiziana; Marzioni, Marco; De Minicis, Samuele; Nobili, Liliana; Salzano, Renata; Omenetti, Alessia; Pacetti, Deborah; Sigmund, Soeren; Benedetti, Antonio; Casini, Alessandro

    2006-01-01

    Insulin resistance induces nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH). We used a high-fat, high-calorie solid diet (HFD) to create a model of insulin resistance and NASH in nongenetically modified rats and to study the relationship between visceral adipose tissue and liver. Obesity and insulin resistance occurred in HFD rats, accompanied by a progressive increase in visceral adipose tissue tumor necrosis factor (TNF)-α mRNA and in circulating free fatty acids. HFD also decreased adiponectin mRNA and peroxisome proliferator-activated receptor (PPAR)-α expression in the visceral adipose tissue and the liver, respectively, and induced hepatic insulin resistance through TNF-α-mediated c-Jun N-terminal kinase (JNK)-dependent insulin receptor substrate-1Ser307 phosphorylation. These modifications lead to hepatic steatosis accompanied by oxidative stress phenomena, necroinflammation, and hepatocyte apoptosis at 4 weeks and by pericentral fibrosis at 6 months. Supplementation of n-3 polyunsaturated fatty acid, a PPARα ligand, to HFD-treated animals restored hepatic adiponectin and PPARα expression, reduced TNF-α hepatic levels, and ameliorated fatty liver and the degree of liver injury. Thus, our model mimics the most common features of NASH in humans and provides an ideal tool to study the role of individual pathogenetic events (as for PPARα down-regulation) and to define any future experimental therapy, such as n-3 polyunsaturated fatty acid, which ameliorated the degree of liver injury. PMID:16936261

  11. Impaired protein metabolism: interlinks between obesity, insulin resistance and inflammation.

    PubMed

    Guillet, C; Masgrau, A; Walrand, S; Boirie, Y

    2012-12-01

    Metabolic and structural changes in skeletal muscle that accompany obesity are often associated with the development of insulin resistance. The first events in the pathogenesis of this disorder are considered as an accumulation of lipids within skeletal muscle due to blunted muscle capacity to oxidize fatty acids. Fat infiltration is also associated with muscle fibre typology modification, decrease in muscle mass and impairments in muscle strength. Thus, as a result of obesity, mobility and quality of life are affected, and this is in part due to quantitative and qualitative impairments in skeletal muscle. In addition, the insulin resistance related to obesity results not only in defective insulin-stimulated glucose disposal but has also detrimental consequences on protein metabolism at the skeletal muscle level and whole-body level. This review highlights the involvement of fat accumulation and insulin resistance in metabolic disorders occurring in skeletal muscle during the development of obesity, and the impairments in the regulation of protein metabolism and protein turnover in the links between obesity, metabolic inflammation and insulin resistance. PMID:23107259

  12. Inflammation and insulin resistance: an old story with new ideas.

    PubMed

    Kim, Jason K

    2010-06-01

    Years before insulin was discovered, anti-inflammatory sodium salicylate was used to treat diabetes in 1901. Intriguingly for many years that followed, diabetes was viewed as a disorder of glucose metabolism, and then it was described as a disease of dysregulated lipid metabolism. The diabetes research focused on the causal relationship between obesity and insulin resistance, a major characteristic of type 2 diabetes. It is only within the past 20 years when the notion of inflammation as a cause of insulin resistance began to surface. In obesity, inflammation develops when macrophages infiltrate adipose tissue and stimulate adipocyte secretion of inflammatory cytokines, that in turn affect energy balance, glucose and lipid metabolism, leading to insulin resistance. This report reviews recent discoveries of stress kinase signaling involving molecular scaffolds and endoplasmic reticulum chaperones that regulate energy balance and glucose homeostasis. As we advance from a conceptual understanding to molecular discoveries, a century-old story of inflammation and insulin resistance is re-born with new ideas. PMID:20617073

  13. Adiponectin Dysregulation and Insulin Resistance in Type 1 Diabetes

    PubMed Central

    Snell-Bergeon, Janet K.; Erickson, Christopher; Schauer, Irene E.; Bergman, Bryan C.; Rewers, Marian; Maahs, David M.

    2012-01-01

    Context: Type 1 diabetes (T1D) is associated with insulin resistance despite elevated levels of the insulin-sensitizing protein adiponectin. Whether the expected positive correlation between adiponectin and insulin sensitivity is preserved in a T1D population is unknown. Objective: We measured the correlation between total and high-molecular-weight (HMW) adiponectin and insulin sensitivity in T1D patients and nondiabetic controls and identified determinants of adiponectin levels in patients with T1D. Design and Participants: Fasting total and HMW adiponectin were measured in 86 subjects from the Coronary Artery Calcification in T1D (CACTI) cohort (39 T1D, 47 nondiabetic; age 45 ± 8 yr; 55% female). The association of adiponectin levels with insulin sensitivity was analyzed. Setting: The study was conducted at an academic research institute. Methods: Fasting total and HMW adiponectin were measured by RIA and ELISA, respectively. Insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp. Multivariate linear regression was used to identify determinants of adiponectin levels. Results: Adiponectin levels positively correlated with insulin sensitivity in both subject groups (total adiponectin, r = 0.33 P < 0.05 for T1D, r = 0.29 P < 0.05 controls), but insulin sensitivity was lower in T1D subjects at any given level of total or HMW adiponectin. Adiponectin levels were independently associated with age, gender, and trunk fat, but these variables did not account for increased adiponectin in patients with T1D. Conclusion: Adiponectin levels are positively correlated with insulin sensitivity in T1D patients. However, T1D patients have decreased insulin sensitivity compared with controls at every level of adiponectin, suggesting an important adaptive change of adiponectin set point. PMID:22278421

  14. D-chiro-inositol--its functional role in insulin action and its deficit in insulin resistance.

    PubMed

    Larner, Joseph

    2002-01-01

    In this review we discuss the biological significance of D-chiro-inositol, originally discovered as a component of a putative mediator of intracellular insulin action, where as a putative mediator, it accelerates the dephosphorylation of glycogen synthase and pyruvate dehydrogenase, rate limiting enzymes of non-oxidative and oxidative glucose disposal. Early studies demonstrated a linear relationship between its decreased urinary excretion and the degree of insulin resistance present. When tissue contents, including muscle, of type 2 diabetic subjects were assayed, they demonstrated a more general body deficiency. Administration of D-chiro-inositol to diabetic rats, Rhesus monkeys and now to humans accelerated glucose disposal and sensitized insulin action. A defect in vivo in the epimerization of myo-inositol to chiro-inositol in insulin sensitive tissues of the GK type 2 diabetic rat has been elucidated. Thus, administered D-chiro-inositol may act to bypass a defective normal epimerization of myo-inositol to D-chiro-inositol associated with insulin resistance and act to at least partially restore insulin sensitivity and glucose disposal. PMID:11900279

  15. In utero origins of adult insulin resistance and vascular dysfunction.

    PubMed

    Thompson, Jennifer A; Regnault, Timothy R H

    2011-05-01

    The metabolic syndrome (or syndrome X) is a constellation of risk factors including insulin resistance, hypertension, dyslipidemia, and central obesity that predispose to the development of cardiovascular disease and type 2 diabetes in adult life. Insulin resistance is believed to be a critical pathophysiological event early in the disease process, impacting both skeletal muscle metabolic function and vascular responses. Adverse changes in insulin sensitivity have been found to originate in utero; for instance, prenatal events such as placental insufficiency/oxidative stress leading to altered fetal growth trajectories are associated with increased rates of metabolic syndrome in adult life. Such intrauterine insults result in reduced skeletal muscle mass in conjunction with altered insulin signaling, decreased oxidative fibers, and impaired mitochondrial function. These developmental disturbances set the stage for development of muscle triglyceride accumulation and depressed insulin sensitivity in childhood. Abnormalities of vascular structure and function arising from deprived intrauterine conditions that are exacerbated by insulin resistance account for the progression of hypertension from childhood to adulthood. Arterial changes initiated in utero include reduced endothelial nitric oxide (NO) bioavailability, vascular smooth muscle cell proliferation and inflammation, events leading to endothelial dysfunction, and atherosclerosis that are present in those destined for metabolic syndrome. In addition, the hypertensive phenotype that is a hallmark of metabolic syndrome may also be traced to blunted kidney development and renin-angiotensin system activation in growth-restricted offspring. The summative impact of these intrauterine programmed changes in terms of influencing adult health and disease encompasses dietary and lifestyle factors introduced postnatally. Establishing novel therapeutic interventions aimed at preventing and/or reducing in utero

  16. Dietary patterns and the insulin resistance phenotype among non-diabetic adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Information on the relation between dietary patterns derived by cluster analysis and insulin resistance is scarce. Objective: To compare insulin resistance phenotypes, including waist circumference, body mass index, fasting and 2-hour post-challenge insulin, insulin sensitivity index (I...

  17. Grizzly bears exhibit augmented insulin sensitivity while obese prior to a reversible insulin resistance during hibernation.

    PubMed

    Nelson, O Lynne; Jansen, Heiko T; Galbreath, Elizabeth; Morgenstern, Kurt; Gehring, Jamie Lauren; Rigano, Kimberly Scott; Lee, Jae; Gong, Jianhua; Shaywitz, Adam J; Vella, Chantal A; Robbins, Charles T; Corbit, Kevin C

    2014-08-01

    The confluence of obesity and diabetes as a worldwide epidemic necessitates the discovery of new therapies. Success in this endeavor requires translatable preclinical studies, which traditionally employ rodent models. As an alternative approach, we explored hibernation where obesity is a natural adaptation to survive months of fasting. Here we report that grizzly bears exhibit seasonal tripartite insulin responsiveness such that obese animals augment insulin sensitivity but only weeks later enter hibernation-specific insulin resistance (IR) and subsequently reinitiate responsiveness upon awakening. Preparation for hibernation is characterized by adiposity coupled to increased insulin sensitivity via modified PTEN/AKT signaling specifically in adipose tissue, suggesting a state of "healthy" obesity analogous to humans with PTEN haploinsufficiency. Collectively, we show that bears reversibly cope with homeostatic perturbations considered detrimental to humans and describe a mechanism whereby IR functions not as a late-stage metabolic adaptation to obesity, but rather a gatekeeper of the fed-fasting transition. PMID:25100064

  18. The Insulin-Like Growth Factor System in Obesity, Insulin Resistance and Type 2 Diabetes Mellitus

    PubMed Central

    Lewitt, Moira S.; Dent, Mairi S.; Hall, Kerstin

    2014-01-01

    The insulin-like growth factor (IGF) system, acting in concert with other hormone axes, is important in normal metabolism. In obesity, the hyperinsulinaemia that accompanies peripheral insulin resistance leads to reduced growth hormone (GH) secretion, while total IGF-I levels are relatively unchanged due to increased hepatic GH sensitivity. IGF-binding protein (IGFBP)-1 levels are suppressed in relation to the increase in insulin levels in obesity and low levels predict the development of type 2 diabetes several years later. Visceral adiposity and hepatic steatosis, along with a chronic inflammation, contribute to the IGF system phenotype in individuals with metabolic syndrome and type 2 diabetes mellitus, including changes in the normal inverse relationship between IGFBP-1 and insulin, with IGFBP-1 concentrations that are inappropriately normal or elevated. The IGF system is implicated in the vascular and other complications of these disorders and is therefore a potential therapeutic target. PMID:26237614

  19. Obesity-associated Gingival Vascular Inflammation and Insulin Resistance.

    PubMed

    Mizutani, K; Park, K; Mima, A; Katagiri, S; King, G L

    2014-06-01

    Obesity is a risk factor for periodontitis, but the pathogenic mechanism involved is unclear. We studied the effects of insulin in periodontal tissues during the state of obesity-induced insulin resistance. Gingival samples were collected from fatty (ZF) and lean (ZL, control) Zucker rats. Endothelial nitric oxide synthase (eNOS) expression was decreased, and activities of protein kinase C (PKC) α, ß2, δ, and ϵ isoforms were significantly increased in the gingiva from ZF rats compared with those from ZL rats. Expression of oxidative stress markers (mRNA) and the p65 subunit of NF-κB was significantly increased in ZF rats. Immunohistochemistry revealed that NF-κB activation was also increased in the gingival endothelial cells from transgenic mice overexpressing NF-κB-dependent enhanced green fluorescent protein (GFP) and on a high-fat vs. normal chow diet. Analysis of the gingiva showed that insulin-induced phosphorylation of IRS-1, Akt, and eNOS was significantly decreased in ZF rats, but Erk1/2 activation was not affected. General PKC inhibitor and an anti-oxidant normalized the action of insulin on Akt and eNOS activation in the gingiva from ZF rats. This provided the first documentation of obesity-induced insulin resistance in the gingiva. Analysis of our data suggested that PKC activation and oxidative stress may selectively inhibit insulin-induced Akt and eNOS activation, causing endothelial dysfunction and inflammation. PMID:24744283

  20. Differences in Cardiometabolic Risk between Insulin-Sensitive and Insulin-Resistant Overweight and Obese Children

    PubMed Central

    McGinn, Aileen P.; Isasi, Carmen R.; Groisman-Perelstein, Adriana; Diamantis, Pamela M.; Ginsberg, Mindy; Wylie-Rosett, Judith

    2015-01-01

    Abstract Background: It is known that 15–30% overweight/obese adults do not suffer cardiometabolic consequences. There is limited literature examining factors that can be used to assess cardiometabolic health in overweight/obese children. If such factors can be identified, they would aid in differentiating those most in need for aggressive management. Methods: Baseline data from 7- to 12-year-old, overweight, and obese children enrolled in a weight management program at an urban hospital were analyzed. Homeostatic model assessment for insulin resistance (HOMA-IR) <2.6 was used to define insulin-sensitive and HOMA-IR ≥2.6 was used to defined insulin-resistant participants. Demographics, physical activity measures, and cardiometabolic risk factors were compared between the two phenotypes. Odds ratios (ORs) examining the association between intermediate endpoints (metabolic syndrome [MetS], nonalcoholic fatty liver disease [NAFLD], systemic inflammation, and microalbuminuria) and the two metabolic phenotypes were evaluated. Results: Of the 362 overweight/obese participants, 157 (43.5%) were insulin sensitive and 204 (56.5%) were insulin resistant. Compared to the insulin-sensitive group, the insulin-resistant group was older (8.6±1.6 vs. 9.9±1.7; p<0.001) and had a higher BMI z-score (1.89±0.42 vs. 2.04±0.42; p=0.001). After multivariable adjustment, compared to the insulin-sensitive group, the insulin-resistant group had higher odds of having MetS (OR, 5.47; 95% confidence interval [CI]: 1.72, 17.35; p=0.004) and NAFLD (OR, 8.66; 95% CI, 2.48, 30.31; p=0.001), but not systemic inflammation (OR, 1.06; 95% CI: 0.56, 2.03; p=0.86) or microalbuminuria (OR, 1.71; 95% CI, 0.49, 6.04; p=0.403). Conclusions: Using a HOMA-IR value of ≥2.6, clinical providers can identify prepubertal and early pubertal children most at risk. Focusing limited resources on aggressive weight interventions may lead to improvement in cardiometabolic health. PMID:25774664

  1. Blood pressure, sodium intake, insulin resistance, and urinary nitrate excretion.

    PubMed

    Facchini, F S; DoNascimento, C; Reaven, G M; Yip, J W; Ni, X P; Humphreys, M H

    1999-04-01

    The objective of this study was to investigate the relationships among various humoral factors thought to be involved in the regulation of blood pressure during high NaCl intake. Nineteen healthy subjects underwent sequential 5-day periods ingesting a low-sodium (25 mmol/d) or high-sodium (200 mmol/d) diet. Insulin resistance was assessed by the steady-state plasma glucose concentration at the end of a 3-hour insulin suppression test. Insulin resistance correlated inversely with natriuresis (P=0.04) and directly with increase in weight (P=0.03). The increase in mean arterial pressure associated with the high-sodium diet correlated directly with the gain in weight (P<0.05) and inversely with the increase in urinary nitrate excretion (P<0.0001). In a multiple regression model, more than 2/3 of the variance in mean arterial pressure was accounted for by the gain in weight and change in urinary nitrate excretion. The steady-state plasma glucose concentrations obtained with the 2 diets were similar, indicating that insulin resistance was unaffected by sodium intake. During high sodium intake, plasma renin activity and aldosterone decreased and plasma atrial natriuretic peptide increased; these changes did not correlate with the change in mean arterial pressure, insulin resistance, or change in urinary nitrate excretion. To the extent that urinary nitrate excretion reflects activity of the endogenous nitric oxide system, these results suggest that the salt sensitivity of mean arterial pressure may be related to blunted generation of endogenous nitric oxide. The results also demonstrate that insulin-resistant individuals have an impaired natriuretic response to high sodium intake. PMID:10205239

  2. Role of PTEN in TNFα induced insulin resistance

    SciTech Connect

    Bulger, David A.; Conley, Jermaine; Conner, Spencer H.; Majumdar, Gipsy; Solomon, Solomon S.

    2015-06-05

    Aims/hypothesis: PTEN may play a reversible role in TNFα induced insulin resistance, which has been linked to obesity-associated insulin resistance (IR). Methods: Western blots for PTEN and p-Akt were performed on H-411E liver cells incubated with insulin, TNFα, and in selected experiments VO-OHpic vanadium complex in the presence and absence of PTEN siRNA. Total PTEN was compared to β-actin loading control and p-Akt was compared to total Akt. Results: Western blot and Real Time RT-PCR experiments showed increased PTEN after TNFα treatment (p = 0.04); slightly decreased PTEN after insulin treatment; and slightly increased PTEN after insulin + TNFα treatment. PTEN siRNA markedly inhibited the TNFα-induced increase in PTEN (p < 0.01) without significantly changing the p-Akt levels. The vanadium complex, exhibiting insulin-like effects, also significantly prevented the TNFα-induced increase in PTEN. Combining insulin and VO-OHpic was additive, providing both proof of concept and insight into mechanism. Discussion: The PTEN increase due to TNFα treatment was reversible by both PTEN siRNA knockdown and VO-OHpic treatment. Thus, PTEN is identified as a potential new therapeutic target for reducing IR in Type 2 DM. - Highlights: • TNFα treatment induced a significant increase in PTEN in H-411E liver cells. • PTEN siRNA knockdown prevented this effect. • VO-OHpic (vanadium complex) treatment, like insulin, decreased PTEN protein levels. • Thus, PTEN is identified as a potential therapeutic target in DM Type 2.

  3. Insulin Resistance Induces Posttranslational Hepatic Sortilin 1 Degradation in Mice*

    PubMed Central

    Li, Jibiao; Matye, David J.; Li, Tiangang

    2015-01-01

    Insulin promotes hepatic apolipoprotein B100 (apoB100) degradation, whereas insulin resistance is a major cause of hepatic apoB100/triglyceride overproduction in type 2 diabetes. The cellular trafficking receptor sortilin 1 (Sort1) was recently identified to transport apoB100 to the lysosome for degradation in the liver and thus regulate plasma cholesterol and triglyceride levels. Genetic variation of SORT1 was strongly associated with cardiovascular disease risk in humans. The major goal of this study is to investigate the effect and molecular mechanism of insulin regulation of Sort1. Results showed that insulin induced Sort1 protein, but not mRNA, in AML12 cells. Treatment of PI3K or AKT inhibitors decreased Sort1 protein, whereas expression of constitutively active AKT induced Sort1 protein in AML12 cells. Consistently, hepatic Sort1 was down-regulated in diabetic mice, which was partially restored after the administration of the insulin sensitizer metformin. LC-MS/MS analysis further revealed that serine phosphorylation of Sort1 protein was required for insulin induction of Sort1 in a casein kinase 2-dependent manner and that inhibition of PI3K signaling or prevention of Sort1 phosphorylation accelerated proteasome-dependent Sort1 degradation. Administration of a PI3K inhibitor to mice decreased hepatic Sort1 protein and increased plasma cholesterol and triglyceride levels. Adenovirus-mediated overexpression of Sort1 in the liver prevented PI3K inhibitor-induced Sort1 down-regulation and decreased plasma triglyceride but had no effect on plasma cholesterol in mice. This study identified Sort1 as a novel target of insulin signaling and suggests that Sort1 may play a role in altered hepatic apoB100 metabolism in insulin-resistant conditions. PMID:25805502

  4. The Epoxyeicosatrienoic Acid Pathway Enhances Hepatic Insulin Signaling and is Repressed in Insulin-Resistant Mouse Liver.

    PubMed

    Schäfer, Alexander; Neschen, Susanne; Kahle, Melanie; Sarioglu, Hakan; Gaisbauer, Tobias; Imhof, Axel; Adamski, Jerzy; Hauck, Stefanie M; Ueffing, Marius

    2015-10-01

    Although it is widely accepted that ectopic lipid accumulation in the liver is associated with hepatic insulin resistance, the underlying molecular mechanisms have not been well characterized.Here we employed time resolved quantitative proteomic profiling of mice fed a high fat diet to determine which pathways were affected during the transition of the liver to an insulin-resistant state. We identified several metabolic pathways underlying altered protein expression. In order to test the functional impact of a critical subset of these alterations, we focused on the epoxyeicosatrienoic acid (EET) eicosanoid pathway, whose deregulation coincided with the onset of hepatic insulin resistance. These results suggested that EETs may be positive modulators of hepatic insulin signaling. Analyzing EET activity in primary hepatocytes, we found that EETs enhance insulin signaling on the level of Akt. In contrast, EETs did not influence insulin receptor or insulin receptor substrate-1 phosphorylation. This effect was mediated through the eicosanoids, as overexpression of the deregulated enzymes in absence of arachidonic acid had no impact on insulin signaling. The stimulation of insulin signaling by EETs and depression of the pathway in insulin resistant liver suggest a likely role in hepatic insulin resistance. Our findings support therapeutic potential for inhibiting EET degradation. PMID:26070664

  5. Effects of Diet and Exercise on Insulin Resistance during Pregnancy.

    PubMed

    Clapp, James F

    2006-01-01

    Current evidence suggests that both diet and exercise can alter the usual increase in insulin resistance seen in Western societies during mid and late pregnancy. A low-glycemic diet combined with a low-volume exercise regimen during pregnancy decreases the glucose and insulin response to both mixed caloric intake and exercise, and probably lowers both 24-h blood glucose concentrations and the maternal substrate utilization ratio of carbohydrate/fat. The end result is a marked decrease in both maternal weight gain and size at birth. Regular weight-bearing exercise alone lowers markers of insulin resistance and lowers blood glucose concentration during and immediately after exercise during pregnancy. Changes in diet and/or physical activity appear to prevent the onset of gestational diabetes mellitus in at-risk women and may be of value in the treatment of those who develop gestational diabetes. PMID:18370754

  6. Nonobese, insulin-deficient Ins2Akita mice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling.

    PubMed

    Hong, Eun-Gyoung; Jung, Dae Young; Ko, Hwi Jin; Zhang, Zhiyou; Ma, Zhexi; Jun, John Y; Kim, Jae Hyeong; Sumner, Andrew D; Vary, Thomas C; Gardner, Thomas W; Bronson, Sarah K; Kim, Jason K

    2007-12-01

    Although insulin resistance has been traditionally associated with type 2 diabetes, recent evidence in humans and animal models indicates that insulin resistance may also develop in type 1 diabetes. A point mutation of insulin 2 gene in Ins2(Akita) mice leads to pancreatic beta-cell apoptosis and hyperglycemia, and these mice are commonly used to investigate type 1 diabetes and complications. Since insulin resistance plays an important role in diabetic complications, we performed hyperinsulinemic-euglycemic clamps in awake Ins2(Akita) and wild-type mice to measure insulin action and glucose metabolism in vivo. Nonobese Ins2(Akita) mice developed insulin resistance, as indicated by an approximately 80% reduction in glucose infusion rate during clamps. Insulin resistance was due to approximately 50% decreases in glucose uptake in skeletal muscle and brown adipose tissue as well as hepatic insulin action. Skeletal muscle insulin resistance was associated with a 40% reduction in total GLUT4 and a threefold increase in PKCepsilon levels in Ins2(Akita) mice. Chronic phloridzin treatment lowered systemic glucose levels and normalized muscle insulin action, GLUT4 and PKCepsilon levels in Ins2(Akita) mice, indicating that hyperglycemia plays a role in insulin resistance. Echocardiography showed significant cardiac remodeling with ventricular hypertrophy that was ameliorated following chronic phloridzin treatment in Ins2(Akita) mice. Overall, we report for the first time that nonobese, insulin-deficient Ins2(Akita) mice develop type 2 diabetes phenotypes including peripheral and hepatic insulin resistance and cardiac remodeling. Our findings provide important insights into the pathogenesis of metabolic abnormalities and complications affecting type 1 diabetes and lean type 2 diabetes subjects. PMID:17911348

  7. The role of endoplasmic reticulum stress in hippocampal insulin resistance.

    PubMed

    Sims-Robinson, Catrina; Bakeman, Anna; Glasser, Rebecca; Boggs, Janet; Pacut, Crystal; Feldman, Eva L

    2016-03-01

    Metabolic syndrome, which includes hypertension, hyperglycemia, obesity, insulin resistance, and dyslipidemia, has a negative impact on cognitive health. Endoplasmic reticulum (ER) stress is activated during metabolic syndrome, however it is not known which factor associated with metabolic syndrome contributes to this stress. ER stress has been reported to play a role in the development of insulin resistance in peripheral tissues. The role of ER stress in the development of insulin resistance in hippocampal neurons is not known. In the current study, we investigated ER stress in the hippocampus of 3 different mouse models of metabolic syndrome: the C57BL6 mouse on a high fat (HF) diet; apolipoprotein E, leptin, and apolipoprotein B-48 deficient (ApoE 3KO) mice; and the low density lipoprotein receptor, leptin, and apolipoprotein B-48 deficient (LDLR 3KO) mice. We demonstrate that ER stress is activated in the hippocampus of HF mice, and for the first time, in ApoE 3KO mice, but not LDLR 3KO mice. The HF and ApoE 3KO mice are hyperglycemic; however, the LDLR 3KO mice have normal glycemia. This suggests that hyperglycemia may play a role in the activation of ER stress in the hippocampus. Similarly, we also demonstrate that impaired insulin signaling is only present in the HF and ApoE 3KO mice, which suggests that ER stress may play a role in insulin resistance in the hippocampus. To confirm this we pharmacologically induced ER stress with thapsigargin in human hippocampal neurons. We demonstrate for the first time that thapsigargin leads to ER stress and impaired insulin signaling in human hippocampal neurons. Our results may provide a potential mechanism that links metabolic syndrome and cognitive health. PMID:26775176

  8. Vitamin D insufficiency and insulin resistance in obese adolescents

    PubMed Central

    Tosh, Aneesh K.; Belenchia, Anthony M.

    2014-01-01

    Obese adolescents represent a particularly vulnerable group for vitamin D deficiency which appears to have negative consequences on insulin resistance and glucose homeostasis. Poor vitamin D status is also associated with future risk of type 2 diabetes and metabolic syndrome in the obese. The biological mechanisms by which vitamin D influences glycemic control in obesity are not well understood, but are thought to involve enhancement of peripheral/hepatic uptake of glucose, attenuation of inflammation and/or regulation of insulin synthesis/secretion by pancreatic β cells. Related to the latter, recent data suggest that the active form of vitamin, 1,25-dihydroxyvitamin D, does not impact insulin release in healthy pancreatic islets; instead they require an environmental stressor such as inflammation or vitamin D deficiency to see an effect. To date, a number of observational studies exploring the relationship between the vitamin D status of obese adolescents and markers of glucose homeostasis have been published. Most, although not all, show significant associations between circulating 25-hydroxyvitamn D concentrations and insulin sensitivity/resistance indices. In interpreting the collective findings of these reports, significant considerations surface including the effects of pubertal status, vitamin D status, influence of parathyroid hormone status and the presence of nonalcoholic fatty liver disease. The few published clinical trials using vitamin D supplementation to improve insulin resistance and impaired glucose tolerance in obese adolescents have yielded beneficial effects. However, there is a need for more randomized controlled trials. Future investigations should involve larger sample sizes of obese adolescents with documented vitamin D deficiency, and careful selection of the dose, dosing regimen and achievement of target 25-hydroxyvitamn D serum concentrations. These trials should also include clamp-derived measures of in vivo sensitivity and

  9. Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance

    SciTech Connect

    Watanabe, Tomoyuki; Saotome, Masao; Nobuhara, Mamoru; Sakamoto, Atsushi; Urushida, Tsuyoshi; Katoh, Hideki; Satoh, Hiroshi; Funaki, Makoto; Hayashi, Hideharu

    2014-05-01

    Purpose: Evidence suggests an association between aberrant mitochondrial dynamics and cardiac diseases. Because myocardial metabolic deficiency caused by insulin resistance plays a crucial role in heart disease, we investigated the role of dynamin-related protein-1 (DRP1; a mitochondrial fission protein) in the pathogenesis of myocardial insulin resistance. Methods and Results: DRP1-expressing H9c2 myocytes, which had fragmented mitochondria with mitochondrial membrane potential (ΔΨ{sub m}) depolarization, exhibited attenuated insulin signaling and 2-deoxy-D-glucose (2-DG) uptake, indicating insulin resistance. Treatment of the DRP1-expressing myocytes with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (TMPyP) significantly improved insulin resistance and mitochondrial dysfunction. When myocytes were exposed to hydrogen peroxide (H{sub 2}O{sub 2}), they increased DRP1 expression and mitochondrial fragmentation, resulting in ΔΨ{sub m} depolarization and insulin resistance. When DRP1 was suppressed by siRNA, H{sub 2}O{sub 2}-induced mitochondrial dysfunction and insulin resistance were restored. Our results suggest that a mutual enhancement between DRP1 and reactive oxygen species could induce mitochondrial dysfunction and myocardial insulin resistance. In palmitate-induced insulin-resistant myocytes, neither DRP1-suppression nor TMPyP restored the ΔΨ{sub m} depolarization and impaired 2-DG uptake, however they improved insulin signaling. Conclusions: A mutual enhancement between DRP1 and ROS could promote mitochondrial dysfunction and inhibition of insulin signal transduction. However, other mechanisms, including lipid metabolite-induced mitochondrial dysfunction, may be involved in palmitate-induced insulin resistance. - Highlights: • DRP1 promotes mitochondrial fragmentation and insulin-resistance. • A mutual enhancement between DRP1 and ROS ipromotes insulin-resistance. • Palmitate increases DRP1 expression and induces insulin-resistance

  10. Compensatory Islet Response to Insulin Resistance Revealed by Quantitative Proteomics

    PubMed Central

    Gedeon, Nicholas; Kahraman, Sevim; De Jesus, Dario F.; Bhatt, Shweta; Kim, Jong-Seo; Clauss, Therese RW; Camp, David G.; Smith, Richard D.; Qian, Wei-Jun; Kulkarni, Rohit N.

    2015-01-01

    Compensatory islet response is a distinct feature of the pre-diabetic insulin resistant state in humans and rodents. To identify alterations in the islet proteome that characterize the adaptive response, we analyzed islets from five-month-old male control, high-fat diet fed (HFD) or obese ob/ob mice by LC-MS(/MS) and quantified ~1,100 islet proteins (at least two peptides) with a false discovery rate <1%. Significant alterations in abundance were observed for ~350 proteins between groups. A majority of alterations were common to both models, and the changes of a subset of ~40 proteins and 12 proteins were verified by targeted quantification using selected reaction monitoring and Western blots, respectively. The insulin resistant islets in both groups exhibited reduced expression of proteins controlling energy metabolism, oxidative phosphorylation, hormone processing, and secretory pathways. Conversely, an increased expression of molecules involved in protein synthesis and folding suggested effects in endoplasmic reticulum stress response, cell survival, and proliferation in both insulin resistant models. In summary, we report a unique comparison of the islet proteome that is focused on the compensatory response in two insulin resistant rodent models that are not overtly diabetic. These data provide a valuable resource of candidate proteins to the scientific community to undertake further studies aimed at enhancing β-cell mass in patients with diabetes. The data are available via the MassIVE repository, with accession MSV000079093. PMID:26151086

  11. Colonic Macrophages "Remote Control" Adipose Tissue Inflammation and Insulin Resistance.

    PubMed

    Biswas, Subhra K; Bonecchi, Raffaella

    2016-08-01

    The early events linking diet-induced adipose tissue inflammation and insulin resistance remain poorly understood. In this issue of Cell Metabolism, Kawano et al. (2016) show that infiltration of colonic pro-inflammatory macrophages orchestrated by the intestinal CCL2/CCR2 axis kick-starts this process during high-fat-diet feeding. PMID:27508866

  12. Physical Training Improves Insulin Resistance Syndrome Markers in Obese Adolescents.

    ERIC Educational Resources Information Center

    Kang, Hyun-Sik; Gutin, Bernard; Barbeau, Paule; Owens, Scott; Lemmon, Christian R.; Allison, Jerry; Litaker, Mark S.; Le, Ngoc-Anh

    2002-01-01

    Tested the hypothesis that physical training (PT), especially high-intensity PT, would favorably affect components of the insulin resistance syndrome (IRS) in obese adolescents. Data on teens randomized into lifestyle education (LSE) alone, LSE plus moderate -intensity PT, and LSE plus high-intensity PT indicated that PT, especially high-intensity…

  13. Compensatory islet response to insulin resistance revealed by quantitative proteomics

    SciTech Connect

    El Ouaamari, Abdelfattah; Zhou, Jian -Ying; Liew, Chong Wee; Shirakawa, Jun; Dirice, Ercument; Gedeon, Nicholas; Kahraman, Sevim; De Jesus, Dario F.; Bhatt, Shweta; Kim, Jong -Seo; Clauss, Therese R. W.; Camp, II, David G.; Smith, Richard D.; Qian, Wei -Jun; Kulkarni, Rohit N.

    2015-07-07

    Compensatory islet response is a distinct feature of the pre-diabetic insulin resistant state in humans and rodents. To identify alterations in the islet proteome that characterize the adaptive response, we analyzed islets from five-month-old male control, high-fat diet fed (HFD) or obese ob/ob mice by LC-MS(/MS) and quantified ~1,100 islet proteins (at least two peptides) with a false discovery rate <1%. Significant alterations in abundance were observed for ~350 proteins between groups. A majority of alterations were common to both models, and the changes of a subset of ~40 proteins and 12 proteins were verified by targeted quantification using selected reaction monitoring and Western blots, respectively. The insulin resistant islets in both groups exhibited reduced expression of proteins controlling energy metabolism, oxidative phosphorylation, hormone processing, and secretory pathways. Conversely, an increased expression of molecules involved in protein synthesis and folding suggested effects in endoplasmic reticulum stress response, cell survival, and proliferation in both insulin resistant models. In conclusion, we report a unique comparison of the islet proteome that is focused on the compensatory response in two insulin resistant rodent models that are not overtly diabetic. In conclusion, these data provide a valuable resource of candidate proteins to the scientific community to undertake further studies aimed at enhancing β-cell mass in patients with diabetes. The data are available via the MassIVE repository, with accession MSV000079093.

  14. Compensatory islet response to insulin resistance revealed by quantitative proteomics

    DOE PAGESBeta

    El Ouaamari, Abdelfattah; Zhou, Jian -Ying; Liew, Chong Wee; Shirakawa, Jun; Dirice, Ercument; Gedeon, Nicholas; Kahraman, Sevim; De Jesus, Dario F.; Bhatt, Shweta; Kim, Jong -Seo; et al

    2015-07-07

    Compensatory islet response is a distinct feature of the pre-diabetic insulin resistant state in humans and rodents. To identify alterations in the islet proteome that characterize the adaptive response, we analyzed islets from five-month-old male control, high-fat diet fed (HFD) or obese ob/ob mice by LC-MS(/MS) and quantified ~1,100 islet proteins (at least two peptides) with a false discovery rate <1%. Significant alterations in abundance were observed for ~350 proteins between groups. A majority of alterations were common to both models, and the changes of a subset of ~40 proteins and 12 proteins were verified by targeted quantification using selectedmore » reaction monitoring and Western blots, respectively. The insulin resistant islets in both groups exhibited reduced expression of proteins controlling energy metabolism, oxidative phosphorylation, hormone processing, and secretory pathways. Conversely, an increased expression of molecules involved in protein synthesis and folding suggested effects in endoplasmic reticulum stress response, cell survival, and proliferation in both insulin resistant models. In conclusion, we report a unique comparison of the islet proteome that is focused on the compensatory response in two insulin resistant rodent models that are not overtly diabetic. In conclusion, these data provide a valuable resource of candidate proteins to the scientific community to undertake further studies aimed at enhancing β-cell mass in patients with diabetes. The data are available via the MassIVE repository, with accession MSV000079093.« less

  15. Associations of erythrocyte fatty acid patterns with insulin resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Synergistic and/or additive effects on cardiometabolic risk may be missed by examining individual fatty acids (FA). A pattern analysis may be a more useful approach. As well, it remains unclear whether erythrocyte fatty acid composition relates to insulin resistance among Hispanic/Latino...

  16. ASSOCIATION BETWEEN ADIPONECTIN, INSULIN RESISTANCE, AND ENDOMETRIAL CANCER

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BACKGROUND: Obesity is a well-known risk factor for the development of endometrial cancer; however, weight alone does not account for all cases. The authors hypothesized that insulin resistance also contributes to an increased risk for endometrial cancer. Adiponectin is a protein secreted by adipose...

  17. Immunity as a link between obesity and insulin resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Type-2 diabetes mellitus (T2DM) is a major health problem in the United States and worldwide. Obesity is causally linked to the pathogenesis of insulin resistance, metabolic syndrome and T2DM. A chronic low-grade inflammation occurring in adipose tissue is at least in part responsible for the obesit...

  18. Effect of fucoidan administration on insulin secretion and insulin resistance in overweight or obese adults.

    PubMed

    Hernández-Corona, Diana M; Martínez-Abundis, Esperanza; González-Ortiz, Manuel

    2014-07-01

    The aim of this article is to evaluate the effect of fucoidan administration on insulin secretion and insulin sensitivity in overweight or obese adults. A randomized, double-blind, placebo-controlled clinical trial was carried out in 25 obese or overweight volunteers. Thirteen patients received an oral dose of 500 mg of fucoidan once daily before breakfast and 12 patients received placebo for 3 months. Before and after the intervention, fasting glucose and 2-h postload, total cholesterol, high-density lipoprotein cholesterol, triglycerides, and insulin levels were measured. Low-density lipoprotein cholesterol (LDL-C) and homeostasis model analysis formulas (HOMA) for β-cell function and insulin resistance were calculated. The results showed a significant decrease in diastolic blood pressure (71.7 ± 12.2 vs. 67.8 ± 13.8 mmHg; P<.05) and LDL-C (3.1 ± 0.5 vs. 2.7 ± 0.6 mmol/l; P<.01) with increase in insulin levels (60.6 ± 24.0 vs. 78.6 ± 32.4 pmol/l; P<.05), HOMA β-cell (35.0 ± 20.8 vs. 50.6 ± 18.7; P<.05) and HOMA IR (1.9 ± 1.2 vs. 2.6 ± 1.8; P<.05) were observed after fucoidan administration. We conclude that fucoidan administration during a 3-month period in overweight or obese adults decreased diastolic blood pressure and LDL-C concentrations, increasing insulin secretion and insulin resistance. PMID:24611906

  19. Insulin resistance and neurodegeneration: Roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis

    PubMed Central

    Longato, Lisa; Tong, Ming; Wands, Jack R

    2015-01-01

    Recent studies have linked obesity, type 2 diabetes mellitus (T2DM) or non-alcoholic steatohepatitis (NASH) to insulin resistance in the brain, cognitive impairment and neurodegeneration. Insulin resistance compromises cell survival, metabolism and neuronal plasticity, and increases oxidative stress, cytokine activation and apoptosis. T2DM/NASH has been demonstrated to be associated with increased ceramide generation, suggesting a mechanistic link between peripheral insulin resistance and neurodegeneration because ceramides mediate insulin resistance and can cross the blood-brain barrier (BBB). Peripheral insulin resistance diseases may potentially cause brain insulin resistance via a liver-brain axis of neurodegeneration as a result of the trafficking of ceramides across the BBB. Therapy that includes insulin-sensitizing agents may help prevent brain insulin resistance-mediated cognitive impairment. PMID:19777393

  20. Intrinsic Frequency and the Single Wave Biopsy: Implications for Insulin Resistance.

    PubMed

    Petrasek, Danny; Pahlevan, Niema M; Tavallali, Peyman; Rinderknecht, Derek G; Gharib, Morteza

    2015-11-01

    Insulin resistance is the hallmark of classical type II diabetes. In addition, insulin resistance plays a central role in metabolic syndrome, which astonishingly affects 1 out of 3 adults in North America. The insulin resistance state can precede the manifestation of diabetes and hypertension by years. Insulin resistance is correlated with a low-grade inflammatory condition, thought to be induced by obesity as well as other conditions. Currently, the methods to measure and monitor insulin resistance, such as the homeostatic model assessment and the euglycemic insulin clamp, can be impractical, expensive, and invasive. Abundant evidence exists that relates increased pulse pressure, pulse wave velocity (PWV), and vascular dysfunction with insulin resistance. We introduce a potential method of assessing insulin resistance that relies on a novel signal-processing algorithm, the intrinsic frequency method (IFM). The method requires a single pulse pressure wave, thus the term " wave biopsy." PMID:26183600

  1. Is myopia another clinical manifestation of insulin resistance?

    PubMed

    Galvis, Virgilio; López-Jaramillo, Patricio; Tello, Alejandro; Castellanos-Castellanos, Yuly Andrea; Camacho, Paul Anthony; Cohen, Daniel Dylan; Gómez-Arbeláez, Diego; Merayo-Lloves, Jesús

    2016-05-01

    Myopia is a multifactorial visual refraction disease, in which the light rays from distant objects are focused in front of retina, causing blurry vision. Myopic eyes are characterized by an increased corneal curvature and/or ocular axial length. The prevalence of myopia has increased in recent decades, a trend that cannot be attributed exclusively to genetic factors. Low and middle income countries have a higher burden of refractive error, which we propose could be a consequence of a shorter exposure time to a westernized lifestyle, a phenomenon that may also explain the rapid increase in cardiometabolic diseases, such as diabetes, among those populations. We suggest that interactions between genetic, epigenetic and a rapidly changing environment are also involved in myopia onset and progression. Furthermore, we discuss several possible mechanisms by which insulin resistance may promote abnormal ocular growth and myopia to support the hypothesis that insulin resistance and hyperinsulinemia are involved in its pathogenesis, providing a link between trends in myopia and those of cardiometabolic diseases. There is evidence that insulin have direct ocular growth promoting effects as well an indirect effect via the induction of insulin-like growth factors leading to decreases insulin-like growth factor-binding protein, also implicated in ocular growth. PMID:27063082

  2. Crosstalk between exercise and galanin system alleviates insulin resistance.

    PubMed

    Fang, Penghua; He, Biao; Shi, Mingyi; Zhu, Yan; Bo, Ping; Zhang, Zhenwen

    2015-12-01

    Studies have demonstrated that aerobic exercise can enhance insulin sensitivity, however, the precise mechanism for this outcome is not entirely identified. Emerging evidences point out that exercise can upregulate galanin protein and mRNA expression, resulting in improvement of insulin sensitivity via an increase in translocation of glucose transporter 4 and subsequent glucose uptake in myocytes and adipocytes of healthy and type 2 diabetic rats, which may be blocked by galanin antagonist. In return, galanin can exert the exercise-protective roles to prevent excessive movement of skeletal muscle and to accelerate exercise trauma repair in exercise-relative tissues. Studies also implicated that combination of aerobic exercise and activation of galanin system may make more significant improvement in insulin sensitivity than that of either one did. These suggest that galanin system is essential for physical activity to alleviate insulin resistance, namely, the beneficial effect of physical activity on glucose uptake is at least partly mediated by galanin system. Besides, co-treatment with galanin and exercise is an effective therapeutic strategy for reducing insulin resistance. PMID:26542124

  3. Insulin Resistance and Muscle Metabolism in Chronic Kidney Disease

    PubMed Central

    Bailey, James L.

    2013-01-01

    Insulin resistance is a common finding in chronic kidney disease (CKD) and is manifested by mild fasting hyperglycemia and abnormal glucose tolerance testing. Circulating levels of glucocorticoids are high. In muscle, changes in the insulin signaling pathway occur. An increase in the regulatory p85 subunit of Class I phosphatidylinositol 3-Kinase enzyme leads to decreased activation of the downstream effector protein kinase B (Akt). Mechanisms promoting muscle proteolysis and atrophy are unleashed. The link of Akt to the ubiquitin proteasome pathway, a major degradation pathway in muscle, is discussed. Another factor associated with insulin resistance in CKD is angiotensin II (Ang II) which appears to induce its intracellular effects through inflammatory cytokines or reactive oxygen species. Skeletal muscle ATP is depleted and the ability of AMP-activated protein kinase (AMPK) to replenish energy stores is blocked. How this can be reversed is discussed. Interleukin-6 (IL-6) levels are elevated in CKD and impair insulin signaling at the level of IRS-1. With exercise, IL-6 levels are reduced; glucose uptake and utilization are increased. For patients with CKD, exercise may improve insulin signaling and build up muscle. Treatment strategies for preventing muscle atrophy are discussed. PMID:23431467

  4. Association of resistin with visceral fat and muscle insulin resistance.

    PubMed

    Borst, Stephen E; Conover, Christine F; Bagby, Gregory J

    2005-10-01

    Maturing Sprague-Dawley (S-D) rats develop obesity and skeletal muscle insulin resistance. To investigate the relationship between fat mass and insulin responses, we performed surgical removal of the epididymal and retroperitoneal depots of visceral adipose tissue (VF) or sham surgery (SHAM) in male rats aged 4 months. At sacrifice, 30 days later, the mass of visceral fat was 48% lower (p<0.05) in VF- compared to SHAM, while subcutaneous fat was essentially unchanged. VF- animals displayed increased insulin responses in isolated strips of skeletal muscle. Insulin-stimulated glucose transport was increased 28% in soleus muscle (p<0.05), with a trend toward a 31% increase in extensor digitorum longus muscle (p=0.058). Glucose tolerance was not significantly affected by surgical fat removal. In VF- animals, serum resistin was reduced 26% (p<0.05) and serum adiponectin was reduced 30% (p<0.05), with trends for reductions in IL-4 (58% reduction, p=0.084) and IL-6 (56% reduction, p=0.123). TNF-alpha, leptin and free fatty acids (NEFAs) were unchanged. We conclude that in maturing S-D rats, increased visceral adiposity leads to an increase in systemic release in resistin and possibly interleukins. Elevation of circulating cytokines may play a role in the development of muscle insulin resistance. PMID:16154759

  5. Insulin as the main regulator of cellular glucose utilization--aetiological aspects of insulin resistance.

    PubMed

    Tatoń, Jan; Czech, Anna; Piatkiewicz, Paweł

    2010-01-01

    This review presents the advances in the molecular biology and the pathophysiology of insulin resistance with emphasis on disturbances in cellular glucose transport. New scientific information about the structure and function of glucotransporters from the GLUT4 and SLGT families underline their significance in endocrinopathies and metabolic disease pathogenesis as related to insulin resistance. The new discoveries in this area also contribute to a better understanding of the regulation of insulin receptor and post-receptor reactivity by hormones and by drugs. They refer to the regulation of glycaemia and to its disturbances in diabetes mellitus, particularly of type 2, to metabolic syndrome, and, in general, to the pathogenesis of many syndromes and clinical disturbances caused by insulin resistance. Impairment of cellular glucose transport may be one of the primary aetiological factors in this respect. Therefore, studies of cellular glucotransporters expression and function promise new clinical and pharmacotherapeutic developments. Progress in this area has already been transformed into many practical proposals which are improving clinical practice. PMID:20806184

  6. Liver Enzymes Are Associated With Hepatic Insulin Resistance, Insulin Secretion, and Glucagon Concentration in Healthy Men and Women

    PubMed Central

    Bonnet, Fabrice; Ducluzeau, Pierre-Henri; Gastaldelli, Amalia; Laville, Martine; Anderwald, Christian H.; Konrad, Thomas; Mari, Andrea; Balkau, Beverley

    2011-01-01

    OBJECTIVE The pathophysiological mechanisms to explain the association between risk of type 2 diabetes and elevated concentrations of γ-glutamyltransferase (GGT) and alanineaminotransferase (ALT) remain poorly characterized. We explored the association of liver enzymes with peripheral and hepatic insulin resistance, insulin secretion, insulin clearance, and glucagon concentration. RESEARCH DESIGN AND METHODS We studied 1,309 nondiabetic individuals from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study; all had a euglycemic-hyperinsulinemic clamp and an oral glucose tolerance test (OGTT) with assessment of insulin secretion and hepatic insulin extraction. The hepatic insulin resistance index was calculated in 393 individuals. RESULTS In both men and women, plasma concentrations of GGT and ALT were inversely related with insulin sensitivity (M/I) (all P < 0.01). Likewise, the hepatic insulin resistance index was positively correlated with both GGT (r = 0.37, P < 0.0001, men; r = 0.36, P < 0.0001, women) and ALT (r = 0.25, P = 0.0005, men; r = 0.18, P = 0.01, women). These associations persisted in multivariable models. Increased GGT and ALT were significantly associated with higher insulin secretion rates and with both reduced endogenous clearance of insulin and hepatic insulin extraction during the OGTT (P = 0.0005 in men; P = 0.003 in women). Plasma fasting glucagon levels increased over ALT quartiles (men, quartile 4 vs. quartile 1 11.2 ± 5.1 vs. 9.3 ± 3.8 pmol/L, respectively, P = 0.0002; women, 9.0 ± 4.3 vs. 7.6 ± 3.1, P = 0.001). CONCLUSIONS In healthy individuals, increased GGT and ALT were biomarkers of both systemic and hepatic insulin resistance with concomitant increased insulin secretion and decreased hepatic insulin clearance. The novel finding of a positive correlation between ALT and fasting glucagon level concentrations warrants confirmation in type 2 diabetes. PMID:21521874

  7. Recent advances in obesity-induced inflammation and insulin resistance.

    PubMed

    Tateya, Sanshiro; Kim, Francis; Tamori, Yoshikazu

    2013-01-01

    It has been demonstrated in rodents and humans that chronic inflammation characterized by macrophage infiltration occurs mainly in adipose tissue or liver during obesity, in which activation of immune cells is closely associated with insulin sensitivity. Macrophages can be classified as classically activated (M1) macrophages that support microbicidal activity or alternatively activated (M2) macrophages that support allergic and antiparasitic responses. In the context of insulin action, M2 macrophages sustain insulin sensitivity by secreting IL-4 and IL-10, while M1 macrophages induce insulin resistance through the secretion of proinflammatory cytokines, such as TNFα. Polarization of M1/M2 is controlled by various dynamic functions of other immune cells. It has been demonstrated that, in a lean state, TH2 cells, Treg cells, natural killer T cells, or eosinophils contribute to the M2 activation of macrophages by secreting IL-4 or IL-10. In contrast, obesity causes alteration of the constituent immune cells, in which TH1 cells, B cells, neutrophils, or mast cells induce M1 activation of macrophages by the elevated secretion of TNFα and IFNγ. Increased secretion of TNFα and free fatty acids from hypertrophied adipocytes also contributes to the M1 activation of macrophages. Since obesity-induced insulin resistance is established by macrophage infiltration and the activation of immune cells inside tissues, identification of the factors that regulate accumulation and the intracellular signaling cascades that define polarization of M1/M2 would be indispensable. Regulation of these factors would lead to the pharmacological inhibition of obesity-induced insulin resistance. In this review, we introduce molecular mechanisms relevant to the pathophysiology and review the most recent studies of clinical applications targeting chronic inflammation. PMID:23964268

  8. Inflammation-induced microvascular insulin resistance is an early event in diet-induced obesity

    PubMed Central

    Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W.; Barrett, Eugene J.; Cao, Wenhong

    2015-01-01

    Endothelial dysfunction and vascular insulin resistance usually coexist and chronic inflammation engenders both. In the present study, we investigate the temporal relationship between vascular insulin resistance and metabolic insulin resistance. We assessed insulin responses in all arterial segments, including aorta, distal saphenous artery and the microvasculature, as well as the metabolic insulin responses in muscle in rats fed on a high-fat diet (HFD) for various durations ranging from 3 days to 4 weeks with or without sodium salicylate treatment. Compared with controls, HFD feeding significantly blunted insulin-mediated Akt (protein kinase B) and eNOS [endothelial nitric oxide (NO) synthase] phosphorylation in aorta in 1 week, blunted vasodilatory response in small resistance vessel in 4 weeks and microvascular recruitment in as early as 3 days. Insulin-stimulated whole body glucose disposal did not begin to progressively decrease until after 1 week. Salicylate treatment fully inhibited vascular inflammation, prevented microvascular insulin resistance and significantly improved muscle metabolic responses to insulin. We conclude that microvascular insulin resistance is an early event in diet-induced obesity and insulin resistance and inflammation plays an essential role in this process. Our data suggest microvascular insulin resistance contributes to the development of metabolic insulin resistance in muscle and muscle microvasculature is a potential therapeutic target in the prevention and treatment of diabetes and its related complications. PMID:26265791

  9. Inflammation-induced microvascular insulin resistance is an early event in diet-induced obesity.

    PubMed

    Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W; Barrett, Eugene J; Cao, Wenhong; Liu, Zhenqi

    2015-12-01

    Endothelial dysfunction and vascular insulin resistance usually coexist and chronic inflammation engenders both. In the present study, we investigate the temporal relationship between vascular insulin resistance and metabolic insulin resistance. We assessed insulin responses in all arterial segments, including aorta, distal saphenous artery and the microvasculature, as well as the metabolic insulin responses in muscle in rats fed on a high-fat diet (HFD) for various durations ranging from 3 days to 4 weeks with or without sodium salicylate treatment. Compared with controls, HFD feeding significantly blunted insulin-mediated Akt (protein kinase B) and eNOS [endothelial nitric oxide (NO) synthase] phosphorylation in aorta in 1 week, blunted vasodilatory response in small resistance vessel in 4 weeks and microvascular recruitment in as early as 3 days. Insulin-stimulated whole body glucose disposal did not begin to progressively decrease until after 1 week. Salicylate treatment fully inhibited vascular inflammation, prevented microvascular insulin resistance and significantly improved muscle metabolic responses to insulin. We conclude that microvascular insulin resistance is an early event in diet-induced obesity and insulin resistance and inflammation plays an essential role in this process. Our data suggest microvascular insulin resistance contributes to the development of metabolic insulin resistance in muscle and muscle microvasculature is a potential therapeutic target in the prevention and treatment of diabetes and its related complications. PMID:26265791

  10. Influence of Gut Microbiota on Subclinical Inflammation and Insulin Resistance

    PubMed Central

    Carvalho, Bruno Melo; Abdalla Saad, Mario Jose

    2013-01-01

    Obesity is the main condition that is correlated with the appearance of insulin resistance, which is the major link among its comorbidities, such as type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular and neurodegenerative diseases, and several types of cancer. Obesity affects a large number of individuals worldwide; it degrades human health and quality of life. Here, we review the role of the gut microbiota in the pathophysiology of obesity and type 2 diabetes, which is promoted by a bacterial diversity shift mediated by overnutrition. Whole bacteria, their products, and metabolites undergo increased translocation through the gut epithelium to the circulation due to degraded tight junctions and the consequent increase in intestinal permeability that culminates in inflammation and insulin resistance. Several strategies focusing on modulation of the gut microbiota (antibiotics, probiotics, and prebiotics) are being experimentally employed in metabolic derangement in order to reduce intestinal permeability, increase the production of short chain fatty acids and anorectic gut hormones, and promote insulin sensitivity to counteract the inflammatory status and insulin resistance found in obese individuals. PMID:23840101

  11. Skeletal muscle fatty acid handling in insulin resistant men.

    PubMed

    van Hees, Anneke M J; Jans, Anneke; Hul, Gabby B; Roche, Helen M; Saris, Wim H M; Blaak, Ellen E

    2011-07-01

    Disturbances in skeletal muscle lipid metabolism may precede or contribute to the development of whole body insulin resistance. In this study, we examined fasting and postprandial skeletal muscle fatty acid (FA) handling in insulin resistant (IR) men. Thirty men with the metabolic syndrome (MetS) (National Cholesterol Education Program-Adult Treatment Panel III) were included in this sub-study to the LIPGENE study, and divided in two groups (IR and control) based on the median of insulin sensitivity (S(I) = 2.06 (mU/l(-1))·min(-1)·10(-4)). Fasting and postprandial skeletal muscle FA handling were examined by combining the forearm balance technique with stable isotopes of palmitate. [(2)H(2)]-palmitate was infused intravenously to label endogenous triacylglycerol (TAG) and free FAs (FFAs) in the circulation and [U-(13)C]-palmitate was incorporated in a high-fat mixed meal (2.6 MJ, 61 E% fat) to label chylomicron-TAG. Muscle biopsies were taken to determine muscle TAG, diacylglycerol (DAG), FFA, and phospholipid (PL) content, their fractional synthetic rates (FSRs) and degree of saturation, as well as messenger RNA (mRNA) expression of genes involved in lipid metabolism. In the first 2 h after meal consumption, forearm muscle [(2)H(2)]-labeled TAG extraction was higher in IR vs. control (P = 0.05). Fasting percentage saturation of muscle DAG was higher in IR vs. control (P = 0.016). No differences were observed for intramuscular TAG, DAG, FFA, and PL content, FSR, and muscle mRNA expression. In conclusion, increased muscle (hepatically derived) TAG extraction during postprandial conditions and increased saturation of intramuscular DAG are associated with insulin resistance, suggesting that disturbances in skeletal muscle FA handling could play a role in the development of whole body insulin resistance and type 2 diabetes. PMID:21331063

  12. Early hepatic insulin resistance in mice: a metabolomics analysis.

    PubMed

    Li, Lei O; Hu, Yun-Fu; Wang, Lily; Mitchell, Matthew; Berger, Alvin; Coleman, Rosalind A

    2010-03-01

    When fed with a high-fat safflower oil diet for 3 wk, wild-type mice develop hepatic insulin resistance, whereas mice lacking glycerol-3-phosphate acyltransferase-1 retain insulin sensitivity. We examined early changes in the development of insulin resistance via liver and plasma metabolome analyses that compared wild-type and glycerol-3-phosphate acyltransferase-deficient mice fed with either a low-fat or the safflower oil diet for 3 wk. We reasoned that diet-induced changes in metabolites that occurred only in the wild-type mice would reflect those metabolites that were specifically related to hepatic insulin resistance. Of the identifiable metabolites (from 322 metabolites) in liver, wild-type mice fed with the high-fat diet had increases in urea cycle intermediates, consistent with increased deamination of amino acids used for gluconeogenesis. Also increased were stearoylglycerol, gluconate, glucarate, 2-deoxyuridine, and pantothenate. Decreases were observed in S-adenosylhomocysteine, lactate, the bile acid taurocholate, and 1,5-anhydroglucitol, a previously identified marker of short-term glycemic control. Of the identifiable metabolites (from 258 metabolites) in plasma, wild-type mice fed with the high-fat diet had increases in plasma stearate and two pyrimidine-related metabolites, whereas decreases were found in plasma bradykinin, alpha-ketoglutarate, taurocholate, and the tryptophan metabolite, kynurenine. This study identified metabolites previously not known to be associated with insulin resistance and points to the utility of metabolomics analysis in identifying unrecognized biochemical pathways that may be important in understanding the pathophysiology of diabetes. PMID:20150186

  13. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus

    PubMed Central

    Tangvarasittichai, Surapon

    2015-01-01

    Oxidative stress is increased in metabolic syndrome and type 2 diabetes mellitus (T2DM) and this appears to underlie the development of cardiovascular disease, T2DM and diabetic complications. Increased oxidative stress appears to be a deleterious factor leading to insulin resistance, dyslipidemia, β-cell dysfunction, impaired glucose tolerance and ultimately leading to T2DM. Chronic oxidative stress, hyperglycemia and dyslipidemia are particularly dangerous for β-cells from lowest levels of antioxidant, have high oxidative energy requirements, decrease the gene expression of key β-cell genes and induce cell death. If β-cell functioning is impaired, it results in an under production of insulin, impairs glucose stimulated insulin secretion, fasting hyperglycemia and eventually the development of T2DM. PMID:25897356

  14. The role of endothelial insulin signaling in the regulation of vascular tone and insulin resistance

    PubMed Central

    Vicent, David; Ilany, Jacob; Kondo, Tatsuya; Naruse, Keiko; Fisher, Simon J.; Kisanuki, Yaz Y.; Bursell, Sven; Yanagisawa, Masashi; King, George L.; Kahn, C. Ronald

    2003-01-01

    Insulin receptors (IRs) on vascular endothelial cells have been suggested to participate in insulin-regulated glucose homeostasis. To directly address the role of insulin action in endothelial function, we have generated a vascular endothelial cell IR knockout (VENIRKO) mouse using the Cre-loxP system. Cultured endothelium of VENIRKO mice exhibited complete rearrangement of the IR gene and a more than 95% decrease in IR mRNA. VENIRKO mice were born at the expected Mendelian ratio, grew normally, were fertile, and exhibited normal patterns of vasculature in the retina and other tissues. Glucose homeostasis under basal condition was comparable in VENIRKO mice. Both eNOS and endothelin-1 mRNA levels, however, were reduced by approximately 30–60% in endothelial cells, aorta, and heart, while vascular EGF expression was maintained at normal levels. Arterial pressure tended to be lower in VENIRKO mice on both low- and high-salt diets, and on a low-salt diet VENIRKO mice showed insulin resistance. Thus, inactivation of the IR on endothelial cell has no major consequences on vascular development or glucose homeostasis under basal conditions, but alters expression of vasoactive mediators and may play a role in maintaining vascular tone and regulation of insulin sensitivity to dietary salt intake. PMID:12727929

  15. Peroxynitrite mediates muscle insulin resistance in mice via nitration of IRbeta/IRS-1 and Akt

    SciTech Connect

    Zhou Jun; Huang Kaixun

    2009-11-15

    Accumulating evidence suggests that peroxynitrite (ONOO{sup -}) is involved in the pathogenesis of insulin resistance. In the current study, we investigated whether insulin resistance in vivo could be mediated by nitration of proteins involved in the early steps of the insulin signal transduction pathway. Exogenous peroxynitrite donated by 3-morpholinosydnonimine hydrochloride (SIN-1) induced in vivo nitration of the insulin receptor beta subunit (IRbeta), insulin receptor substrate (IRS)-1, and protein kinase B/Akt (Akt) in skeletal muscle of mice and dramatically reduced whole-body insulin sensitivity and muscle insulin signaling. Moreover, in high-fat diet (HFD)-fed insulin-resistant mice, we observed enhanced nitration of IRbeta and IRS-1 in skeletal muscle, in parallel with impaired whole-body insulin sensitivity and muscle insulin signaling. Reversal of nitration of these proteins by treatment with the peroxynitrite decomposition catalyst FeTPPS yielded an improvement in whole-body insulin sensitivity and muscle insulin signaling in HFD-fed mice. Taken together, these findings provide new mechanistic insights for the involvement of peroxynitrite in the development of insulin resistance and suggest that nitration of proteins involved in the early steps of insulin signal transduction is a novel molecular mechanism of HFD-induced muscle insulin resistance.

  16. Metabolic programming in the pathogenesis of insulin resistance.

    PubMed

    Devaskar, Sherin U; Thamotharan, Manikkavasagar

    2007-06-01

    This review focuses on different animal models of nutrient perturbations, inclusive of restrictive and excessive states mimicking human situations during pregnancy and lactation that cause aberrations in the offspring. These aberrations consist of diminished insulin sensitivity in the presence of defective insulin production. These phenotypic changes are due to altered peripheral tissue post-insulin receptor signaling mechanisms and pancreatic beta-islet insulin synthesis and secretion defects. While these changes during in utero or postnatal life serve as essential adaptations to overcome adverse conditions, they become maladaptive subsequently and set the stage for type 2 diabetes mellitus. Pregnancy leads to gestational diabetes with trans-generational propagation of the insulin resistant phenotype. This is in response to the metabolically aberrant maternal in utero environment, and tissue specific epigenetic perturbations that permanently alter expression of critical genes transmitted to future generations. These heritable aberrations consisting of altered DNA methylation and histone modifications remodel chromatin and affect transcription of key genes. Along with an altered in utero environment, these chromatin modifications contribute to the world-wide epidemic of type 2 diabetes mellitus, with nutrient excess dominating in developed and nutrient restriction in developing countries. PMID:17657604

  17. Blockade of Multidrug Resistance-Associated Proteins Aggravates Acute Pancreatitis and Blunts Atrial Natriuretic Factor’s Beneficial Effect in Rats: Role of MRP4 (ABCC4)

    PubMed Central

    Ventimiglia, María Silvia; Najenson, Ana Clara; Perazzo, Juan Carlos; Carozzo, Alejandro; Vatta, Marcelo S; Davio, Carlos A; Bianciotti, Liliana G

    2015-01-01

    We previously reported that atrial natriuretic factor (ANF) stimulates secretin-evoked cAMP efflux through multidrug resistance-associated protein 4 (MRP4) in the exocrine pancreas. Here we sought to establish in vivo whether this mechanism was involved in acute pancreatitis onset in the rat. Rats pretreated with or without probenecid (MRPs general inhibitor) were infused with secretin alone or with ANF. A set of these animals were given repetitive cerulein injections to induce acute pancreatitis. Plasma amylase and intrapancreatic trypsin activities were measured and histological examination of the pancreas performed. Secretin alone activated trypsinogen but induced no pancreatic histological changes. Blockade by probenecid in secretin-treated rats increased trypsin and also induced vacuolization, a hallmark of acute pancreatitis. ANF prevented the secretin response but in the absence of probenecid. In rats with acute pancreatitis, pretreatment with secretin aggravated the disease, but ANF prevented secretin-induced changes. Blockade of MRPs in rats with acute pancreatitis induced trypsinogen activation and larger cytoplasmic vacuoles as well as larger areas of necrosis and edema that were aggravated by secretin but not prevented by ANF. The temporal resolution of intracellular cAMP levels seems critical in the onset of acute pancreatitis, since secretin-evoked cAMP in a context of MRP inhibition makes the pancreas prone to injury in normal rats and aggravates the onset of acute pancreatitis. Present findings support a protective role for ANF mediated by cAMP extrusion through MRP4 and further suggest that the regulation of MRP4 by ANF would be relevant to maintain pancreatic acinar cell homeostasis. PMID:25569802

  18. Chromium Therapy for Insulin Resistance Associated with HIV-Disease

    PubMed Central

    Stein, Seth A; Mc Nurlan, Margaret; Phillips, Brett T; Messina, Catherine; Mynarcik, Dennis; Gelato, Marie

    2014-01-01

    Objective With the advent of highly active anti-retroviral therapy, HIV disease has become a chronic condition, but with a number of metabolic complications including insulin resistance and diabetes mellitus, dyslipidemia and hypertension and an increased incidence of atherosclerosis. The aim of the current study was to test the safety and efficacy of chromium picolinate for HIV- associated insulin resistance. Materials/Methods The study was a randomized, double-blind, placebo-controlled trial with subjects receiving 500μg of chromium picolinate or placebo twice daily for two months. HIV- infected subjects were selected based on a fasting concentration of plasma glucose greater than 5.5mmol/L or a plasma glucose concentration of greater than 7.7mmol/L (but less than 11mmol/L) 2h after oral ingestion of 75g of glucose. Insulin sensitivity was assessed with a hyper-insulinemic-euglycemic clamp and glucose tolerance was assessed with the oral glucose tolerance test. Subjects were monitored closely for alterations in viral load, CD4+ cells, hemoglobin and hematocrit, kidney and liver function, and fasting lipid profiles. Results Forty-three subjects were enrolled and 39 completed the protocol (20 in the chromium-supplemented and 19 in the placebo arm). Following chromium-supplementation, there were no significant changes in either insulin sensitivity or glucose tolerance. There was a significant improvement in serum HDL cholesterol concentration in the group supplemented with chromium. Conclusions Chromium picolinate supplementation at this level was well-tolerated, but overall was not an effective therapy for insulin resistance in these HIV-infected subjects. PMID:25346863

  19. The Importance of Palmitoleic Acid to Adipocyte Insulin Resistance and Whole-Body Insulin Sensitivity in Type 1 Diabetes

    PubMed Central

    Howard, David; Schauer, Irene E.; Maahs, David M.; Snell-Bergeon, Janet K.; Clement, Timothy W.; Eckel, Robert H.; Perreault, Leigh; Rewers, Marian

    2013-01-01

    Context: Type 1 diabetes is an insulin-resistant state, but it is less clear which tissues are affected. Our previous report implicated skeletal muscle and liver insulin resistance in people with type 1 diabetes, but this occurred independently of generalized, visceral, or ectopic fat. Objective: The aim of the study was to measure adipose tissue insulin sensitivity and plasma triglyceride composition in individuals with type 1 diabetes after overnight insulin infusion to lower fasting glucose. Design, Patients, and Methods: Fifty subjects (25 individuals with type 1 diabetes and 25 controls without) were studied. After 3 d of dietary control and overnight insulin infusion, we performed a three-stage hyperinsulinemic/euglycemic clamp infusing insulin at 4, 8, and 40 mU/m2 · min. Infusions of [1,1,2,3,3-2H2]glycerol and [1-13C]palmitate were used to quantify lipid metabolism. Results: Basal glycerol and palmitate rates of appearance were similar between groups, decreased more in control subjects during the first two stages of the clamp, and similarly suppressed during the highest insulin dose. The concentration of insulin required for 50% inhibition of lipolysis was twice as high in individuals with type 1 diabetes. Plasma triglyceride saturation was similar between groups, but palmitoleic acid in plasma triglyceride was inversely related to adipocyte insulin sensitivity. Unesterified palmitoleic acid in plasma was positively related to insulin sensitivity in controls, but not in individuals with type 1 diabetes. Conclusions: Adipose tissue insulin resistance is a significant feature of type 1 diabetes. Palmitoleic acid is not related to insulin sensitivity in type 1 diabetes, as it was in controls, suggesting a novel mechanism for insulin resistance in this population. PMID:23150678

  20. Defect in tyrosine kinase activity of the insulin receptor from a patient with insulin resistance and acanthosis nigricans.

    PubMed

    Yamamoto, R; Shiba, T; Tobe, K; Shibasaki, Y; Koshio, O; Izumi, T; Odawara, M; Mikami, Y; Matsuura, N; Akanuma, Y

    1990-04-01

    We report here a defect in tyrosine kinase activity of the insulin receptor from an insulin-resistant patient with acanthosis nigricans using cultured Ebstein-Barr virus (EBV)-transformed B-lymphocytes. As judged by affinity labeling and immunoblotting, the alpha- and beta-subunits of insulin receptors from the patient's lymphocytes exhibited the same mol wt as those from control subjects. Lectin-purified extracts from lymphocytes of the patient and the control subjects containing the same insulin-binding capacity were assayed for autophosphorylation and the ability to phosphorylate histone H2B. The degree of insulin-dependent autophosphorylation and the tyrosine kinase activity of the insulin receptor from the patient's lymphocytes were decreased to 15% and 13%, respectively, in a cell-free system. The insulin-dependent autophosphorylation of the insulin receptor was also impaired in intact EBV lymphocytes from the patient. Consistent with these results, we found that one of this patient's alleles had a mutation in which valine is substituted for Gly996, the third glycine in the conserved Gly-X-Gly-X-X-Gly motif in the kinase domain. Thus, it seems likely that the defect in tyrosine kinase activity of the insulin receptor cause the insulin resistance in this patient. The EBV lymphocyte can be a good system to detect genetically determined abnormalities in the insulin receptor. PMID:2180980

  1. The Impact of Organokines on Insulin Resistance, Inflammation, and Atherosclerosis.

    PubMed

    Choi, Kyung Mook

    2016-03-01

    Immoderate energy intake, a sedentary lifestyle, and aging have contributed to the increased prevalence of obesity, sarcopenia, metabolic syndrome, type 2 diabetes, and cardiovascular disease. There is an urgent need for the development of novel pharmacological interventions that can target excessive fat accumulation and decreased muscle mass and/or strength. Adipokines, bioactive molecules derived from adipose tissue, are involved in the regulation of appetite and satiety, inflammation, energy expenditure, insulin resistance and secretion, glucose and lipid metabolism, and atherosclerosis. Recently, there is emerging evidence that skeletal muscle and the liver also function as endocrine organs that secrete myokines and hepatokines, respectively. Novel discoveries and research into these organokines (adipokines, myokines, and hepatokines) may lead to the development of promising biomarkers and therapeutics for cardiometabolic disease. In this review, I summarize recent data on these organokines and focus on the role of adipokines, myokines, and hepatokines in the regulation of insulin resistance, inflammation, and atherosclerosis. PMID:26996418

  2. Exercise Training and Insulin Resistance: A Current Review

    PubMed Central

    Keshel, Tyler E; Coker, Robert H

    2015-01-01

    There is a general perception that increased physical activity will improve glucose homeostasis in all individuals. While this is an attractive concept, this conclusion may be overly simplistic and even misleading. The topic was reviewed extensively over 30 years ago and it was concluded that acute exercise enhances glucose uptake. However, in some cases the chronic influence of interventions utilizing exercise may have little effect on glucose metabolism. Moreover, insulin resistance often returns to near baseline levels within a couple of days following cessation of the exercise bout; leaving the overall effectiveness of the intervention in question. Since improving glucose homeostasis should be the focal endpoint of any intervention designed to mitigate the overwhelming degree of insulin resistance in individuals at risk for metabolic disease, it is essential to evaluate the key components of a successful approach. PMID:26523243

  3. The Impact of Organokines on Insulin Resistance, Inflammation, and Atherosclerosis

    PubMed Central

    2016-01-01

    Immoderate energy intake, a sedentary lifestyle, and aging have contributed to the increased prevalence of obesity, sarcopenia, metabolic syndrome, type 2 diabetes, and cardiovascular disease. There is an urgent need for the development of novel pharmacological interventions that can target excessive fat accumulation and decreased muscle mass and/or strength. Adipokines, bioactive molecules derived from adipose tissue, are involved in the regulation of appetite and satiety, inflammation, energy expenditure, insulin resistance and secretion, glucose and lipid metabolism, and atherosclerosis. Recently, there is emerging evidence that skeletal muscle and the liver also function as endocrine organs that secrete myokines and hepatokines, respectively. Novel discoveries and research into these organokines (adipokines, myokines, and hepatokines) may lead to the development of promising biomarkers and therapeutics for cardiometabolic disease. In this review, I summarize recent data on these organokines and focus on the role of adipokines, myokines, and hepatokines in the regulation of insulin resistance, inflammation, and atherosclerosis. PMID:26996418

  4. Heart Rate Variability, Insulin Resistance, and Insulin Sensitivity in Japanese Adults: The Toon Health Study

    PubMed Central

    Saito, Isao; Hitsumoto, Shinichi; Maruyama, Koutatsu; Nishida, Wataru; Eguchi, Eri; Kato, Tadahiro; Kawamura, Ryoichi; Takata, Yasunori; Onuma, Hiroshi; Osawa, Haruhiko; Tanigawa, Takeshi

    2015-01-01

    Background Although impaired cardiac autonomic function is associated with an increased risk of type 2 diabetes in Caucasians, evidence in Asian populations with a lower body mass index is limited. Methods Between 2009–2012, the Toon Health Study recruited 1899 individuals aged 30–79 years who were not taking medication for diabetes. A 75-g oral glucose tolerance test was used to diagnose type 2 diabetes, and fasting and 2-h-postload glucose and insulin concentrations were measured. We assessed the homeostasis model assessment index for insulin resistance (HOMA-IR) and Gutt’s insulin sensitivity index (ISI). Pulse was recorded for 5 min, and time-domain heart rate variability (HRV) indices were calculated: the standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive difference (RMSSD). Power spectral analysis provided frequency domain measures of HRV: high frequency (HF) power, low frequency (LF) power, and the LF:HF ratio. Results Multivariate-adjusted logistic regression models showed decreased SDNN, RMSSD, and HF, and increased LF:HF ratio were associated significantly with increased HOMA-IR and decreased ISI. When stratified by overweight status, the association of RMSSD, HF, and LF:HF ratio with decreased ISI was also apparent in non-overweight individuals. The interaction between LF:HF ratio and decreased ISI in overweight individuals was significant, with the odds ratio for decreased ISI in the highest quartile of LF:HF ratio in non-overweight individuals being 2.09 (95% confidence interval, 1.41–3.10). Conclusions Reduced HRV was associated with insulin resistance and lower insulin sensitivity. Decreased ISI was linked with parasympathetic dysfunction, primarily in non-overweight individuals. PMID:26277879

  5. Hepatic circadian-clock system altered by insulin resistance, diabetes and insulin sensitizer in mice.

    PubMed

    Tseng, Huey-Ling; Yang, Shu-Chuan; Yang, Shih-Hsien; Shieh, Kun-Ruey

    2015-01-01

    Circadian rhythms are intrinsic rhythms that are coordinated with the rotation of the Earth and are also generated by a set of circadian-clock genes at the intracellular level. Growing evidence suggests a strong link between circadian rhythms and energy metabolism; however, the fundamental mechanisms remain unclear. In the present study, neonatal streptozotocin (STZ)-treated mice were used to model the molecular and physiological progress from insulin resistance to diabetes. Two-day-old male C57BL/6 mice received a single injection of STZ and were tested for non-obese, hyperglycemic and hyperinsulinemic conditions in the early stage, insulin resistance in the middle stage, and diabetes in the late stage. Gene expression levels of the hepatic circadian-clock system were examined by real-time quantitative PCR. Most of the components of the hepatic circadian-clock gene expression system, such as the mRNAs of Bmal1 (brain and muscle Arnt-like protein-1), Per2 (period 2) and Cry1 (cryptochrome 1), were elevated, and circadian patterns were retained in the early and middle stages of insulin-resistant conditions. The insulin sensitizer, rosiglitazone, returns the physiological and molecular changes associated with the diabetic phenotype to normal levels through peroxisome proliferator-activated receptor γ (PPARγ) rather than PPARα. Early and chronic treatment with rosiglitazone has been shown to be effective to counter the diabetic condition. Over time, this effect acts to attenuate the increased gene expression levels of the hepatic circadian-clock system and delay the severity of diabetic conditions. Together, these results support an essential role for the hepatic circadian-clock system in the coordinated regulation and/or response of metabolic pathways. PMID:25799429

  6. Hepatic Circadian-Clock System Altered by Insulin Resistance, Diabetes and Insulin Sensitizer in Mice

    PubMed Central

    Yang, Shih-Hsien; Shieh, Kun-Ruey

    2015-01-01

    Circadian rhythms are intrinsic rhythms that are coordinated with the rotation of the Earth and are also generated by a set of circadian-clock genes at the intracellular level. Growing evidence suggests a strong link between circadian rhythms and energy metabolism; however, the fundamental mechanisms remain unclear. In the present study, neonatal streptozotocin (STZ)-treated mice were used to model the molecular and physiological progress from insulin resistance to diabetes. Two-day-old male C57BL/6 mice received a single injection of STZ and were tested for non-obese, hyperglycemic and hyperinsulinemic conditions in the early stage, insulin resistance in the middle stage, and diabetes in the late stage. Gene expression levels of the hepatic circadian-clock system were examined by real-time quantitative PCR. Most of the components of the hepatic circadian-clock gene expression system, such as the mRNAs of Bmal1 (brain and muscle Arnt-like protein-1), Per2 (period 2) and Cry1 (cryptochrome 1), were elevated, and circadian patterns were retained in the early and middle stages of insulin-resistant conditions. The insulin sensitizer, rosiglitazone, returns the physiological and molecular changes associated with the diabetic phenotype to normal levels through peroxisome proliferator-activated receptor γ (PPARγ) rather than PPARα. Early and chronic treatment with rosiglitazone has been shown to be effective to counter the diabetic condition. Over time, this effect acts to attenuate the increased gene expression levels of the hepatic circadian-clock system and delay the severity of diabetic conditions. Together, these results support an essential role for the hepatic circadian-clock system in the coordinated regulation and/or response of metabolic pathways. PMID:25799429

  7. Mechanisms for greater insulin-stimulated glucose uptake in normal and insulin-resistant skeletal muscle after acute exercise.

    PubMed

    Cartee, Gregory D

    2015-12-15

    Enhanced skeletal muscle and whole body insulin sensitivity can persist for up to 24-48 h after one exercise session. This review focuses on potential mechanisms for greater postexercise and insulin-stimulated glucose uptake (ISGU) by muscle in individuals with normal or reduced insulin sensitivity. A model is proposed for the processes underlying this improvement; i.e., triggers initiate events that activate subsequent memory elements, which store information that is relayed to mediators, which translate memory into action by controlling an end effector that directly executes increased insulin-stimulated glucose transport. Several candidates are potential triggers or memory elements, but none have been conclusively verified. Regarding potential mediators in both normal and insulin-resistant individuals, elevated postexercise ISGU with a physiological insulin dose coincides with greater Akt substrate of 160 kDa (AS160) phosphorylation without improved proximal insulin signaling at steps from insulin receptor binding to Akt activity. Causality remains to be established between greater AS160 phosphorylation and improved ISGU. The end effector for normal individuals is increased GLUT4 translocation, but this remains untested for insulin-resistant individuals postexercise. Following exercise, insulin-resistant individuals can attain ISGU values similar to nonexercising healthy controls, but after a comparable exercise protocol performed by both groups, ISGU for the insulin-resistant group has been consistently reported to be below postexercise values for the healthy group. Further research is required to fully understand the mechanisms underlying the improved postexercise ISGU in individuals with normal or subnormal insulin sensitivity and to explain the disparity between these groups after similar exercise. PMID:26487009

  8. Insulin stimulation of hepatic triacylglycerol secretion and the etiology of insulin resistance.

    PubMed

    Zammit, V A; Waterman, I J; Topping, D; McKay, G

    2001-08-01

    The recent observations that insulin can either stimulate or inhibit triacylglycerol secretion by the liver, depending on prior metabolic (possibly insulinemic) state, have rationalized the many apparently contradictory observations, obtained over the past three decades, on the effects of the hormone on this aspect of hepatic metabolism. Extrapolation to the situation in vivo suggests that frequent stimulation of insulin secretion may result in a chronic stimulation of VLDL secretion, and increased delivery of acyl moieties to muscle, where they induce insulin resistance if provided in excess of the oxidative needs (mostly due to exercise) of the tissue. High fructose/sucrose diets, which also stimulate hepatic VLDL secretion, will have the same effect, especially if consumed frequently during the diurnal cycle. Due to the quantitative importance of muscle as a site for insulin-sensitive glucose metabolism, these effects may initiate the metabolic vicious cycle that results in the development of the metabolic syndrome, well in advance of overt obesity or the diagnosis of type-2 diabetes. PMID:11481396

  9. Vitamin D Supplementation Does Not Impact Insulin Resistance in Black and White Children.

    PubMed

    Ferira, Ashley J; Laing, Emma M; Hausman, Dorothy B; Hall, Daniel B; McCabe, George P; Martin, Berdine R; Hill Gallant, Kathleen M; Warden, Stuart J; Weaver, Connie M; Peacock, Munro; Lewis, Richard D

    2016-04-01

    This study sought to determine the dose-response effect of vitamin D supplementation on fasting glucose, insulin and insulin resistance in healthy children. We conclude that vitamin D had no impact on these measures after 12 weeks. PMID:26885880

  10. Role of insulin receptor substrate-1 serine 307 phosphorylation and adiponectin in adipose tissue insulin resistance in late pregnancy.

    PubMed

    Sevillano, Julio; de Castro, Javier; Bocos, Carlos; Herrera, Emilio; Ramos, M Pilar

    2007-12-01

    Insulin resistance is a hallmark of late pregnancy both in human and rat. Adipose tissue is one of the tissues that most actively contributes to this reduced insulin sensitivity. The aim of the present study was to characterize the molecular mechanisms of insulin resistance in adipose tissue at late pregnancy. To this end, we analyzed the insulin signaling cascade in lumbar adipose tissue of nonpregnant and pregnant (d 20) rats both under basal and insulin-stimulated conditions. We found that the levels of relevant signaling proteins, such as insulin receptor (IR), IR substrate-1 (IRS-1), phosphatidylinositol 3-kinase, 3-phosphoinositide-dependent kinase-1, ERK1/2, and phosphatase and tensin homolog (PTEN) did not change at late pregnancy. However, insulin-stimulated tyrosine phosphorylation of both IR and IRS-1 were significantly decreased, coincident with decreased IRS-1/p85 association and impaired phosphorylation of AKR mouse thymoma viral protooncogene (Akt) and ERK1/2. This impaired activation of IRS-1 occurred together with an increase of IRS-1 phosphorylation at serine 307 and a decrease in adiponectin levels. To corroborate the role of IRS-1 in adipose tissue insulin resistance during pregnancy, we treated pregnant rats with the antidiabetic drug englitazone. Englitazone improved glucose tolerance, and this pharmacological reversal of insulin resistance was paralleled by an increase of adiponectin levels in adipose tissue as well as by a reduction of IRS-1 serine phosphorylation. Furthermore, the impaired insulin-stimulated tyrosine phosphorylation of IRS-1 in adipose tissue of pregnant animals could be restored ex vivo by treating isolated adipocytes with adiponectin. Together, our findings support a role for adiponectin and serine phosphorylation of IRS-1 in the modulation of insulin resistance in adipose tissue at late pregnancy. PMID:17823255

  11. Exercise ameliorates insulin resistance via Ca2+ signals distinct from those of insulin for GLUT4 translocation in skeletal muscles.

    PubMed

    Park, Dae-Ryoung; Park, Kwang-Hyun; Kim, Byung-Ju; Yoon, Chung-Su; Kim, Uh-Hyun

    2015-04-01

    Muscle contraction and insulin induce glucose uptake in skeletal muscle through GLUT4 membrane translocation. Beneficial effects of exercise on glucose homeostasis in insulin-resistant individuals are known to be due to their distinct mechanism between contraction and insulin action on glucose uptake in skeletal muscle. However, the underlying mechanisms are not clear. Here we show that in skeletal muscle, distinct Ca(2+) second messengers regulate GLUT4 translocation by contraction and insulin treatment; d-myo-inositol 1,4,5-trisphosphate/nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose/NAADP are main players for insulin- and contraction-induced glucose uptake, respectively. Different patterns of phosphorylation of AMPK and Ca(2+)/calmodulin-dependent protein kinase II were shown in electrical stimuli (ES)- and insulin-induced glucose uptake pathways. ES-induced Ca(2+) signals and glucose uptake are dependent on glycolysis, which influences formation of NAD(P)-derived signaling messengers, whereas insulin-induced signals are not. High-fat diet (HFD) induced a defect in only insulin-mediated, but not ES-mediated, Ca(2+) signaling for glucose uptake, which is related to a specifically lower NAADP formation. Exercise decreases blood glucose levels in HFD-induced insulin resistance mice via NAADP formation. Thus we conclude that different usage of Ca(2+) signaling in contraction/insulin-stimulated glucose uptake in skeletal muscle may account for the mechanism by which exercise ameliorates glucose homeostasis in individuals with type 2 diabetes. PMID:25409702

  12. Insulin Resistance, Brain Atrophy, and Cognitive Performance in Late Middle–Aged Adults

    PubMed Central

    Willette, Auriel A.; Xu, Guofan; Johnson, Sterling C.; Birdsill, Alex C.; Jonaitis, Erin M.; Sager, Mark A.; Hermann, Bruce P.; La Rue, Asenath; Asthana, Sanjay; Bendlin, Barbara B.

    2013-01-01

    OBJECTIVE Insulin resistance dysregulates glucose uptake and other functions in brain areas affected by Alzheimer disease. Insulin resistance may play a role in Alzheimer disease etiopathogenesis. This longitudinal study examined whether insulin resistance among late middle–aged, cognitively healthy individuals was associated with 1) less gray matter in Alzheimer disease–sensitive brain regions and 2) worse cognitive performance. RESEARCH DESIGN AND METHODS Homeostasis model assessment of insulin resistance, gray matter volume, and the Rey Auditory Verbal Learning Test (RAVLT) were acquired in 372 participants at baseline and a consecutive subset of 121 individuals ~4 years later. Voxel-based morphometry and tensor-based morphometry were used, respectively, to test the association of insulin resistance with baseline brain volume and progressive gray matter atrophy. RESULTS Higher insulin resistance predicted less gray matter at baseline and 4 years later in medial temporal lobe, prefrontal cortices, precuneus, and other parietal gyri. A region-of-interest analysis, independent of the voxel-wise analyses, confirmed that higher insulin resistance was related to medial temporal lobe atrophy. Atrophy itself corresponded to cognitive deficits in the RAVLT. Temporal lobe atrophy that was predicted by higher insulin resistance significantly mediated worse RAVLT encoding performance. CONCLUSIONS These results suggest that insulin resistance in an asymptomatic, late middle–aged cohort is associated with progressive atrophy in regions affected by early Alzheimer disease. Insulin resistance may also affect the ability to encode episodic information by negatively influencing gray matter volume in medial temporal lobe. PMID:23069842

  13. Genetic Forms of Severe Insulin Resistance: What Endocrinologists Should Know

    PubMed Central

    Parker, Victoria E. R.; Semple, Robert K.

    2015-01-01

    Insulin resistance” is a widely used clinical term. It is usually defined as a state characterised by reduced glucose-lowering activity of insulin, but is also sometimes used as a shorthand label for a clinical syndrome encompassing major pathologies such as type 2 diabetes, polycystic ovary syndrome, fatty liver disease, and atherosclerosis. Nevertheless the precise cellular origins of insulin resistance (IR), the causal links among these phenomena, and the mechanisms underlying them, remain poorly understood or contentious. Prevalent IR usually results from a genetic predisposition interacting with acquired obesity, however even in some lean individuals very severe degrees of IR are seen. It is important to identify these people as they often harbour identifiable single gene defects, and they may benefit from molecular diagnosis, genetic counselling, and sometimes tailored therapies. Observation of people with known single gene defects also offers the opportunity to make inferences about the mechanistic links between IR and common pathologies. We now summarise the currently known monogenic forms of severe IR, with an emphasis on practical aspects of their recognition, diagnosis and management. In particular, we draw distinctions among the biochemical subphenotypes of IR that arise from primary adipose tissue dysfunction or from primary insulin signalling defects, and discuss the implications of this dichotomy for management. PMID:23857978

  14. Association Between Insulin Resistance and Luminal B Subtype Breast Cancer in Postmenopausal Women.

    PubMed

    Nam, Sanggeun; Park, Seho; Park, Hyung Seok; Kim, Sanghwa; Kim, Jee Ye; Kim, Seung Il

    2016-03-01

    Currently, there is limited information on the clinical characteristics of breast cancer patients with insulin resistance. Hence, the purpose of this study was to investigate the association between insulin resistance and clinicopathological factors in newly diagnosed breast cancer patients without diabetes. We assessed 760 patients with breast cancer treated between 2012 and 2014. We compared the clinicopathological characteristics between patients with and without insulin resistance using univariate and multivariate analyses, including after stratification by menopausal status. Insulin resistance was defined according to the homeostatic model assessment of insulin resistance. Of 760 patients, 26.4% had insulin resistance. Age, menopausal status, body mass index, tumor size, histologic grade, Ki-67 expression, and breast cancer subtype significantly differed according to the presence of insulin resistance. Multivariate analysis revealed that postmenopausal status and obesity were significantly associated with insulin resistance. In postmenopausal women, older age, obesity, larger tumor size, advanced stage, and high proliferative luminal B subtype were significantly associated with insulin resistance. In contrast, in premenopausal patients, only obesity was related to insulin resistance. Multivariate analysis indicated that insulin resistance was independently correlated with obesity, larger tumor size, and the luminal B/human epidermal growth factor receptor-2-negative subtype in postmenopausal but not premenopausal patients. Insulin resistance was significantly associated with larger tumors and proliferative luminal B subtype breast cancer in postmenopausal women only. These findings suggest that insulin resistance could mechanistically induce tumor progression and might be a good prognostic factor, and that it could represent a therapeutic target in postmenopausal patients with breast cancer. PMID:26945364

  15. Association Between Insulin Resistance and Luminal B Subtype Breast Cancer in Postmenopausal Women

    PubMed Central

    Nam, Sanggeun; Park, Seho; Park, Hyung Seok; Kim, Sanghwa; Kim, Jee Ye; Kim, Seung Il

    2016-01-01

    Abstract Currently, there is limited information on the clinical characteristics of breast cancer patients with insulin resistance. Hence, the purpose of this study was to investigate the association between insulin resistance and clinicopathological factors in newly diagnosed breast cancer patients without diabetes. We assessed 760 patients with breast cancer treated between 2012 and 2014. We compared the clinicopathological characteristics between patients with and without insulin resistance using univariate and multivariate analyses, including after stratification by menopausal status. Insulin resistance was defined according to the homeostatic model assessment of insulin resistance. Of 760 patients, 26.4% had insulin resistance. Age, menopausal status, body mass index, tumor size, histologic grade, Ki-67 expression, and breast cancer subtype significantly differed according to the presence of insulin resistance. Multivariate analysis revealed that postmenopausal status and obesity were significantly associated with insulin resistance. In postmenopausal women, older age, obesity, larger tumor size, advanced stage, and high proliferative luminal B subtype were significantly associated with insulin resistance. In contrast, in premenopausal patients, only obesity was related to insulin resistance. Multivariate analysis indicated that insulin resistance was independently correlated with obesity, larger tumor size, and the luminal B/human epidermal growth factor receptor-2-negative subtype in postmenopausal but not premenopausal patients. Insulin resistance was significantly associated with larger tumors and proliferative luminal B subtype breast cancer in postmenopausal women only. These findings suggest that insulin resistance could mechanistically induce tumor progression and might be a good prognostic factor, and that it could represent a therapeutic target in postmenopausal patients with breast cancer. PMID:26945364

  16. Mitochondrial involvement in skeletal muscle insulin resistance: A case of imbalanced bioenergetics.

    PubMed

    Affourtit, Charles

    2016-10-01

    Skeletal muscle insulin resistance in obesity associates with mitochondrial dysfunction, but the causality of this association is controversial. This review evaluates mitochondrial models of nutrient-induced muscle insulin resistance. It transpires that all models predict that insulin resistance arises as a result of imbalanced cellular bioenergetics. The nature and precise origin of the proposed insulin-numbing molecules differ between models but all species only accumulate when metabolic fuel supply outweighs energy demand. This observation suggests that mitochondrial deficiency in muscle insulin resistance is not merely owing to intrinsic functional defects, but could instead be an adaptation to nutrient-induced changes in energy expenditure. Such adaptive effects are likely because muscle ATP supply is fully driven by energy demand. This market-economic control of myocellular bioenergetics offers a mechanism by which insulin-signalling deficiency can cause apparent mitochondrial dysfunction, as insulin resistance lowers skeletal muscle anabolism and thus dampens ATP demand and, consequently, oxidative ATP synthesis. PMID:27473535

  17. Role of reduced insulin-stimulated bone blood flow in the pathogenesis of metabolic insulin resistance and diabetic bone fragility.

    PubMed

    Hinton, Pamela S

    2016-08-01

    Worldwide, 387 million adults live with type 2 diabetes (T2D) and an additional 205 million cases are projected by 2035. Because T2D has numerous complications, there is significant morbidity and mortality associated with the disease. Identification of early events in the pathogenesis of insulin resistance and T2D might lead to more effective treatments that would mitigate health and monetary costs. Here, we present our hypothesis that impaired bone blood flow is an early event in the pathogenesis of whole-body metabolic insulin resistance that ultimately leads to T2D. Two recent developments in different fields form the basis for this hypothesis. First, reduced vascular function has been identified as an early event in the development of T2D. In particular, before the onset of tissue or whole body metabolic insulin resistance, insulin-stimulated, endothelium-mediated skeletal muscle blood flow is impaired. Insulin resistance of the vascular endothelium reduces delivery of insulin and glucose to skeletal muscle, which leads to tissue and whole-body metabolic insulin resistance. Second is the paradigm-shifting discovery that the skeleton has an endocrine function that is essential for maintenance of whole-body glucose homeostasis. Specifically, in response to insulin signaling, osteoblasts secret osteocalcin, which stimulates pancreatic insulin production and enhances insulin sensitivity in skeletal muscle, adipose, and liver. Furthermore, the skeleton is not metabolically inert, but contributes to whole-body glucose utilization, consuming 20% that of skeletal muscle and 50% that of white adipose tissue. Without insulin signaling or without osteocalcin activity, experimental animals become hyperglycemic and insulin resistant. Currently, it is not known if insulin-stimulated, endothelium-mediated blood flow to bone plays a role in the development of whole body metabolic insulin resistance. We hypothesize that it is a key, early event. Microvascular dysfunction is a

  18. REGULATION OF OBESITY AND INSULIN RESISTANCE BY NITRIC OXIDE

    PubMed Central

    Sansbury, Brian E.; Hill, Bradford G.

    2014-01-01

    Obesity is a risk factor for developing type 2 diabetes and cardiovascular disease and has quickly become a world-wide pandemic with few tangible and safe treatment options. While it is generally accepted that the primary cause of obesity is energy imbalance, i.e., the calories consumed are greater than are utilized, understanding how caloric balance is regulated has proven a challenge. Many “distal” causes of obesity, such as the structural environment, occupation, and social influences, are exceedingly difficult to change or manipulate. Hence, molecular processes and pathways more proximal to the origins of obesity—those that directly regulate energy metabolism or caloric intake—appear to be more feasible targets for therapy. In particular, nitric oxide (NO) is emerging as a central regulator of energy metabolism and body composition. NO bioavailability is decreased in animal models of diet-induced obesity and in obese and insulin resistant patients, and increasing NO output has remarkable effects on obesity and insulin resistance. This review discusses the role of NO in regulating adiposity and insulin sensitivity and places its modes of action into context with the known causes and consequences of metabolic disease. PMID:24878261

  19. Relationship Between Glucocorticoids and Insulin Resistance in Healthy Individuals.

    PubMed

    Zhou, Peng-Zhen; Zhu, Yong-Mei; Zou, Guang-Hui; Sun, Yu-Xia; Xiu, Xiao-Lin; Huang, Xin; Zhang, Qun-Hui

    2016-01-01

    BACKGROUND The aim of this study was to determine the correlation between glucocorticoids (GCs) and insulin resistance (IR) in healthy individuals by conducting a systematic meta-analysis. MATERIAL AND METHODS A systematic literature review was conducted using 9 electronic databases. Only case-control studies investigating fasting plasma glucose (FPG) and IR were enrolled based on strictly established selection criteria. Statistical analyses were performed by Stata software, version 12.0 (Stata Corporation, College Station, Texas, USA). RESULTS Among 496 initially retrieved articles, only 6 papers published in English were eventually included in this meta-analysis. A total of 201 healthy individuals (105 in GC group and 96 in control group) were included in the 6 studies. In 4 of these 6 studies, dexamethasone was used, and in the other 2 studies prednisolone was given. This meta-analysis revealed that the FPG, fasting insulin (FINS), and homeostasis model assessment of insulin resistance (HOMA-IR) levels in the GC group were all significantly higher than that in the control group (FPG: SMD=2.65, 95%CI=1.42~3.88, P<0.001; FINS: SMD=2.48, 95%CI=1.01~3.95, P=0.001; HOMA-IR: SMD=38.30, 95%CI=24.38~52.22, P<0.001). CONCLUSIONS In conclusion, our present study revealed that therapies using GCs might result in elevated FPG, FINS, and HOMA-IR, and thereby contribute to IR in healthy individuals. PMID:27258456

  20. Relationship Between Glucocorticoids and Insulin Resistance in Healthy Individuals

    PubMed Central

    Zhou, Peng-Zhen; Zhu, Yong-Mei; Zou, Guang-Hui; Sun, Yu-Xia; Xiu, Xiao-Lin; Huang, Xin; Zhang, Qun-Hui

    2016-01-01

    Background The aim of this study was to determine the correlation between glucocorticoids (GCs) and insulin resistance (IR) in healthy individuals by conducting a systematic meta-analysis. Material/Methods A systematic literature review was conducted using 9 electronic databases. Only case-control studies investigating fasting plasma glucose (FPG) and IR were enrolled based on strictly established selection criteria. Statistical analyses were performed by Stata software, version 12.0 (Stata Corporation, College Station, Texas, USA). Results Among 496 initially retrieved articles, only 6 papers published in English were eventually included in this meta-analysis. A total of 201 healthy individuals (105 in GC group and 96 in control group) were included in the 6 studies. In 4 of these 6 studies, dexamethasone was used, and in the other 2 studies prednisolone was given. This meta-analysis revealed that the FPG, fasting insulin (FINS), and homeostasis model assessment of insulin resistance (HOMA-IR) levels in the GC group were all significantly higher than that in the control group (FPG: SMD=2.65, 95%CI=1.42~3.88, P<0.001; FINS: SMD=2.48, 95%CI=1.01~3.95, P=0.001; HOMA-IR: SMD=38.30, 95%CI=24.38~52.22, P<0.001). Conclusions In conclusion, our present study revealed that therapies using GCs might result in elevated FPG, FINS, and HOMA-IR, and thereby contribute to IR in healthy individuals. PMID:27258456

  1. Pseudohypoparathyroidism type 1a and insulin resistance in a child.

    PubMed

    Nwosu, Benjamin U; Lee, Mary M

    2009-06-01

    Background. A 5-year-old white girl with a history of hypothyroidism in infancy presented to the endocrinology clinic of a tertiary hospital. Her physical examination noted a stocky physique, broad chest, short neck and short digits. Two years later, skin examination revealed subcutaneous nodules and acanthosis nigricans.Investigations. Measurement of levels of serum phosphate, parathyroid hormone, ionized calcium and insulin; measurement of peak growth hormone by the arginine-levodopa stimulation test; calculation of homeostasis model assessment of insulin resistance; assessment of bone age; DNA analysis of the GNAS gene.Diagnosis. Pseudohypoparathyroidism type 1a in a patient with Albright hereditary osteodystrophy, characterized by hypocalcemia, hypothyroidism, growth-hormone deficiency and insulin resistance.Management. The child continued to take levothyroxine 25 microg once daily, and at 5 years of age she was started on 40 mg/kg elemental calcium as calcium carbonate daily, and calcitriol (active vitamin D) 0.25 microg twice daily. Lifestyle modifications were also recommended for weight control. At 6 years and 4 months of age, treatment with growth hormone was initiated at a dose of 0.3 mg/kg weekly. PMID:19465898

  2. A novel insulin receptor-signaling platform and its link to insulin resistance and type 2 diabetes.

    PubMed

    Alghamdi, Farah; Guo, Merry; Abdulkhalek, Samar; Crawford, Nicola; Amith, Schammim Ray; Szewczuk, Myron R

    2014-06-01

    Insulin-induced insulin receptor (IR) tyrosine kinase activation and insulin cell survival responses have been reported to be under the regulation of a membrane associated mammalian neuraminidase-1 (Neu1). The molecular mechanism(s) behind this process is unknown. Here, we uncover a novel Neu1 and matrix metalloproteinase-9 (MMP-9) cross-talk in alliance with neuromedin B G-protein coupled receptor (GPCR), which is essential for insulin-induced IR activation and cellular signaling. Neu1, MMP-9 and neuromedin B GPCR form a complex with IRβ subunit on the cell surface. Oseltamivir phosphate (Tamiflu®), anti-Neu1 antibodies, broad range MMP inhibitors piperazine and galardin (GM6001), MMP-9 specific inhibitor (MMP-9i), and GPCR neuromedin B specific antagonist BIM-23127 dose-dependently inhibited Neu1 activity associated with insulin stimulated rat hepatoma cells (HTCs) that overly express human IRs (HTC-IR). Tamiflu, anti-Neu1 antibodies and MMP-9i attenuated phosphorylation of IRβ and insulin receptor substrate-1 (IRS1) associated with insulin-stimulated cells. Olanzapine, an antipsychotic agent associated with insulin resistance, induced Neu3 sialidase activity in WG544 or 1140F01 human sialidosis fibroblast cells genetically defective in Neu1. Neu3 antagonist 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) and anti-Neu3 antibodies inhibited sialidase activity associated with olanzapine treated murine Neu4 knockout macrophage cells. Olanzapine attenuated phosphorylation of IGF-R and IRS1 associated with insulin-stimulated human wild-type fibroblast cells. Our findings identify a novel insulin receptor-signaling platform that is critically essential for insulin-induced IRβ tyrosine kinase activation and cellular signaling. Olanzapine-induced Neu3 sialidase activity attenuated insulin-induced IGF-R and IRS1 phosphorylation contributing to insulin resistance. PMID:24583283

  3. Genetic variation within IL18 is associated with insulin levels, insulin resistance and postprandial measures☆

    PubMed Central

    Smart, M.C.; Dedoussis, G.; Yiannakouris, N.; Grisoni, M.L.; Dror, G.K.; Yannakoulia, M.; Papoutsakis, C.; Louizou, E.; Mantzoros, C.S.; Melistas, L.; Kontogianni, M.D.; Cooper, J.A.; Humphries, S.E.; Talmud, P.J.

    2011-01-01

    Background and aims IL-18 expression is up-regulated in atherosclerotic plaques, and higher levels are seen in obese and Type 2 Diabetic individuals. More recently, a possible role for IL-18 in glucose and energy homeostasis has been suggested. Methods and results We investigated variation within the IL18 gene and its association with measures of obesity and the metabolic syndrome. Five IL18 tagging single nucleotide polymorphisms (rs1946519, rs2043055, rs549908, rs360729, rs3882891) were selected and genotyped in the Gene-Diet Attica Investigation on childhood obesity (GENDAI) (age range 10–14 yrs); in young European men in the second European Atherosclerosis Research offspring Study (EARSII), an offspring study (age range 18–28 yrs) and in a group of healthy women from the Greek Obese Women study (GrOW) (age range 18–74 yrs). Six common haplotypes were observed. In GrOW, Hap6 (Frequency-2.6%) was associated with higher insulin levels (p < 0.0001), estimates of HOMA-Insulin Resistance (p < 0.0001) and HOMA-β-cell (p < 0.0001) compared to the common haplotype Hap1 (Frequency-33.2%). In EARSII, rs2043055 was associated with peak and area under the curve triglycerides (p = 0.001 and p = 0.002, respectively) after an oral fat tolerance test in ‘cases’ but not ‘controls’. None of the haplotypes were associated with measures of body fatness in any of the studies. Conclusion Association of IL18 variation with insulin levels and estimates of insulin resistance were only observed in our adult study, suggesting that the effects of IL-18 are only associated with increasing age. Taken together with the association of IL18 variants with post-prandial measures, this provides support for IL-18 as a metabolic factor. PMID:20227263

  4. Blood glucose levels, insulin concentrations, and insulin resistance in healthy women and women with premenstrual syndrome: a comparative study

    PubMed Central

    Zarei, Safar; Mosalanejad, Leili

    2013-01-01

    Objective To compare the blood glucose levels, insulin concentrations, and insulin resistance during the two phases of the menstrual cycle between healthy women and patients with premenstrual syndrome (PMS). Methods From January of 2011 to the August of 2012, a descriptive cross-sectional study was performed among students in the School of Medicine of Jahrom University of Medical Sciences. We included 30 students with the most severe symptoms of PMS and 30 age frequency-matched healthy controls. We analyzed the serum concentrations of glucose, insulin, and insulin resistance by using the glucose oxidase method, radioimmunometric assay, and homeostasis model assessment of insulin resistance equation, respectively. Results No significant differences between the demographic data of the control and PMS groups were observed. The mean concentrations of glucose of the two study groups were significantly different during the follicular and luteal phases (p=0.011 vs. p<0.0001, respectively). The amounts of homeostasis model assessment of insulin resistance of the two study groups were significantly different in the luteal phase (p=0.0005). Conclusion The level of blood glucose and insulin resistance was lower during the two phases of the menstrual cycle of the PMS group than that of the controls. PMID:23875163

  5. Hypoglycemic effects and mechanisms of electroacupuncture on insulin resistance

    PubMed Central

    Yin, Jieyun; Kuang, Jian; Chandalia, Manisha; Tuvdendorj, Demidmaa; Tumurbaatar, Batbayar; Abate, Nicola

    2014-01-01

    The aim of this study was to investigate effects and mechanisms of electroacupuncture (EA) on blood glucose and insulin sensitivity in mice fed a high-fat diet. Both wild-type (WT) and adipose ectonucleotide pyrophosphate phosphodiesterase (ENPP1) transgenic (TG) mice were fed a high-fat diet for 12 wk; for each mouse, an intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT) were performed with or without EA at abdomen or auricular areas. A high-fat diet-induced insulin resistance in both WT and TG mice. In the WT mice, EA at 3 Hz and 15 Hz, but not at 1 Hz or 100 Hz, via CV4+CV12 significantly reduced postprandial glucose levels; EA at 3 Hz was most potent. The glucose level was reduced by 61.7% at 60 min and 74.5% at 120 min with EA at 3 Hz (all P < 0.001 vs. control). Similar hypoglycemic effect was noted in the TG mice. On the contrary, EA at auricular points increased postprandial glucose level (P < 0.03). 4). EA at 3 Hz via CV4+CV12 significantly enhanced the decrease of blood glucose after insulin injection, suggesting improvement of insulin sensitivity. Plasma free fatty acid was significantly suppressed by 42.5% at 15 min and 50.8% at 30 min with EA (P < 0.01) in both WT and TG mice. EA improves glucose tolerance in both WT and TG mice fed a high-fat diet, and the effect is associated with stimulation parameters and acupoints and is probably attributed to the reduction of free fatty acid. PMID:24848362

  6. Hypoglycemic effects and mechanisms of electroacupuncture on insulin resistance.

    PubMed

    Yin, Jieyun; Kuang, Jian; Chandalia, Manisha; Tuvdendorj, Demidmaa; Tumurbaatar, Batbayar; Abate, Nicola; Chen, Jiande D Z

    2014-08-01

    The aim of this study was to investigate effects and mechanisms of electroacupuncture (EA) on blood glucose and insulin sensitivity in mice fed a high-fat diet. Both wild-type (WT) and adipose ectonucleotide pyrophosphate phosphodiesterase (ENPP1) transgenic (TG) mice were fed a high-fat diet for 12 wk; for each mouse, an intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT) were performed with or without EA at abdomen or auricular areas. A high-fat diet-induced insulin resistance in both WT and TG mice. In the WT mice, EA at 3 Hz and 15 Hz, but not at 1 Hz or 100 Hz, via CV4+CV12 significantly reduced postprandial glucose levels; EA at 3 Hz was most potent. The glucose level was reduced by 61.7% at 60 min and 74.5% at 120 min with EA at 3 Hz (all P < 0.001 vs. control). Similar hypoglycemic effect was noted in the TG mice. On the contrary, EA at auricular points increased postprandial glucose level (P < 0.03). 4). EA at 3 Hz via CV4+CV12 significantly enhanced the decrease of blood glucose after insulin injection, suggesting improvement of insulin sensitivity. Plasma free fatty acid was significantly suppressed by 42.5% at 15 min and 50.8% at 30 min with EA (P < 0.01) in both WT and TG mice. EA improves glucose tolerance in both WT and TG mice fed a high-fat diet, and the effect is associated with stimulation parameters and acupoints and is probably attributed to the reduction of free fatty acid. PMID:24848362

  7. Silymarin ameliorates fructose induced insulin resistance syndrome by reducing de novo hepatic lipogenesis in the rat.

    PubMed

    Prakash, Prem; Singh, Vishal; Jain, Manish; Rana, Minakshi; Khanna, Vivek; Barthwal, Manoj Kumar; Dikshit, Madhu

    2014-03-15

    High dietary fructose causes insulin resistance syndrome (IRS), primarily due to simultaneous induction of genes involved in glucose, lipid and mitochondrial oxidative metabolism. The present study evaluates effect of a hepatoprotective agent, silymarin (SYM) on fructose-induced metabolic abnormalities in the rat and also assessed the associated thrombotic complications. Wistar rats were kept on high fructose (HFr) diet throughout the 12-week study duration (9 weeks of HFr feeding and subsequently 3 weeks of HFr plus SYM oral administration [once daily]). SYM treatment significantly reduced the HFr diet-induced increase expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α/β, peroxisome proliferator-activated receptor (PPAR)-α, forkhead box protein O1 (FOXO1), sterol regulatory element binding protein (SREBP)-1c, liver X receptor (LXR)-β, fatty acid synthase (FAS) and PPARγ genes in rat liver. SYM also reduced HFr diet mediated increase in plasma triglycerides (TG), non-esterified fatty acids (NEFA), uric acid, malondialdehyde (MDA), total nitrite and pro-inflammatory cytokines (C-reactive protein [CRP], interleukin-6 [IL-6], interferon-gamma [IFN-γ] and tumor necrosis factor [TNF]) levels. Moreover, SYM ameliorated HFr diet induced reduction in glucose utilization and endothelial dysfunction. Additionally, SYM significantly reduced platelet activation (adhesion and aggregation), prolonged ferric chloride-induced blood vessel occlusion time and protected against exacerbated myocardial ischemia reperfusion (MI-RP) injury. SYM treatment prevented HFr induced mRNA expression of hepatic PGC-1α/β and also its target transcription factors which was accompanied with recovery in insulin sensitivity and reduced propensity towards thrombotic complications and aggravated MI-RP injury. PMID:24486395

  8. Cocoa-rich diet ameliorates hepatic insulin resistance by modulating insulin signaling and glucose homeostasis in Zucker diabetic fatty rats.

    PubMed

    Cordero-Herrera, Isabel; Martín, María Ángeles; Escrivá, Fernando; Álvarez, Carmen; Goya, Luis; Ramos, Sonia

    2015-07-01

    Insulin resistance is the primary characteristic of type 2 diabetes and results from insulin signaling defects. Cocoa has been shown to exert anti-diabetic effects by lowering glucose levels. However, the molecular mechanisms responsible for this preventive activity and whether cocoa exerts potential beneficial effects on the insulin signaling pathway in the liver remain largely unknown. Thus, in this study, the potential anti-diabetic properties of cocoa on glucose homeostasis and insulin signaling were evaluated in type 2 diabetic Zucker diabetic fatty (ZDF) rats. Male ZDF rats were fed a control or cocoa-rich diet (10%), and Zucker lean animals received the control diet. ZDF rats supplemented with cocoa (ZDF-Co) showed a significant decrease in body weight gain, glucose and insulin levels, as well as an improved glucose tolerance and insulin resistance. Cocoa-rich diet further ameliorated the hepatic insulin resistance by abolishing the increased serine-phosphorylated levels of the insulin receptor substrate 1 and preventing the inactivation of the glycogen synthase kinase 3/glycogen synthase pathway in the liver of cocoa-fed ZDF rats. The anti-hyperglycemic effect of cocoa appeared to be at least mediated through the decreased levels of hepatic phosphoenolpyruvate carboxykinase and increased values of glucokinase and glucose transporter 2 in the liver of ZDF-Co rats. Moreover, cocoa-rich diet suppressed c-Jun N-terminal kinase and p38 activation caused by insulin resistance. These findings suggest that cocoa has the potential to alleviate both hyperglycemia and hepatic insulin resistance in type 2 diabetic ZDF rats. PMID:25814291

  9. Mammalian Tribbles homolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance

    PubMed Central

    Liu, Jiarong; Franklin, John L.; Messina, Joseph L.; Hill, Helliner S.; Moellering, Douglas R.; Walton, R. Grace; Martin, Mitchell; Garvey, W. Timothy

    2009-01-01

    Tribbles homolog 3 (TRIB3) was found to inhibit insulin-stimulated Akt phosphorylation and modulate gluconeogenesis in rodent liver. Currently, we examined a role for TRIB3 in skeletal muscle insulin resistance. Ten insulin-sensitive, ten insulin-resistant, and ten untreated type 2 diabetic (T2DM) patients were metabolically characterized by hyperinsulinemic euglycemic glucose clamps, and biopsies of vastus lateralis were obtained. Skeletal muscle samples were also collected from rodent models including streptozotocin (STZ)-induced diabetic rats, db/db mice, and Zucker fatty rats. Finally, L6 muscle cells were used to examine regulation of TRIB3 by glucose, and stable cell lines hyperexpressing TRIB3 were generated to identify mechanisms underlying TRIB3-induced insulin resistance. We found that 1) skeletal muscle TRIB3 protein levels are significantly elevated in T2DM patients; 2) muscle TRIB3 protein content is inversely correlated with glucose disposal rates and positively correlated with fasting glucose; 3) skeletal muscle TRIB3 protein levels are increased in STZ-diabetic rats, db/db mice, and Zucker fatty rats; 4) stable TRIB3 hyperexpression in muscle cells blocks insulin-stimulated glucose transport and glucose transporter 4 (GLUT4) translocation and impairs phosphorylation of Akt, ERK, and insulin receptor substrate-1 in insulin signal transduction; and 5) TRIB3 mRNA and protein levels are increased by high glucose concentrations, as well as by glucose deprivation in muscle cells. These data identify TRIB3 induction as a novel molecular mechanism in human insulin resistance and diabetes. TRIB3 acts as a nutrient sensor and could mediate the component of insulin resistance attributable to hyperglycemia (i.e., glucose toxicity) in diabetes. PMID:19996382

  10. Role of resistant starch in improving gut health, adiposity, and insulin resistance.

    PubMed

    Keenan, Michael J; Zhou, June; Hegsted, Maren; Pelkman, Christine; Durham, Holiday A; Coulon, Diana B; Martin, Roy J

    2015-03-01

    The realization that low-glycemic index diets were formulated using resistant starch led to more than a decade of research on the health effects of resistant starch. Determination of the metabolizable energy of the resistant starch product allowed for the performance of isocaloric studies. Fermentation of resistant starch in rodent studies results in what appears to be a healthier gut, demonstrated by increased amounts of short-chain fatty acids, an apparent positive change in the microbiota, and increased gene expression for gene products involved in normal healthy proliferation and apoptosis of potential cancer cells. Additionally, consumption of resistant starch was associated with reduced abdominal fat and improved insulin sensitivity. Increased serum glucagon-like peptide 1 (GLP-1) likely plays a role in promoting these health benefits. One rodent study that did not use isocaloric diets demonstrated that the use of resistant starch at 8% of the weight of the diet reduced body fat. This appears to be approximately equivalent to the human fiber requirement. In human subjects, insulin sensitivity is increased with the feeding of resistant starch. However, only 1 of several studies reports an increase in serum GLP-1 associated with resistant starch added to the diet. This means that other mechanisms, such as increased intestinal gluconeogenesis or increased adiponectin, may be involved in the promotion of improved insulin sensitivity. Future research may confirm that there will be improved health if human individuals consume the requirement for dietary fiber and a large amount of the fiber is fermentable. PMID:25770258

  11. Role of Resistant Starch in Improving Gut Health, Adiposity, and Insulin Resistance1234

    PubMed Central

    Keenan, Michael J; Zhou, June; Hegsted, Maren; Pelkman, Christine; Durham, Holiday A; Coulon, Diana B; Martin, Roy J

    2015-01-01

    The realization that low–glycemic index diets were formulated using resistant starch led to more than a decade of research on the health effects of resistant starch. Determination of the metabolizable energy of the resistant starch product allowed for the performance of isocaloric studies. Fermentation of resistant starch in rodent studies results in what appears to be a healthier gut, demonstrated by increased amounts of short-chain fatty acids, an apparent positive change in the microbiota, and increased gene expression for gene products involved in normal healthy proliferation and apoptosis of potential cancer cells. Additionally, consumption of resistant starch was associated with reduced abdominal fat and improved insulin sensitivity. Increased serum glucagon-like peptide 1 (GLP-1) likely plays a role in promoting these health benefits. One rodent study that did not use isocaloric diets demonstrated that the use of resistant starch at 8% of the weight of the diet reduced body fat. This appears to be approximately equivalent to the human fiber requirement. In human subjects, insulin sensitivity is increased with the feeding of resistant starch. However, only 1 of several studies reports an increase in serum GLP-1 associated with resistant starch added to the diet. This means that other mechanisms, such as increased intestinal gluconeogenesis or increased adiponectin, may be involved in the promotion of improved insulin sensitivity. Future research may confirm that there will be improved health if human individuals consume the requirement for dietary fiber and a large amount of the fiber is fermentable. PMID:25770258

  12. Insulin sensitizers prevent fine particulate matter-induced vascular insulin resistance and changes in endothelial progenitor cell homeostasis.

    PubMed

    Haberzettl, Petra; McCracken, James P; Bhatnagar, Aruni; Conklin, Daniel J

    2016-06-01

    Exposure to fine particular matter (PM2.5) increases the risk of developing cardiovascular disease and Type 2 diabetes. Because blood vessels are sensitive targets of air pollutant exposure, we examined the effects of concentrated ambient PM2.5 (CAP) on vascular insulin sensitivity and circulating levels of endothelial progenitor cells (EPCs), which reflect cardiovascular health. We found that CAP exposure for 9 days decreased insulin-stimulated Akt phosphorylation in the aorta of mice maintained on control diet. This change was accompanied by the induction of IL-1β and increases in the abundance of cleaved IL-18 and p10 subunit of Casp-1, consistent with the activation of the inflammasome pathway. CAP exposure also suppressed circulating levels of EPCs (Flk-1(+)/Sca-1(+) cells), while enhancing the bone marrow abundance of these cells. Although similar changes in vascular insulin signaling and EPC levels were observed in mice fed high-fat diet, CAP exposure did not exacerbate diet-induced changes in vascular insulin resistance or EPC homeostasis. Treatment with an insulin sensitizer, metformin or rosiglitazone, prevented CAP-induced vascular insulin resistance and NF-κB and inflammasome activation and restored peripheral blood and bone marrow EPC levels. These findings suggest that PM2.5 exposure induces diet-independent vascular insulin resistance and inflammation and prevents EPC mobilization, and that this EPC mobilization defect could be mediated by vascular insulin resistance. Impaired vascular insulin sensitivity may be an important mechanism underlying PM2.5-induced vascular injury, and pharmacological sensitization to insulin action could potentially prevent deficits in vascular repair and mitigate vascular inflammation due to exposure to elevated levels of ambient air pollution. PMID:27016579

  13. Role of cardiotrophin-1 in obesity and insulin resistance

    PubMed Central

    Moreno-Aliaga, María J.; Romero-Lozano, M. Asunción; Castaño, David; Prieto, Jesús; Bustos, Matilde

    2012-01-01

    Cardiotrophin-1 (CT-1) is a member of the gp130 family of cytokines. In a recent study we examined the metabolic features of ct-1 null mice and the effects on body composition, glucose and lipid metabolism of acute and chronic administration of recombinant CT-1. Our data revealed that CT-1 is a key regulator of energy metabolism with potential applications in the treatment of obesity and the metabolic syndrome. This commentary discusses the significance of these findings in the context of other key studies in the field of obesity and insulin resistance. PMID:23700521

  14. Is this patient insulin resistant? How much does it matter?

    PubMed

    Sheeder, Jeanelle; Travers, Sharon H; Stevens-Simon, Catherine

    2003-01-01

    Alex was an obese 10-year-old girl with a family history of type 2 diabetes, hypertension, and perhaps polycystic ovarian syndrome. Her physical examination was significant for a central accumulation of body fat and acanthosis nigricans. Although the laboratory studies indicated that Alex was not diabetic and probably not glucose intolerant, she could be insulin resistant (IR). Should any further evaluation be done? If Alex is IR, what kind of treatment should be offered? The following discussion addresses these questions by reviewing the pathophysiology, diagnosis, and consequences of isolated IR. PMID:14686557

  15. Atherogenic dyslipidemia associated with metabolic syndrome and insulin resistance.

    PubMed

    Grundy, Scott M

    2006-01-01

    Atherogenic dyslipidemia, a component of metabolic syndrome, is characterized by high levels of apolipoprotein B (apo B)-containing lipoproteins, including very-low-density lipoprotein remnants and small low-density lipoprotein particles, and reduced levels of high-density lipoprotein cholesterol. Although the National Cholesterol Education Program Adult Treatment Panel III includes elevations in blood pressure and plasma glucose in the definition of metabolic syndrome, the broader scope of metabolic syndrome includes proinflammatory and prothrombotic states, which derive from the secretory activity of adipose tissue. Abdominal fat can adversely affect insulin action and the disposal of glucose through an increase in the release of free fatty acid, resulting in accumulation of triglyceride in muscle and liver, thereby depressing insulin action and increasing output of apo B-containing lipoproteins. Impaired regulation of adipokines, bioactive substances secreted from adipose tissue, likely produces systemic inflammation, which can promote atherogenesis. Insulin resistance is recognized as an important metabolic defect linking the components of metabolic syndrome. One molecule that may play an important role in metabolic syndrome to regulate metabolic and vascular pathways is the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Studies have established PPAR-gamma deficiency as a cause of lipodystrophy and confirmed its adipogenic role. Patients with atherogenic dyslipidemia and metabolic syndrome should undergo global risk assessment for cardiovascular disease and future cardiovascular events to determine an overall treatment strategy. PMID:16903166

  16. Therapeutic targets of brain insulin resistance in sporadic Alzheimer's disease

    PubMed Central

    de la Monte, Suzanne M.

    2015-01-01

    Growing evidence supports roles for brain insulin and insulin-like growth factor (IGF) resistance and metabolic dysfunction in the pathogenesis of Alzheimer's disease (AD). Whether the underlying problem stems from a primary disorder of central nervous system (CNS) neurons and glia, or secondary effects of systemic diseases such as obesity, Type 2 diabetes, or metabolic syndrome, the end-results include impaired glucose utilization, mitochondrial dysfunction, increased oxidative stress, neuroinflammation, and the propagation of cascades that result in the accumulation of neurotoxic misfolded, aggregated, and ubiquitinated fibrillar proteins. This article reviews the roles of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism, and discusses therapeutic strategies and lifestyle approaches that could be used to prevent, delay the onset, or reduce the severity of AD. Finally, it is critical to recognize that AD is heterogeneous and has a clinical course that fully develops over a period of several decades. Therefore, early and multi-modal preventive and treatment approaches should be regarded as essential. PMID:22201977

  17. Developmental Programming by Maternal Insulin Resistance: Hyperinsulinemia, Glucose Intolerance, and Dysregulated Lipid Metabolism in Male Offspring of Insulin-Resistant Mice

    PubMed Central

    Isganaitis, Elvira; Woo, Melissa; Ma, Huijuan; Chen, Michael; Kong, Wen; Lytras, Aristides; Sales, Vicencia; DeCoste-Lopez, Jennifer; Lee, Kyung-Ju; Leatherwood, Cianna; Lee, Deborah; Fitzpatrick, Connor; Gall, Walter; Watkins, Steven; Patti, Mary-Elizabeth

    2014-01-01

    Maternal obesity and gestational diabetes mellitus (GDM) are associated with obesity and diabetes risk in offspring. We tested whether maternal insulin resistance, which frequently coexists with GDM and obesity, could independently contribute to dysregulation of offspring metabolism. Female mice haploinsufficient for insulin receptor substrate-1 (IRS1-het) are hyperinsulinemic and insulin resistant during pregnancy, despite normal plasma glucose and body weight, and thus serve as a model of isolated maternal insulin resistance. Wild-type (WT) offspring of IRS1-het dams insulin resistance-exposed [IR-exposed] were compared with WT offspring of WT dams. Despite no differences in adiposity, male IR-exposed pups were glucose intolerant (P = 0.04) and hyperinsulinemic (1.3-fold increase, P = 0.02) by 1 month of age and developed progressive fasting hyperglycemia. Moreover, male IR-exposed pups challenged with high-fat diet exhibited insulin resistance. Liver lipidomic analysis of 3-week-old IR-exposed males revealed increases in the 16:1n7 fraction of several lipid classes, suggesting increased Scd1 activity. By 6 months of age, IR-exposed males had increased lipid accumulation in liver as well as increased plasma refed fatty acids, consistent with disrupted lipid metabolism. Our results indicate that isolated maternal insulin resistance, even in the absence of hyperglycemia or obesity, can promote metabolic perturbations in male offspring. PMID:24186867

  18. Human gut microbes impact host serum metabolome and insulin sensitivity.

    PubMed

    Pedersen, Helle Krogh; Gudmundsdottir, Valborg; Nielsen, Henrik Bjørn; Hyotylainen, Tuulia; Nielsen, Trine; Jensen, Benjamin A H; Forslund, Kristoffer; Hildebrand, Falk; Prifti, Edi; Falony, Gwen; Le Chatelier, Emmanuelle; Levenez, Florence; Doré, Joel; Mattila, Ismo; Plichta, Damian R; Pöhö, Päivi; Hellgren, Lars I; Arumugam, Manimozhiyan; Sunagawa, Shinichi; Vieira-Silva, Sara; Jørgensen, Torben; Holm, Jacob Bak; Trošt, Kajetan; Kristiansen, Karsten; Brix, Susanne; Raes, Jeroen; Wang, Jun; Hansen, Torben; Bork, Peer; Brunak, Søren; Oresic, Matej; Ehrlich, S Dusko; Pedersen, Oluf

    2016-07-21

    Insulin resistance is a forerunner state of ischaemic cardiovascular disease and type 2 diabetes. Here we show how the human gut microbiome impacts the serum metabolome and associates with insulin resistance in 277 non-diabetic Danish individuals. The serum metabolome of insulin-resistant individuals is characterized by increased levels of branched-chain amino acids (BCAAs), which correlate with a gut microbiome that has an enriched biosynthetic potential for BCAAs and is deprived of genes encoding bacterial inward transporters for these amino acids. Prevotella copri and Bacteroides vulgatus are identified as the main species driving the association between biosynthesis of BCAAs and insulin resistance, and in mice we demonstrate that P. copri can induce insulin resistance, aggravate glucose intolerance and augment circulating levels of BCAAs. Our findings suggest that microbial targets may have the potential to diminish insulin resistance and reduce the incidence of common metabolic and cardiovascular disorders. PMID:27409811

  19. Sustained βAR Stimulation Mediates Cardiac Insulin Resistance in a PKA-Dependent Manner.

    PubMed

    Mangmool, Supachoke; Denkaew, Tananat; Phosri, Sarawuth; Pinthong, Darawan; Parichatikanond, Warisara; Shimauchi, Tsukasa; Nishida, Motohiro

    2016-01-01

    Insulin resistance is a condition in which cells are defective in response to the actions of insulin in tissue glucose uptake. Overstimulation of β-adrenergic receptors (βARs) leads to the development of heart failure and is associated with the pathogenesis of insulin resistance in the heart. However, the mechanisms by which sustained βAR stimulation affects insulin resistance in the heart are incompletely understood. In this study, we demonstrate that sustained βAR stimulation resulted in the inhibition of insulin-induced glucose uptake, and a reduction of insulin induced glucose transporter (GLUT)4 expression that were mediated by the β2AR subtype in cardiomyocytes and heart tissue. Overstimulation of β2AR inhibited the insulin-induced translocation of GLUT4 to the plasma membrane of cardiomyocytes. Additionally, βAR mediated cardiac insulin resistance by reducing glucose uptake and GLUT4 expression via the cAMP-dependent and protein kinase A-dependent pathways. Treatment with β-blockers, including propranolol and metoprolol antagonized isoproterenol-mediated insulin resistance in the heart. The data in this present study confirm a critical role for protein kinase A in βAR-mediated insulin resistance. PMID:26652903

  20. Severe Brown Fat Lipoatrophy Aggravates Atherosclerotic Process in Male Mice.

    PubMed

    Gómez-Hernández, Almudena; Beneit, Nuria; Escribano, Óscar; Díaz-Castroverde, Sabela; García-Gómez, Gema; Fernández, Silvia; Benito, Manuel

    2016-09-01

    Obesity is one of the major risk factors for the development of cardiovascular diseases and is characterized by abnormal accumulation of adipose tissue, including perivascular adipose tissue (PVAT). However, brown adipose tissue (BAT) activation reduces visceral adiposity. To demonstrate that severe brown fat lipoatrophy might accelerate atherosclerotic process, we generated a new mouse model without insulin receptor (IR) in BAT and without apolipoprotein (Apo)E (BAT-specific IR knockout [BATIRKO];ApoE(-/-) mice) and assessed vascular and metabolic alterations associated to obesity. In addition, we analyzed the contribution of the adipose organ to vascular inflammation. Brown fat lipoatrophy induces visceral adiposity, mainly in gonadal depot (gonadal white adipose tissue [gWAT]), severe glucose intolerance, high postprandial glucose levels, and a severe defect in acute insulin secretion. BATIRKO;ApoE(-/-) mice showed greater hypertriglyceridemia than the obtained in ApoE(-/-) and hypercholesterolemia similar to ApoE(-/-) mice. BATIRKO;ApoE(-/-) mice, in addition to primary insulin resistance in BAT, also showed a significant decrease in insulin signaling in liver, gWAT, heart, aorta artery, and thoracic PVAT. More importantly, our results suggest that severe brown fat lipoatrophy aggravates the atherosclerotic process, characterized by a significant increase of lipid depots, atherosclerotic coverage, lesion size and complexity, increased macrophage infiltration, and proinflammatory markers expression. Finally, an increase of TNF-α and leptin as well as a decrease of adiponectin by BAT, gWAT, and thoracic PVAT might also be responsible of vascular damage. Our results suggest that severe brown lipoatrophy aggravates atherosclerotic process. Thus, BAT activation might protect against obesity and its associated metabolic alterations. PMID:27414981

  1. Hyperandrogenism-Insulin Resistance-Acanthosis Nigricans Syndrome

    PubMed Central

    Dédjan, A. H.; Chadli, A.; El Aziz, S.; Farouqi, A.

    2015-01-01

    Introduction. Female hyperandrogenism is a frequent motive of consultation. It is revealed by hirsutism, acne or seborrhea, and disorders in menstruation cycle combined or not with virilisation signs. Several etiologies are incriminated but the hyperandrogenism-insulin resistance-acanthosis nigricans syndrome is rare. Observation. A 20-year-old girl, having had a five-year-old secondary amenorrhea. The exam revealed a patient, normotensive with a body mass index at 30 kg/m2 and a waist measurement of 120 cm, a severe hirsutism assessed to be 29 according to Ferriman Gallwey scale, virilisation signs of male morphotype, clitoridic hypertrophy and frontal alopecia, and an acanthosis nigricans behind the neck, in the armpits and elbows. The assessment carried out revealed testosteronemia at 1.28 ng/mL, which is more than twice the upper norm of the laboratory. Imaging studies were negative for both ovarian and adrenal masses. The retained diagnosis is HAIR-AN syndrome probably related to ovarian hyperthecosis and she was provided with androcur 50 mg/day and estradiol pills 2 mg/day and under hygiene-dietetic conditions. Conclusion. This case proves that HAIR-AN syndrome could be responsible for severe hyperandrogenism with virilisation signs. It must be retained after discarding the tumoral causes and when there are signs of insulin resistance. PMID:26229697

  2. Protein Carbonylation, Mitochondrial Dysfunction, and Insulin Resistance123

    PubMed Central

    Frohnert, Brigitte I.; Bernlohr, David A.

    2013-01-01

    Oxidative stress has been identified as a common mechanism for cellular damage and dysfunction in a wide variety of disease states. Current understanding of the metabolic changes associated with obesity and the development of insulin resistance has focused on the role of oxidative stress and its interaction with inflammatory processes at both the tissue and organismal level. Obesity-related oxidative stress is an important contributing factor in the development of insulin resistance in the adipocyte as well as the myocyte. Moreover, oxidative stress has been linked to mitochondrial dysfunction, and this is thought to play a role in the metabolic defects associated with oxidative stress. Of the various effects of oxidative stress, protein carbonylation has been identified as a potential mechanism underlying mitochondrial dysfunction. As such, this review focuses on the relationship between protein carbonylation and mitochondrial biology and addresses those features that point to either the causal or casual relationship of lipid peroxidation–induced protein carbonylation as a determining factor in mitochondrial dysfunction. PMID:23493532

  3. Maternal and Perinatal Outcomes in Women with Insulin Resistance.

    PubMed

    Temming, Lorene A; Tuuli, Methodius G; Stout, Molly J; Macones, George A; Cahill, Alison G

    2016-07-01

    Objective This study aims to estimate the risks of adverse maternal and perinatal outcomes in women with insulin resistance below the threshold of gestational diabetes mellitus (GDM). Methods This was a retrospective cohort study of 5,983 women with singleton pregnancies undergoing universal GDM screening between 24 and 28 weeks gestation. Subjects were divided into those with a normal 1-hour glucose challenge test (GCT), those with an elevated GCT with all normal values on a 3-hour glucose tolerance test (GTT), and those with an elevated GCT with one abnormal value on GTT. Outcomes included macrosomia, pregnancy-induced hypertension (PIH), cesarean section and operative delivery, shoulder dystocia, indicated-preterm birth, and other neonatal outcomes. Logistic regression was performed to compare outcomes among groups. Results The risk of macrosomia was increased for those with an elevated GCT and all normal values on GTT (adjusted odds ratio [aOR], 1.71; 95% confidence interval [CI]: 1.12, 1.97), and for those with an elevated GCT and one abnormal value (aOR, 2.69; 95% CI: 1.49, 4.83). Risks of PIH, cesarean section, and indicated-preterm birth were also increased in those with an elevated 1-hour GCT and no GDM. Conclusion There are increased risks of macrosomia, PIH, indicated-preterm birth, and cesarean section among those with insulin resistance even in the absence of GDM. PMID:26906185

  4. Insulin sensitivity indices: a proposal of cut-off points for simple identification of insulin-resistant subjects.

    PubMed

    Radikova, Z; Koska, J; Huckova, M; Ksinantova, L; Imrich, R; Vigas, M; Trnovec, T; Langer, P; Sebokova, E; Klimes, I

    2006-05-01

    Demanding measurement of insulin sensitivity using clamp methods does not simplify the identification of insulin resistant subjects in the general population. Other approaches such as fasting- or oral glucose tolerance test-derived insulin sensitivity indices were proposed and validated with the euglycemic clamp. Nevertheless, a lack of reference values for these indices prevents their wider use in epidemiological studies and clinical practice. The aim of our study was therefore to define the cut-off points of insulin resistance indices as well as the ranges of the most frequently obtained values for selected indices. A standard 75 g oral glucose tolerance test was carried out in 1156 subjects from a Caucasian rural population with no previous evidence of diabetes or other dysglycemias. Insulin resistance/sensitivity indices (HOMA-IR, HOMA-IR2, ISI Cederholm, and ISI Matsuda) were calculated. The 75th percentile value as the cut-off point to define IR corresponded with a HOMA-IR of 2.29, a HOMA-IR2 of 1.21, a 25th percentile for ISI Cederholm, and ISI Matsuda of 57 and 5.0, respectively. For the first time, the cut-off points for selected indices and their most frequently obtained values were established for groups of subjects as defined by glucose homeostasis and BMI. Thus, insulin-resistant subjects can be identified using this simple approach. PMID:16804799

  5. Molecular characterization of insulin resistance and glycolytic metabolism in the rat uterus.

    PubMed

    Zhang, Yuehui; Sun, Xue; Sun, Xiaoyan; Meng, Fanci; Hu, Min; Li, Xin; Li, Wei; Wu, Xiao-Ke; Brännström, Mats; Shao, Ruijin; Billig, Håkan

    2016-01-01

    Peripheral insulin resistance and hyperandrogenism are the primary features of polycystic ovary syndrome (PCOS). However, how insulin resistance and hyperandrogenism affect uterine function and contribute to the pathogenesis of PCOS are open questions. We treated rats with insulin alone or in combination with human chorionic gonadotropin (hCG) and showed that peripheral insulin resistance and hyperandrogenism alter uterine morphology, cell phenotype, and cell function, especially in glandular epithelial cells. These defects are associated with an aberration in the PI3K/Akt signaling pathway that is used as an indicator for the onset of insulin resistance in classical metabolic tissues. Concomitantly, increased GSK3β (Ser-9) phosphorylation and decreased ERK1/2 phosphorylation in rats treated with insulin and hCG were also observed. We also profiled the expression of glucose transporter (Glut) isoform genes in the uterus under conditions of insulin resistance and/or hyperandrogenism. Finally, we determined the expression pattern of glycolytic enzymes and intermediates during insulin resistance and hyperandrogenism in the uterus. These findings suggest that the PI3K/Akt and MAPK/ERK signaling pathways play a role in the onset of uterine insulin resistance, and they also suggest that changes in specific Glut isoform expression and alterations to glycolytic metabolism contribute to the endometrial dysfunction observed in PCOS patients. PMID:27461373

  6. Molecular characterization of insulin resistance and glycolytic metabolism in the rat uterus

    PubMed Central

    Zhang, Yuehui; Sun, Xue; Sun, Xiaoyan; Meng, Fanci; Hu, Min; Li, Xin; Li, Wei; Wu, Xiao-Ke; Brännström, Mats; Shao, Ruijin; Billig, Håkan

    2016-01-01

    Peripheral insulin resistance and hyperandrogenism are the primary features of polycystic ovary syndrome (PCOS). However, how insulin resistance and hyperandrogenism affect uterine function and contribute to the pathogenesis of PCOS are open questions. We treated rats with insulin alone or in combination with human chorionic gonadotropin (hCG) and showed that peripheral insulin resistance and hyperandrogenism alter uterine morphology, cell phenotype, and cell function, especially in glandular epithelial cells. These defects are associated with an aberration in the PI3K/Akt signaling pathway that is used as an indicator for the onset of insulin resistance in classical metabolic tissues. Concomitantly, increased GSK3β (Ser-9) phosphorylation and decreased ERK1/2 phosphorylation in rats treated with insulin and hCG were also observed. We also profiled the expression of glucose transporter (Glut) isoform genes in the uterus under conditions of insulin resistance and/or hyperandrogenism. Finally, we determined the expression pattern of glycolytic enzymes and intermediates during insulin resistance and hyperandrogenism in the uterus. These findings suggest that the PI3K/Akt and MAPK/ERK signaling pathways play a role in the onset of uterine insulin resistance, and they also suggest that changes in specific Glut isoform expression and alterations to glycolytic metabolism contribute to the endometrial dysfunction observed in PCOS patients. PMID:27461373

  7. Anesthesia with propofol induces insulin resistance systemically in skeletal and cardiac muscles and liver of rats

    SciTech Connect

    Yasuda, Yoshikazu; Fukushima, Yuji; Kaneki, Masao; Martyn, J.A. Jeevendra

    2013-02-01

    Highlights: ► Propofol, as a model anesthetic drug, induced whole body insulin resistance. ► Propofol anesthesia decreased glucose infusion rate to maintain euglycemia. ► Propofol decreased insulin-mediated glucose uptake in skeletal and cardiac muscles. ► Propofol increased hepatic glucose output confirming hepatic insulin resistance. -- Abstract: Hyperglycemia together with hepatic and muscle insulin resistance are common features in critically ill patients, and these changes are associated with enhanced inflammatory response, increased susceptibility to infection, muscle wasting, and worsened prognosis. Tight blood glucose control by intensive insulin treatment may reduce the morbidity and mortality in intensive care units. Although some anesthetics have been shown to cause insulin resistance, it remains unknown how and in which tissues insulin resistance is induced by anesthetics. Moreover, the effects of propofol, a clinically relevant intravenous anesthetic, also used in the intensive care unit for sedation, on insulin sensitivity have not yet been investigated. Euglycemic hyperinsulinemic clamp study was performed in rats anesthetized with propofol and conscious unrestrained rats. To evaluate glucose uptake in tissues and hepatic glucose output [{sup 3}H]glucose and 2-deoxy[{sup 14}C]glucose were infused during the clamp study. Anesthesia with propofol induced a marked whole-body insulin resistance compared with conscious rats, as reflected by significantly decreased glucose infusion rate to maintain euglycemia. Insulin-stimulated tissue glucose uptake was decreased in skeletal muscle and heart, and hepatic glucose output was increased in propofol anesthetized rats. Anesthesia with propofol induces systemic insulin resistance along with decreases in insulin-stimulated glucose uptake in skeletal and heart muscle and attenuation of the insulin-mediated suppression of hepatic glucose output in rats.

  8. Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance

    PubMed Central

    Choi, Cheol Soo; Fillmore, Jonathan J.; Kim, Jason K.; Liu, Zhen-Xiang; Kim, Sheene; Collier, Emily F.; Kulkarni, Ameya; Distefano, Alberto; Hwang, Yu-Jin; Kahn, Mario; Chen, Yan; Yu, Chunli; Moore, Irene K.; Reznick, Richard M.; Higashimori, Takamasa; Shulman, Gerald I.

    2007-01-01

    Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and is strongly associated with obesity. Increased concentrations of intracellular fatty acid metabolites have been postulated to interfere with insulin signaling by activation of a serine kinase cascade involving PKCθ in skeletal muscle. Uncoupling protein 3 (UCP3) has been postulated to dissipate the mitochondrial proton gradient and cause metabolic inefficiency. We therefore hypothesized that overexpression of UCP3 in skeletal muscle might protect against fat-induced insulin resistance in muscle by conversion of intramyocellular fat into thermal energy. Wild-type mice fed a high-fat diet were markedly insulin resistant, a result of defects in insulin-stimulated glucose uptake in skeletal muscle and hepatic insulin resistance. Insulin resistance in these tissues was associated with reduced insulin-stimulated insulin receptor substrate 1– (IRS-1–) and IRS-2–associated PI3K activity in muscle and liver, respectively. In contrast, UCP3-overexpressing mice were completely protected against fat-induced defects in insulin signaling and action in these tissues. Furthermore, these changes were associated with a lower membrane-to-cytosolic ratio of diacylglycerol and reduced PKCθ activity in whole-body fat–matched UCP3 transgenic mice. These results suggest that increasing mitochondrial uncoupling in skeletal muscle may be an excellent therapeutic target for type 2 diabetes mellitus. PMID:17571165

  9. Hepatocyte-Specific Ptpn6 Deletion Protects From Obesity-Linked Hepatic Insulin Resistance

    PubMed Central

    Xu, Elaine; Charbonneau, Alexandre; Rolland, Yannève; Bellmann, Kerstin; Pao, Lily; Siminovitch, Katherine A.; Neel, Benjamin G.; Beauchemin, Nicole; Marette, André

    2012-01-01

    The protein-tyrosine phosphatase Shp1 negatively regulates insulin action on glucose homeostasis in liver and muscle, but its potential role in obesity-linked insulin resistance has not been examined. To investigate the role of Shp1 in hepatic insulin resistance, we generated hepatocyte-specific Shp1 knockout mice (Ptpn6H-KO), which were subjected to extensive metabolic monitoring throughout an 8-week standard chow diet (SD) or high-fat diet (HFD) feeding. We report for the first time that Shp1 expression is upregulated in metabolic tissues of HFD-fed obese mice. When compared with their Shp1-expressing Ptpn6f/f littermates, Ptpn6H-KO mice exhibited significantly lowered fasting glycemia and heightened hepatic insulin sensitivity. After HFD feeding, Ptpn6H-KO mice developed comparable levels of obesity as Ptpn6f/f mice, but they were remarkably protected from liver insulin resistance, as revealed by euglycemic clamps and hepatic insulin signaling determinations. Although Ptpn6H-KO mice still acquired diet-induced peripheral insulin resistance, they were less hyperinsulinemic during a glucose tolerance test because of reduced insulin secretion. Ptpn6H-KO mice also exhibited increased insulin clearance in line with enhanced CC1 tyrosine phosphorylation in liver. These results show that hepatocyte Shp1 plays a critical role in the development of hepatic insulin resistance and represents a novel therapeutic target for obesity-linked diabetes. PMID:22698917

  10. Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance

    PubMed Central

    Iovino, Salvatore; Burkart, Alison M.; Warren, Laura; Patti, Mary Elizabeth; Kahn, C. Ronald

    2016-01-01

    Induced pluripotent stem cells (iPS cells) represent a unique tool for the study of the pathophysiology of human disease, because these cells can be differentiated into multiple cell types in vitro and used to generate patient- and tissue-specific disease models. Given the critical role for skeletal muscle insulin resistance in whole-body glucose metabolism and type 2 diabetes, we have created a novel cellular model of human muscle insulin resistance by differentiating iPS cells from individuals with mutations in the insulin receptor (IR-Mut) into functional myotubes and characterizing their response to insulin in comparison with controls. Morphologically, IR-Mut cells differentiated normally, but had delayed expression of some muscle differentiation-related genes. Most importantly, whereas control iPS-derived myotubes exhibited in vitro responses similar to primary differentiated human myoblasts, IR-Mut myotubes demonstrated severe impairment in insulin signaling and insulin-stimulated 2-deoxyglucose uptake and glycogen synthesis. Transcriptional regulation was also perturbed in IR-Mut myotubes with reduced insulin-stimulated expression of metabolic and early growth response genes. Thus, iPS-derived myotubes from individuals with genetically determined insulin resistance demonstrate many of the defects observed in vivo in insulin-resistant skeletal muscle and provide a new model to analyze the molecular impact of muscle insulin resistance. PMID:26831110

  11. Go-6976 reverses hyperglycemia-induced insulin resistance independently of cPKC inhibition in adipocytes.

    PubMed

    Robinson, Katherine A; Hegyi, Krisztina; Hannun, Yusuf A; Buse, Maria G; Sethi, Jaswinder K

    2014-01-01

    Chronic hyperglycemia induces insulin resistance by mechanisms that are incompletely understood. One model of hyperglycemia-induced insulin resistance involves chronic preincubation of adipocytes in the presence of high glucose and low insulin concentrations. We have previously shown that the mTOR complex 1 (mTORC1) plays a partial role in the development of insulin resistance in this model. Here, we demonstrate that treatment with Go-6976, a widely used "specific" inhibitor of cPKCs, alleviates hyperglycemia-induced insulin resistance. However, the effects of mTOR inhibitor, rapamycin and Go-6976 were not additive and only rapamycin restored impaired insulin-stimulated AKT activation. Although, PKCα, (but not -β) was abundantly expressed in these adipocytes, our studies indicate cPKCs do not play a major role in causing insulin-resistance in this model. There was no evidence of changes in the expression or phosphorylation of PKCα, and PKCα knock-down did not prevent the reduction of insulin-stimulated glucose transport. This was also consistent with lack of IRS-1 phosphorylation on Ser-24 in hyperglycemia-induced insulin-resistant adipocytes. Treatment with Go-6976 did inhibit a component of the mTORC1 pathway, as evidenced by decreased phosphorylation of S6 ribosomal protein. Raptor knock-down enhanced the effect of insulin on glucose transport in insulin resistant adipocytes. Go-6976 had the same effect in control cells, but was ineffective in cells with Raptor knock-down. Taken together these findings suggest that Go-6976 exerts its effect in alleviating hyperglycemia-induced insulin-resistance independently of cPKC inhibition and may target components of the mTORC1 signaling pathway. PMID:25330241

  12. Insulin resistance and the metabolism of branched-chain amino acids in humans.

    PubMed

    Adeva, María M; Calviño, Jesús; Souto, Gema; Donapetry, Cristóbal

    2012-07-01

    Peripheral resistance to insulin action is the major mechanism causing the metabolic syndrome and eventually type 2 diabetes mellitus. The metabolic derangement associated with insulin resistance is extensive and not restricted to carbohydrates. The branched-chain amino acids (BCAAs) are particularly responsive to the inhibitory insulin action on amino acid release by skeletal muscle and their metabolism is profoundly altered in conditions featuring insulin resistance, insulin deficiency, or both. Obesity, the metabolic syndrome and diabetes mellitus display a gradual increase in the plasma concentration of BCAAs, from the obesity-related low-grade insulin-resistant state to the severe deficiency of insulin action in diabetes ketoacidosis. Obesity-associated hyperinsulinemia succeeds in maintaining near-normal or slightly elevated plasma concentration of BCAAs, despite the insulin-resistant state. The low circulating levels of insulin and/or the deeper insulin resistance occurring in diabetes mellitus are associated with more marked elevation in the plasma concentration of BCAAs. In diabetes ketoacidosis, the increase in plasma BCAAs is striking, returning to normal when adequate metabolic control is achieved. The metabolism of BCAAs is also disturbed in other situations typically featuring insulin resistance, including kidney and liver dysfunction. However, notwithstanding the insulin-resistant state, the plasma level of BCAAs in these conditions is lower than in healthy subjects, suggesting that these organs are involved in maintaining BCAAs blood concentration. The pathogenesis of the decreased BCAAs plasma level in kidney and liver dysfunction is unclear, but a decreased afflux of these amino acids into the blood stream has been observed. PMID:21984377

  13. Features of Hepatic and Skeletal Muscle Insulin Resistance Unique to Type 1 Diabetes

    PubMed Central

    Howard, David; Schauer, Irene E.; Maahs, David M.; Snell-Bergeon, Janet K.; Eckel, Robert H.; Perreault, Leigh; Rewers, Marian

    2012-01-01

    Context: Type 1 diabetes is known to be a state of insulin resistance; however, the tissues involved in whole-body insulin resistance are less well known. It is unclear whether insulin resistance is due to glucose toxicity in the post-Diabetes Control and Complications Trial era of tighter glucose control. Objective: We performed this study to determine muscle and liver insulin sensitivity individuals with type 1 diabetes after overnight insulin infusion to lower fasting glucose concentration. Design, Patients, and Methods: Fifty subjects [25 controls without and 25 individuals with type 1 diabetes (diabetes duration 22.9 ± 1.7 yr, without known end organ damage] were frequency matched on age and body mass index by group and studied. After 3 d of dietary control and overnight insulin infusion to normalize glucose, we performed a three-stage hyperinsulinemic/euglycemic clamp infusing insulin at 4, 8, and 40 mU/m2 · min. Glucose metabolism was quantified using an infusion of [6,6-2H2]glucose. Hepatic insulin sensitivity was measured using the insulin IC50 for glucose rate of appearance (Ra), whereas muscle insulin sensitivity was measured using the glucose rate of disappearance during the highest insulin dose. Results: Throughout the study, glucose Ra was significantly greater in individuals compared with those without type 1 diabetes. The concentration of insulin required for 50% suppression of glucose Ra was 2-fold higher in subjects with type 1 diabetes. Glucose rate of disappearance was significantly lower in individuals with type 1 diabetes during the 8- and 40-mU/m2 · min stages. Conclusion: Insulin resistance in liver and skeletal muscle was a significant feature in type 1 diabetes. Nevertheless, the etiology of insulin resistance was not explained by body mass index, percentage fat, plasma lipids, visceral fat, and physical activity and was also not fully explained by hyperglycemia. PMID:22362823

  14. Genetic insulin resistance is a potent regulator of gene expression and proliferation in human iPS cells.

    PubMed

    Iovino, Salvatore; Burkart, Alison M; Kriauciunas, Kristina; Warren, Laura; Hughes, Katelyn J; Molla, Michael; Lee, Youn-Kyoung; Patti, Mary-Elizabeth; Kahn, C Ronald

    2014-12-01

    Insulin resistance is central to diabetes and metabolic syndrome. To define the consequences of genetic insulin resistance distinct from those secondary to cellular differentiation or in vivo regulation, we generated induced pluripotent stem cells (iPSCs) from individuals with insulin receptor mutations and age-appropriate control subjects and studied insulin signaling and gene expression compared with the fibroblasts from which they were derived. iPSCs from patients with genetic insulin resistance exhibited altered insulin signaling, paralleling that seen in the original fibroblasts. Insulin-stimulated expression of immediate early genes and proliferation were also potently reduced in insulin resistant iPSCs. Global gene expression analysis revealed marked differences in both insulin-resistant iPSCs and corresponding fibroblasts compared with control iPSCs and fibroblasts. Patterns of gene expression in patients with genetic insulin resistance were particularly distinct in the two cell types, indicating dependence on not only receptor activity but also the cellular context of the mutant insulin receptor. Thus, iPSCs provide a novel approach to define effects of genetically determined insulin resistance. This study demonstrates that effects of insulin resistance on gene expression are modified by cellular context and differentiation state. Moreover, altered insulin receptor signaling and insulin resistance can modify proliferation and function of pluripotent stem cell populations. PMID:25059784

  15. Genetic Insulin Resistance Is a Potent Regulator of Gene Expression and Proliferation in Human iPS Cells

    PubMed Central

    Iovino, Salvatore; Burkart, Alison M.; Kriauciunas, Kristina; Warren, Laura; Hughes, Katelyn J.; Molla, Michael; Lee, Youn-Kyoung

    2014-01-01

    Insulin resistance is central to diabetes and metabolic syndrome. To define the consequences of genetic insulin resistance distinct from those secondary to cellular differentiation or in vivo regulation, we generated induced pluripotent stem cells (iPSCs) from individuals with insulin receptor mutations and age-appropriate control subjects and studied insulin signaling and gene expression compared with the fibroblasts from which they were derived. iPSCs from patients with genetic insulin resistance exhibited altered insulin signaling, paralleling that seen in the original fibroblasts. Insulin-stimulated expression of immediate early genes and proliferation were also potently reduced in insulin resistant iPSCs. Global gene expression analysis revealed marked differences in both insulin-resistant iPSCs and corresponding fibroblasts compared with control iPSCs and fibroblasts. Patterns of gene expression in patients with genetic insulin resistance were particularly distinct in the two cell types, indicating dependence on not only receptor activity but also the cellular context of the mutant insulin receptor. Thus, iPSCs provide a novel approach to define effects of genetically determined insulin resistance. This study demonstrates that effects of insulin resistance on gene expression are modified by cellular context and differentiation state. Moreover, altered insulin receptor signaling and insulin resistance can modify proliferation and function of pluripotent stem cell populations. PMID:25059784

  16. Childhood Wrist Circumference is Not a Predictor of Insulin Resistance in Adulthood

    PubMed Central

    Watkins, Ashley N.; Kelly, Aaron S.; Prineas, Ronald J.; Marlatt, Kara L.; Dengel, Donald R.; Sinaiko, Alan R.; Moran, Antoinette; Steinberger, Julia

    2014-01-01

    We sought to determine if childhood wrist circumference predicts insulin resistance in adulthood. Measures were taken in pre-pubertal children and then approximately 30 years later in the same subjects as adults. Our findings suggest that wrist circumference in childhood is not a predictor of insulin resistance in adulthood. PMID:25596104

  17. Childhood wrist circumference is not a predictor of insulin resistance in adulthood.

    PubMed

    Watkins, Ashley N; Kelly, Aaron S; Prineas, Ronald J; Marlatt, Kara L; Dengel, Donald R; Sinaiko, Alan R; Moran, Antoinette; Steinberger, Julia

    2015-04-01

    We sought to determine whether childhood wrist circumference predicts insulin resistance in adulthood. Measures were taken in prepubertal children and then approximately 30 years later in the same subjects as adults. Our findings suggest that wrist circumference in childhood is not a predictor of insulin resistance in adulthood. PMID:25596104

  18. Key Role for Ceramides in Mediating Insulin Resistance in Human Muscle Cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Elevated non-esterified fatty acids, triglyceride, diacylglycerol and ceramide have all been associated with insulin resistance in muscle. We set out to investigate the role of intramyocellular lipid metabolites in the induction of insulin resistance in human primary myoblast cultures. Muscle cell...

  19. Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chronic low-grade inflammation is a hallmark of obesity and thought to contribute to the development of obesity-related insulin resistance. Toll-like receptor 4 (Tlr4) is a key mediator of pro-inflammatory responses. Mice lacking Tlr4s are protected from diet-induced insulin resistance and inflammat...

  20. Effect of Vitamin K Supplementation on Insulin Resistance in Older Men and Women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Previous studies have suggested a potentially beneficial role for vitamin K on insulin resistance, but this has not been examined in a randomized controlled trial. We tested the hypothesis that vitamin K supplementation for 36 months will improve insulin resistance in older men and women. This is ...

  1. Hyaluronan Accumulates With High-Fat Feeding and Contributes to Insulin Resistance

    PubMed Central

    Kang, Li; Lantier, Louise; Kennedy, Arion; Bonner, Jeffrey S.; Mayes, Wesley H.; Bracy, Deanna P.; Bookbinder, Louis H.; Hasty, Alyssa H.; Thompson, Curtis B.; Wasserman, David H.

    2013-01-01

    Increased deposition of specific extracellular matrix (ECM) components is a characteristic of insulin-resistant skeletal muscle. Hyaluronan (HA) is a major constituent of the ECM. The hypotheses that 1) HA content is increased in the ECM of insulin-resistant skeletal muscle and 2) reduction of HA in the muscle ECM by long-acting pegylated human recombinant PH20 hyaluronidase (PEGPH20) reverses high-fat (HF) diet–induced muscle insulin resistance were tested. We show that muscle HA was increased in HF diet–induced obese (DIO) mice and that treatment of PEGPH20, which dose-dependently reduced HA in muscle ECM, decreased fat mass, adipocyte size, and hepatic and muscle insulin resistance in DIO mice at 10 mg/kg. Reduced muscle insulin resistance was associated with increased insulin signaling, muscle vascularization, and percent cardiac output to muscle rather than insulin sensitization of muscle per se. Dose-response studies revealed that PEGPH20 dose-dependently increased insulin sensitivity in DIO mice with a minimally effective dose of 0.01 mg/kg. PEGPH20 at doses of 0.1 and 1 mg/kg reduced muscle HA to levels seen in chow-fed mice, decreased fat mass, and increased muscle glucose uptake. These findings suggest that ECM HA is a target for treatment of insulin resistance. PMID:23349492

  2. Insulin resistance and response to antiviral therapy in chronic hepatitis C: mechanisms and management.

    PubMed

    del Campo, José A; López, Reyes Aparcero; Romero-Gómez, Manuel

    2010-01-01

    Insulin resistance has been found to be an independent factor predicting sustained response to peginterferon plus ribavirin in patients with chronic hepatitis C. Insulin resistance seems to be involved in decreased sensitivity to interferon and could block interferon intracellular signaling. Insulin resistance promotes steatosis and fibrosis progression, induces pro-inflammatory cytokine secretion and increases adipose tissue, decreasing interferon availability. Moreover, suppressor of cytokines 3 and protein tyrosine-phosphatase seems to be able to block interferon and insulin signaling, building a feed-forward loop. Insulin resistance can be treated with exercise, diet or through the use of drugs that improve insulin sensitivity, like biguanides or glitazones. A recent controlled, randomized, double-blind clinical trial (TRIC-1) examined the effect of adding metformin to standard therapy in the treatment of hepatitis C. This study demonstrated that women infected with hepatitis C virus genotype 1 and HOMA >2 treated with metformin showed a greater drop in viral load during the first 12 weeks and a doubled sustained viral response in comparison with females receiving placebo. Pioglitazone has been used in previous nonresponders and naïve patients with disappointing results in two pilot trials. The mechanisms by which the virus promotes insulin resistance seems to be genotype-dependent and could explain, at least in part, the discrepancies between insulin sensitizers. Insulin resistance is a new target in the challenging management of chronic hepatitis C. PMID:20460925

  3. Hyperinsulinemia improves ischemic LV function in insulin resistant subjects

    PubMed Central

    2010-01-01

    Background Glucose is a more efficient substrate for ATP production than free fatty acid (FFA). Insulin resistance (IR) results in higher FFA concentrations and impaired myocardial glucose use, potentially worsening ischemia. We hypothesized that metabolic manipulation with a hyperinsulinemic euglycemic clamp (HEC) would affect a greater improvement in left ventricular (LV) performance during dobutamine stress echo (DSE) in subjects with IR. Methods 24 subjects with normal LV function and coronary disease (CAD) awaiting revascularization underwent 2 DSEs. Prior to one DSEs they underwent an HEC, where a primed infusion of insulin (rate 43 mU/m 2/min) was co-administered with 20% dextrose at variable rates to maintain euglycemia. At steady-state the DSE was performed and images of the LV were acquired with tissue Doppler at each stage for offline analysis. Segmental peak systolic velocities (Vs) were recorded, as well as LV ejection fraction (EF). Subjects were then divided into two groups based on their insulin sensitivity during the HEC. Results HEC changed the metabolic environment, suppressing FFAs and thereby increasing glucose use. This resulted in improved LV performance at peak stress, measured by EF (IS group mean difference 5.3 (95% CI 2.5-8) %, p = 0.002; IR group mean difference 8.7 (95% CI 5.8-11.6) %, p < 0.0001) and peak V s in ischemic segments (IS group mean improvement 0.7(95% CI 0.07-1.58) cm/s, p = 0.07; IR group mean improvement 1.0 (95% CI 0.54-1.5) cm/s, p < 0.0001) , that was greater in the subjects with IR. Conclusions Increased myocardial glucose use induced by HEC improves LV function under stress in subjects with CAD and IR. Cardiac metabolic manipulation in subjects with IR is a promising target for future therapy. PMID:20576156

  4. Acute Psychological Stress Results in the Rapid Development of Insulin Resistance

    PubMed Central

    Li, Li; Li, Xiaohua; Zhou, Wenjun; Messina, Joseph L.

    2013-01-01

    In recent years, the roles of chronic stress and depression as an independent risk factor for decreased insulin sensitivity and the development of diabetes have been increasingly recognized. However, an understanding and the mechanisms linking insulin resistance and acute psychological stress are very limited. We hypothesized that acute psychological stress may cause the development of insulin resistance, which may be a risk factor in developing type 2 diabetes. We tested the hypothesis in a well-established mouse model using 180 episodes of inescapable foot shock (IES), followed by a behavioral escape test. In this study, mice that received IES treatment were tested for acute insulin resistance by measuring glucose metabolism and insulin signaling. When compared to normal and sham mice, mice that were exposed to IES resulting in escape failure (defined as IES with behavioral escape failure) displayed elevated blood glucose levels in both glucose tolerance and insulin tolerance tests. Furthermore, mice with IES exposure and behavioral escape failure exhibited impaired hepatic insulin signaling via the insulin-induced insulin receptor/insulin receptor substrate 1/Akt pathway, without affecting similar pathways in skeletal muscle, adipose tissue and brain. Additionally, a rise in murine growth-related oncogene KC/GRO was associated with impaired glucose metabolism in IES mice, suggesting a mechanism by which psychological stress by IES may influence glucose metabolism. The present results indicate that psychological stress induced by IES can acutely alter hepatic responsiveness to insulin and affect whole-body glucose metabolism. PMID:23444388

  5. Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans.

    PubMed

    Kullmann, Stephanie; Heni, Martin; Hallschmid, Manfred; Fritsche, Andreas; Preissl, Hubert; Häring, Hans-Ulrich

    2016-10-01

    Ever since the brain was identified as an insulin-sensitive organ, evidence has rapidly accumulated that insulin action in the brain produces multiple behavioral and metabolic effects, influencing eating behavior, peripheral metabolism, and cognition. Disturbances in brain insulin action can be observed in obesity and type 2 diabetes (T2D), as well as in aging and dementia. Decreases in insulin sensitivity of central nervous pathways, i.e., brain insulin resistance, may therefore constitute a joint pathological feature of metabolic and cognitive dysfunctions. Modern neuroimaging methods have provided new means of probing brain insulin action, revealing the influence of insulin on both global and regional brain function. In this review, we highlight recent findings on brain insulin action in humans and its impact on metabolism and cognition. Furthermore, we elaborate on the most prominent factors associated with brain insulin resistance, i.e., obesity, T2D, genes, maternal metabolism, normal aging, inflammation, and dementia, and on their roles regarding causes and consequences of brain insulin resistance. We also describe the beneficial effects of enhanced brain insulin signaling on human eating behavior and cognition and discuss potential applications in the treatment of metabolic and cognitive disorders. PMID:27489306

  6. Chronic cadmium exposure in rats produces pancreatic impairment and insulin resistance in multiple peripheral tissues.

    PubMed

    Treviño, Samuel; Waalkes, Michael P; Flores Hernández, José Angel; León-Chavez, Bertha Alicia; Aguilar-Alonso, Patricia; Brambila, Eduardo

    2015-10-01

    Previous studies have linked cadmium exposure to disturbances in carbohydrate and lipid metabolism. In this study we investigate the effects in Wistar rats of an oral cadmium exposure in drinking water on carbohydrates, lipids and insulin release. Also, using mathematical models we studied the effect of cadmium on insulin resistance and sensitivity in liver, muscle, adipose and cardiovascular tissue. Cadmium exposure induced hyperglycemia, increased insulin release after a glucose load, and caused increases in serum triglycerides, cholesterol, LDL-C and VLDL-C, and a decrease of HDL-C. In addition, there was an accumulation of cadmium in pancreas and an increase of insulin. After exposure, HOMA-IR was increased, while the HOMA-S%, QUICKI and Matsuda-DeFronzo indexes showed decreases. A decrease of insulin sensitivity was shown in muscle and liver. Additionally, cadmium increases insulin resistance in the liver, adipose tissue and cardiovascular system. Finally, β-cell functioning was evaluated by HOMA-B% index and insulin disposition index, which were decreased, while insulin generation index increased. In conclusion, cadmium increases insulin release, induces hyperglycemia and alters lipid metabolism. These changes likely occur as a consequence of reduced sensitivity and increased insulin resistance in multiple insulin-dependent and non-dependent tissues, producing a biochemical phenotype similar to metabolic syndrome and diabetes. PMID:26253262

  7. Depletion of Fat Tregs Prevents Age-Associated Insulin Resistance

    PubMed Central

    Bapat, Sagar P.; Suh, Jae Myoung; Fang, Sungsoon; Liu, Sihao; Zhang, Yang; Cheng, Albert; Zhou, Carmen; Liang, Yuqiong; LeBlanc, Mathias; Liddle, Christopher; Atkins, Annette R.; Yu, Ruth T.; Downes, Michael; Evans, Ronald M.; Zheng, Ye

    2015-01-01

    Age-associated insulin resistance (IR) and obesity-associated IR are two physiologically distinct forms of adult onset diabetes. While macrophage-driven inflammation is a core driver of obesity-associated IR1–6, the underlying mechanisms of the obesity-independent yet highly prevalent age-associated IR7 are largely unexplored. Comparative adipo-immune profiling (AIP) reveals that fat-resident regulatory T cells, termed fTregs, accumulate in adipose tissue as a function of age, but not obesity. Supporting the existence of two distinct mechanisms underlying IR, mice deficient in fTregs are protected against age-associated IR, yet remain susceptible to obesity-associated IR and metabolic disease. In contrast, selective depletion of fTregs via anti-ST2 antibody treatment increases adipose tissue insulin sensitivity. These findings establish that distinct immune cell populations within adipose tissue underlie aging- and obesity-associated IR and implicate fTregs as adipo-immune drivers and potential therapeutic targets in the treatment of age-associated IR. PMID:26580014

  8. The Role of Mitochondria in the Pathophysiology of Skeletal Muscle Insulin Resistance

    PubMed Central

    Pagel-Langenickel, Ines; Bao, Jianjun; Pang, Liyan; Sack, Michael N.

    2010-01-01

    Multiple organs contribute to the development of peripheral insulin resistance, with the major contributors being skeletal muscle, liver, and adipose tissue. Because insulin resistance usually precedes the development of type 2 diabetes mellitus (T2DM) by many years, understanding the pathophysiology of insulin resistance should enable development of therapeutic strategies to prevent disease progression. Some subjects with mitochondrial genomic variants/defects and a subset of lean individuals with hereditary predisposition to T2DM exhibit skeletal muscle mitochondrial dysfunction early in the course of insulin resistance. In contrast, in the majority of subjects with T2DM the plurality of evidence implicates skeletal muscle mitochondrial dysfunction as a consequence of perturbations associated with T2DM, and these mitochondrial deficits then contribute to subsequent disease progression. We review the affirmative and contrarian data regarding skeletal muscle mitochondrial biology in the pathogenesis of insulin resistance and explore potential therapeutic options to intrinsically modulate mitochondria as a strategy to combat insulin resistance. Furthermore, an overview of restricted molecular manipulations of skeletal muscle metabolic and mitochondrial biology offers insight into the mitochondrial role in metabolic substrate partitioning and in promoting innate adaptive and maladaptive responses that collectively regulate peripheral insulin sensitivity. We conclude that skeletal muscle mitochondrial dysfunction is not generally a major initiator of the pathophysiology of insulin resistance, although its dysfunction is integral to this pathophysiology and it remains an intriguing target to reverse/delay the progressive perturbations synonymous with T2DM. PMID:19861693

  9. Reversal of diet-induced obesity and insulin resistance by inducible genetic ablation of GRK2.

    PubMed

    Vila-Bedmar, Rocio; Cruces-Sande, Marta; Lucas, Elisa; Willemen, Hanneke L D M; Heijnen, Cobi J; Kavelaars, Annemieke; Mayor, Federico; Murga, Cristina

    2015-07-21

    Insulin resistance is a common feature of obesity and predisposes individuals to various prevalent pathological conditions. G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor kinase 2 (GRK2) integrates several signal transduction pathways and is emerging as a physiologically relevant inhibitor of insulin signaling. GRK2 abundance is increased in humans with metabolic syndrome and in different murine models of insulin resistance. To support GRK2 as a potential drug target in type 2 diabetes and obesity, we investigated whether lowering GRK2 abundance reversed an ongoing systemic insulin-resistant phenotype, using a mouse model of tamoxifen-induced GRK2 ablation after high-fat diet-dependent obesity and insulin resistance. Tamoxifen-triggered GRK2 deletion impeded further body weight gain, normalized fasting glycemia, improved glucose tolerance, and was associated with preserved insulin sensitivity in skeletal muscle and liver, thereby maintaining whole-body glucose homeostasis. Moreover, when continued to be fed a high-fat diet, these animals displayed reduced fat mass and smaller adipocytes, were resistant to the development of liver steatosis, and showed reduced expression of proinflammatory markers in the liver. Our results indicate that GRK2 acts as a hub to control metabolic functions in different tissues, which is key to controlling insulin resistance development in vivo. These data suggest that inhibiting GRK2 could reverse an established insulin-resistant and obese phenotype, thereby putting forward this enzyme as a potential therapeutic target linking glucose homeostasis and regulation of adiposity. PMID:26198359

  10. Non-invasive cell type selective in vivo monitoring of insulin resistance dynamics

    PubMed Central

    Paschen, Meike; Moede, Tilo; Leibiger, Barbara; Jacob, Stefan; Bryzgalova, Galyna; Leibiger, Ingo B.; Berggren, Per-Olof

    2016-01-01

    Insulin resistance contributes to the development of cardio-vascular disease and diabetes. An important but unresolved task is to study the dynamics of insulin resistance in selective cell types of insulin target tissues in vivo. Here we present a novel technique to monitor insulin resistance dynamics non-invasively and longitudinally in vivo in a cell type-specific manner, exemplified by the pancreatic β-cell situated within the micro-organ the islet of Langerhans. We utilize the anterior chamber of the eye (ACE) as a transplantation site and the cornea as a natural body-window to study the development and reversibility of insulin resistance. Engrafted islets in the ACE that express a FoxO1-GFP-based biosensor in their β-cells, report on insulin resistance measured by fluorescence microscopy at single-cell resolution in the living mouse. This technique allows monitoring of cell type specific insulin sensitivity/resistance in real-time in the context of whole body insulin resistance during progression and intervention of disease. PMID:26899548

  11. Insulin Resistance May Contribute to Upregulation of Adhesion Molecules on Endothelial Cells in Psoriatic Plaques.

    PubMed

    Schlüter, Kathrin; Diehl, Sandra; Lang, Victoria; Kaufmann, Roland; Boehncke, Wolf-Henning; Bürger, Claudia

    2016-02-01

    Psoriasis primarily affects the skin, but also has a systemic dimension and is associated with severe comorbidities. Since endothelial cells play an important role in psoriasis as well as in the development of cardiovascular comorbidities, we investigated whether a common mechanism, namely cytokine-induced insulin resistance, underlies both pathologies. Activation of the insulin pathway was studied in psoriatic skin and dermal endothelial cells. Expression of adhesion molecules was assessed by flow cytometry, as well as their biological function in flow chamber experiments. The phosphorylation status of Akt, a central kinase in the insulin pathway, suggests that endothelial cells within psoriatic plaques are rendered insulin resistant by pro-inflammatory cytokines. Insulin counteracts the expression of adhesion molecules, but has limited effects on interactions between T cells and endothelial cells. Pro-inflammatory cytokines induce insulin resistance in endothelial cells, which may contribute to the development of the inflammatory infiltrate in psoriasis. PMID:26315601

  12. Edible Bird's Nest Prevents High Fat Diet-Induced Insulin Resistance in Rats

    PubMed Central

    Yida, Zhang; Imam, Mustapha Umar; Ismail, Maznah; Ooi, Der-Jiun; Sarega, Nadarajan; Azmi, Nur Hanisah; Ismail, Norsharina; Chan, Kim Wei; Hou, Zhiping; Yusuf, Norhayati Binti

    2015-01-01

    Edible bird's nest (EBN) is used traditionally in many parts of Asia to improve wellbeing, but there are limited studies on its efficacy. We explored the potential use of EBN for prevention of high fat diet- (HFD-) induced insulin resistance in rats. HFD was given to rats with or without simvastatin or EBN for 12 weeks. During the intervention period, weight measurements were recorded weekly. Blood samples were collected at the end of the intervention and oral glucose tolerance test conducted, after which the rats were sacrificed and their liver and adipose tissues collected for further studies. Serum adiponectin, leptin, F2-isoprostane, insulin, and lipid profile were estimated, and homeostatic model assessment of insulin resistance computed. Effects of the different interventions on transcriptional regulation of insulin signaling genes were also evaluated. The results showed that HFD worsened metabolic indices and induced insulin resistance partly through transcriptional regulation of the insulin signaling genes. Additionally, simvastatin was able to prevent hypercholesterolemia but promoted insulin resistance similar to HFD. EBN, on the other hand, prevented the worsening of metabolic indices and transcriptional changes in insulin signaling genes due to HFD. The results suggest that EBN may be used as functional food to prevent insulin resistance. PMID:26273674

  13. Edible Bird's Nest Prevents High Fat Diet-Induced Insulin Resistance in Rats.

    PubMed

    Yida, Zhang; Imam, Mustapha Umar; Ismail, Maznah; Ooi, Der-Jiun; Sarega, Nadarajan; Azmi, Nur Hanisah; Ismail, Norsharina; Chan, Kim Wei; Hou, Zhiping; Yusuf, Norhayati Binti

    2015-01-01

    Edible bird's nest (EBN) is used traditionally in many parts of Asia to improve wellbeing, but there are limited studies on its efficacy. We explored the potential use of EBN for prevention of high fat diet- (HFD-) induced insulin resistance in rats. HFD was given to rats with or without simvastatin or EBN for 12 weeks. During the intervention period, weight measurements were recorded weekly. Blood samples were collected at the end of the intervention and oral glucose tolerance test conducted, after which the rats were sacrificed and their liver and adipose tissues collected for further studies. Serum adiponectin, leptin, F2-isoprostane, insulin, and lipid profile were estimated, and homeostatic model assessment of insulin resistance computed. Effects of the different interventions on transcriptional regulation of insulin signaling genes were also evaluated. The results showed that HFD worsened metabolic indices and induced insulin resistance partly through transcriptional regulation of the insulin signaling genes. Additionally, simvastatin was able to prevent hypercholesterolemia but promoted insulin resistance similar to HFD. EBN, on the other hand, prevented the worsening of metabolic indices and transcriptional changes in insulin signaling genes due to HFD. The results suggest that EBN may be used as functional food to prevent insulin resistance. PMID:26273674

  14. Effect of BI-1 on insulin resistance through regulation of CYP2E1

    PubMed Central

    Lee, Geum-Hwa; Oh, Kyoung-Jin; Kim, Hyung-Ryong; Han, Hye-Sook; Lee, Hwa-Young; Park, Keun-Gyu; Nam, Ki-Hoan; Koo, Seung-Hoi; Chae, Han-Jung

    2016-01-01

    Diet-induced obesity is a major contributing factor to the progression of hepatic insulin resistance. Increased free fatty acids in liver enhances endoplasmic reticulum (ER) stress and production of reactive oxygen species (ROS), both are directly responsible for dysregulation of hepatic insulin signaling. BI-1, a recently studied ER stress regulator, was examined to investigate its association with ER stress and ROS in insulin resistance models. To induce obesity and insulin resistance, BI-1 wild type and BI-1 knock-out mice were fed a high-fat diet for 8 weeks. The BI-1 knock-out mice had hyperglycemia, was associated with impaired glucose and insulin tolerance under high-fat diet conditions. Increased activity of NADPH-dependent CYP reductase-associated cytochrome p450 2E1 (CYP2E1) and exacerbation of ER stress in the livers of BI-1 knock-out mice was also observed. Conversely, stable expression of BI-1 in HepG2 hepatocytes was shown to reduce palmitate-induced ER stress and CYP2E1-dependent ROS production, resulting in the preservation of intact insulin signaling. Stable expression of CYP2E1 led to increased ROS production and dysregulation of insulin signaling in hepatic cells, mimicking palmitate-mediated hepatic insulin resistance. We propose that BI-1 protects against obesity-induced hepatic insulin resistance by regulating CYP2E1 activity and ROS production. PMID:27576594

  15. Effect of BI-1 on insulin resistance through regulation of CYP2E1.

    PubMed

    Lee, Geum-Hwa; Oh, Kyoung-Jin; Kim, Hyung-Ryong; Han, Hye-Sook; Lee, Hwa-Young; Park, Keun-Gyu; Nam, Ki-Hoan; Koo, Seung-Hoi; Chae, Han-Jung

    2016-01-01

    Diet-induced obesity is a major contributing factor to the progression of hepatic insulin resistance. Increased free fatty acids in liver enhances endoplasmic reticulum (ER) stress and production of reactive oxygen species (ROS), both are directly responsible for dysregulation of hepatic insulin signaling. BI-1, a recently studied ER stress regulator, was examined to investigate its association with ER stress and ROS in insulin resistance models. To induce obesity and insulin resistance, BI-1 wild type and BI-1 knock-out mice were fed a high-fat diet for 8 weeks. The BI-1 knock-out mice had hyperglycemia, was associated with impaired glucose and insulin tolerance under high-fat diet conditions. Increased activity of NADPH-dependent CYP reductase-associated cytochrome p450 2E1 (CYP2E1) and exacerbation of ER stress in the livers of BI-1 knock-out mice was also observed. Conversely, stable expression of BI-1 in HepG2 hepatocytes was shown to reduce palmitate-induced ER stress and CYP2E1-dependent ROS production, resulting in the preservation of intact insulin signaling. Stable expression of CYP2E1 led to increased ROS production and dysregulation of insulin signaling in hepatic cells, mimicking palmitate-mediated hepatic insulin resistance. We propose that BI-1 protects against obesity-induced hepatic insulin resistance by regulating CYP2E1 activity and ROS production. PMID:27576594

  16. Genetic Architecture of Insulin Resistance in the Mouse

    PubMed Central

    Parks, Brian W.; Sallam, Tamer; Mehrabian, Margarete; Psychogios, Nikolas; Hui, Simon T.; Norheim, Frode; Castellani, Lawrence W.; Rau, Christoph; Pan, Calvin; Phun, Jennifer; Zhou, Zhenqi; Yang, Wen-Pin; Neuhaus, Isaac; Gargalovic, Peter S.; Kirchgessner, Todd G.; Graham, Mark; Lee, Richard; Tontonoz, Peter; Gerszten, Robert E.; Hevener, Andrea L.; Lusis, Aldons J.

    2015-01-01

    SUMMARY Insulin Resistance (IR) is a complex trait with multiple genetic and environmental components. Confounded by large differences between the sexes, environment and disease pathology, the genetic basis of IR has been difficult to dissect. Here we examine IR and related traits in a diverse population of more than 100 unique male and female inbred mouse strains after feeding a diet rich in fat and refined carbohydrates. Our results show dramatic variation in IR among strains of mice and widespread differences between sexes that is dependent on genotype. We uncover more than 15 genome-wide significant loci and validate a gene, Agpat5, associated with IR. We also integrate plasma metabolite levels and global gene expression from liver and adipose tissue to identify metabolite Quantitative Trait Loci (mQTL) and expression QTL (eQTL), respectively. Our results provide a resource for analysis of interactions between diet, sex and genetic background in IR. PMID:25651185

  17. Effect of recombinant human erythropoietin on insulin resistance in hemodialysis patients.

    PubMed

    Khedr, Essam; El-Sharkawy, Magdy; Abdulwahab, Saed; Eldin, Essam Nor; Ali, Medhat; Youssif, Abla; Ahmed, Bassam

    2009-07-01

    Insulin resistance is a characteristic feature of uremia. Insulin resistance and concomitant hyperinsulinemia are present irrespective of the type of renal disease. Treatment with recombinant human erythropoietin (rHuEPO) was said to be associated with improvement in insulin sensitivity in uremic patients. The aim of this study was to compare insulin resistance in adult uremic hemodialysis (HD) patients including diabetic patients treated with or without rHuEPO. A total of 59 HD patients were studied, patients were divided into 2 groups of subjects: 30 HD patients on regular rHuEPO treatment (group A), and 29 HD patients not receiving rHuEPO (group B) diabetic patients were not excluded. Full medical history and clinical examination, hematological parameters, lipid profile, serum albumin, parathyroid horomone, Kt/V, fasting glucose, and insulin levels were measured in all subjects. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was used to compare insulin resistance. The results of this study showed that the mean insulin level of HD patients treated with rHuEPO (group A) (17.5 +/- 10.6 microU/mL) was significantly lower than patients without rHuEPO (group B) (28.8 +/- 7.7 microU/mL), (P<0.001). Homeostasis Model Assessment of Insulin Resistance levels in group A were significantly lower than in group B (3.8 +/- 2.97, 7.98 +/- 4.9, respectively, P<0.001). Insulin resistance reflected by HOMA-IR levels among diabetic patients in group A was significantly lower than among diabetic patients in group B (3.9 +/- 3.2, 9.4 +/- 7.2, respectively, P<0.001). Also, HOMA-IR levels among nondiabetic patients in group A were significantly lower than among nondiabetic patients in group B (3.7 +/- 2.85, 6.9 +/- 1.43, respectively, P<0.01). We found a statistically significant negative correlation between duration of erythropoietin treatment, fasting blood glucose, insulin levels, and insulin resistance (r=-0.62, -0.71, and -0.57, P<0.001). Patients treated with r

  18. Effects of diet-induced weight gain and turnout to pasture on insulin sensitivity in moderately insulin resistant horses.

    PubMed

    Lindåse, Sanna S; Nostell, Katarina E; Müller, Cecilia E; Jensen-Waern, Marianne; Bröjer, Johan T

    2016-03-01

    OBJECTIVE To quantify insulin sensitivity and monitor glucose, insulin, and lipid concentrations in a group of moderately insulin-resistant horses during induction of obesity by use of a forage diet supplemented with fat and during subsequent turnout to pasture. ANIMALS 9 adult Standardbred mares (11 to 20 years old). PROCEDURES Weight gain of horses was induced during 22 weeks by use of a forage diet supplemented with fat fed in gradually increasing amounts, followed by feeding of that fat-supplemented diet at 2.5 times the daily maintenance requirements. Horses were then turned out to pasture. Insulin sensitivity was measured with the euglycemic hyperinsulinemic clamp method before and after weight gain and after 4 weeks at pasture. Body weight, body condition score, and cresty neck score as well as fasting and postprandial concentrations of plasma insulin, plasma glucose, serum triglyceride, and serum nonesterified fatty acids were measured during the study. RESULTS Body weight typically increased by 10%, and body condition score (scale, 1 to 9) increased by > 1.5 from the start to the end of the weight-gain period. There was no difference in insulin sensitivity or metabolic clearance rate of insulin during the weight-gain period. Four weeks at pasture generally improved insulin sensitivity and metabolic clearance rate of insulin by 54% and 32%, respectively, but there was no change in body weight or body condition score. CONCLUSIONS AND CLINICAL RELEVANCE Findings indicated that dietary composition played a more important role than did short-term weight gain on alterations in insulin sensitivity of horses. PMID:26919602

  19. Efficacy of 2-hour post glucose insulin levels in predicting insulin resistance in polycystic ovarian syndrome with infertility

    PubMed Central

    Saxena, Pikee; Prakash, Anupam; Nigam, Aruna

    2011-01-01

    BACKGROUND: Insulin resistance (IR) is central to the pathogenesis of polycystic ovarian syndrome (PCOS), but tests for determining IR are elaborate, tedious and expensive. AIMS: To evaluate if “2-hour post-glucose insulin level” is an effective indicator of IR and can aid in diagnosing IR in infertile PCOS women. SETTINGS AND DESIGN: Observational study at infertility clinic of a tertiary care center. MATERIALS AND METHODS: 50 infertile women with PCOS and 20 females with tubal/male factor infertility were evaluated for the presence of IR, as defined by the fasting/2-hour post-glucose insulin levels cutoffs of >25/>41 μU/mL, respectively. The clinical, metabolic and endocrinologic profile was determined in both the groups. STATISTICAL ANALYSIS: Statistical analysis was performed using SPSS (Chicago, IL, USA). RESULTS: Body mass index, post load glucose, insulin, glucose/insulin ratio, area under curve (AUC) of glucose and insulin and insulinogenic index were significantly lower in the controls as compared to the PCOS group. “2-hour post-glucose insulin levels” were elevated in 88% of PCOS individuals but were normal in all females not suffering from PCOS. These levels significantly correlated with AUC of glucose and insulin, and insulinogenic index and inversely correlated with 2-hour glucose to insulin ratio (r=0.827, 0.749 and –0.732, respectively). CONCLUSIONS: “2-hour post-glucose insulin levels” appears to be a good indicator of IR. It can be a useful tool, especially in low resource setting where a single sample can confirm the diagnosis, thus reducing cost and repeat visits. PMID:21772735

  20. Suppression of phosphatase and tensin homolog protects insulin-resistant cells from apoptosis.

    PubMed

    Wang, Di-Fei; Yang, Hui-Jing; Gu, Jian-Qiu; Cao, Yan-Li; Meng, Xin; Wang, Xiao-Li; Lin, Yi-Chen; Gao, Ming

    2015-08-01

    In the present study, a glucosamine-induced model of insulin-resistant skeletal muscle cells was established in order to investigate the effect of inhibition of phosphatase and tensin homolog (PTEN)/5'-adenosine monophosphate-activated protein kinase (AMPK) on these cells. The glucosamine-induced insulin-resistant skeletal muscle cells were produced and the rate of glucose uptake was measured using the glucose oxidase-peroxidase method. The expression levels of PTEN and phosphorylated PTEN (p-PTEN) were assessed using western blotting. Glucose transporter 4 (GLUT4) translocation was detected by immunofluorescence. Cell apoptosis was evaluated using flow cytometry. Following insulin stimulation, the rate of glucose uptake was significantly reduced in the cells with glucosamine-induced insulin-resistance in comparison with those in the control group. The expression and translocation of GLUT4 were reduced in the insulin-resistant muscle cells. By contrast, the expression of PTEN and p-PTEN as well as apoptosis were significantly increased. Following treatment with bisperoxopicolinatooxovanadate (BPV) or metformin in the insulin-resistant skeletal muscle cells, there was an increase in the rate of glucose uptake, an increase in GLUT4 expression and its translocation, a reduction in the expression of PTEN and p-PTEN, and a decrease in cell apoptosis compared with untreated insulin-resistant cells. Glucosamine may be used to produce an effective model of insulin-resistant skeletal muscle cells. Cells with glucosamine-induced insulin-resistance exhibited a reduced expression of GLUT4 and dysfunction in GLUT4 translocation, as well as increased activation of PTEN and increased cell apoptosis. Inhibition of PTEN or its upstream regulator, AMPK, protects glucosamine-induced insulin-resistant skeletal muscle cells from apoptosis. PMID:25962562

  1. Metabolomic Response of Skeletal Muscle to Aerobic Exercise Training in Insulin Resistant Type 1 Diabetic Rats

    PubMed Central

    Dotzert, Michelle S.; Murray, Michael R.; McDonald, Matthew W.; Olver, T. Dylan; Velenosi, Thomas J.; Hennop, Anzel; Noble, Earl G.; Urquhart, Brad L.; Melling, C. W. James

    2016-01-01

    The etiology of insulin resistance in Type 1 Diabetes (T1D) is unknown, however it affects approximately 20% of T1D patients. Intramyocellular lipids (IMCL) have been identified as a mechanism of insulin resistance. We examined skeletal muscle of T1D rats to determine if alterations in lipid metabolism were evident and whether aerobic exercise training improves IMCL and insulin resistance. To do so, 48 male Sprague-Dawley rats were divided into control (C), sedentary diabetes (D) and diabetes exercise (DX) groups. Following multiple low-dose Streptozotocin (STZ) injections (20 mg/kg), glycemia (9–15 mM) was maintained using insulin treatment. DX were treadmill trained at high intensity (~75% V02max; 5days/week) for 10 weeks. The results demonstrate that D exhibited insulin resistance compared with C and DX, indicated by decreased glucose infusion rate during a hyperinsulinemic-euglycemic clamp (p < 0.05). There were no differences between C and DX, suggesting that exercise improved insulin resistance (p < 0.05). Metabolomics analysis revealed a significant shift in lipid metabolism whereby notable fatty acid metabolites (arachidonic acid, palmitic acid and several polyunsaturated fatty acids) were significantly elevated in D compared to C and DX. Based on the intermediates observed, insulin resistance in T1D is characterized by an insulin-desensitizing intramyocellular fatty acid metabolite profile that is ameliorated with exercise training. PMID:27197730

  2. Metabolomic Response of Skeletal Muscle to Aerobic Exercise Training in Insulin Resistant Type 1 Diabetic Rats.

    PubMed

    Dotzert, Michelle S; Murray, Michael R; McDonald, Matthew W; Olver, T Dylan; Velenosi, Thomas J; Hennop, Anzel; Noble, Earl G; Urquhart, Brad L; Melling, C W James

    2016-01-01

    The etiology of insulin resistance in Type 1 Diabetes (T1D) is unknown, however it affects approximately 20% of T1D patients. Intramyocellular lipids (IMCL) have been identified as a mechanism of insulin resistance. We examined skeletal muscle of T1D rats to determine if alterations in lipid metabolism were evident and whether aerobic exercise training improves IMCL and insulin resistance. To do so, 48 male Sprague-Dawley rats were divided into control (C), sedentary diabetes (D) and diabetes exercise (DX) groups. Following multiple low-dose Streptozotocin (STZ) injections (20 mg/kg), glycemia (9-15 mM) was maintained using insulin treatment. DX were treadmill trained at high intensity (~75% V02max; 5days/week) for 10 weeks. The results demonstrate that D exhibited insulin resistance compared with C and DX, indicated by decreased glucose infusion rate during a hyperinsulinemic-euglycemic clamp (p < 0.05). There were no differences between C and DX, suggesting that exercise improved insulin resistance (p < 0.05). Metabolomics analysis revealed a significant shift in lipid metabolism whereby notable fatty acid metabolites (arachidonic acid, palmitic acid and several polyunsaturated fatty acids) were significantly elevated in D compared to C and DX. Based on the intermediates observed, insulin resistance in T1D is characterized by an insulin-desensitizing intramyocellular fatty acid metabolite profile that is ameliorated with exercise training. PMID:27197730

  3. A peroxiredoxin, PRDX-2, is required for insulin secretion and insulin/IIS-dependent regulation of stress resistance and longevity.

    PubMed

    Oláhová, Monika; Veal, Elizabeth A

    2015-08-01

    Peroxiredoxins (Prx) are abundant thiol peroxidases with a conserved anti-ageing role. In contrast to most animals, the nematode worm, Caenorhabditis elegans, encodes a single cytosolic 2-Cys Prx, PRDX-2, rendering it an excellent model for examining how peroxiredoxins affect animal physiology and ageing. Our previous work revealed that, although PRDX-2 protects against the toxicity of peroxides, enigmatically, prdx-2-mutant animals are hyper-resistant to other forms of oxidative stress. Here, we have investigated the basis for this increased resistance. Mammalian FOXO and Nrf2 transcription factors directly promote the expression of a range of detoxification enzymes. We show that the FOXO orthologue, DAF-16, and the Nrf2 orthologue, SKN-1, are required for the increased stress resistance of prdx-2-mutant worms. Our data suggest that PRDX-2 is required for normal levels of insulin secretion and hence the inhibition of DAF-16 and SKN-1 by insulin/IGF-1-like signalling (IIS) under nutrient-rich conditions. Intriguingly, loss of PRDX-2 increases DAF-16 and SKN-1 activities sufficiently to increase arsenite resistance without initiating other IIS-inhibited processes. Together, these data suggest that loss of peroxiredoxin function may increase stress resistance by reducing insulin secretion, but that further changes in insulin signalling are required for the reprogramming of development and fat metabolism. In addition, we reveal that the temperature-dependent prolongevity function of PRDX-2 is required for the extended lifespan associated with several pathways, including further reductions in IIS. PMID:25808059

  4. Vibration exercise decreases insulin resistance and modulates the insulin signaling pathway in a type 2 diabetic rat model

    PubMed Central

    Liu, Ying; Liu, Chang; Lu, Mei-Li; Tang, Fu-Tian; Hou, Xu-Wei; Yang, Jing; Liu, Tao

    2015-01-01

    Vibration exercise (VE) is a new type of physical training, but little is known about its effects on insulin resistance at the molecular level. A Sprague-Dawley rat model of type 2 diabetes with insulin resistance was induced with a high-fat diet and low-dose streptozotocin. Animals were then subjected to 8 wk of VE consisting of placing the rats on a vibration stand bracket (8 cm × 8 cm × 20 cm) with a maximum vertical vibration displacement of 52 mm for 15 min twice a day, 6 d each week. Various metabolic markers and the phosphorylation and expression of proteins within the PI3K/AKT insulin signaling pathway were assessed. The high-fat diet and low-dose streptozotocin increased food intake, body weight, and levels of blood glucose, triglycerides, total cholesterol, and free fatty acids, while Kitt rate, 2-deoxyglucose uptake, and glycogen levels were decreased. These effects were ameliorated in animals receiving VE. VE treatment activated the PI3K/AKT insulin-signaling pathway, and also increased the expression of GLUT4. In conclusion, VE improved the metabolic issues associated with the diabetic state by suppressing the reduction of IRS1, AKT2, and GLUT4 in the diabetic condition, indicating that VE could be used as a therapeutic intervention for insulin resistance and type 2 diabetes. PMID:26550236

  5. Low fish oil intake improves insulin sensitivity, lipid profile and muscle metabolism on insulin resistant MSG-obese rats

    PubMed Central

    2011-01-01

    Background Obesity is commonly associated with diabetes, cardiovascular diseases and cancer. The purpose of this study was to determinate the effect of a lower dose of fish oil supplementation on insulin sensitivity, lipid profile, and muscle metabolism in obese rats. Methods Monosodium glutamate (MSG) (4 mg/g body weight) was injected in neonatal Wistar male rats. Three-month-old rats were divided in normal-weight control group (C), coconut fat-treated normal weight group (CO), fish oil-treated normal weight group (FO), obese control group (Ob), coconut fat-treated obese group (ObCO) and fish oil-treated obese group (ObFO). Obese insulin-resistant rats were supplemented with fish oil or coconut fat (1 g/kg/day) for 4 weeks. Insulin sensitivity, fasting blood biochemicals parameters, and skeletal muscle glucose metabolism were analyzed. Results Obese animals (Ob) presented higher Index Lee and 2.5 fold epididymal and retroperitoneal adipose tissue than C. Insulin sensitivity test (Kitt) showed that fish oil supplementation was able to maintain insulin sensitivity of obese rats (ObFO) similar to C. There were no changes in glucose and HDL-cholesterol levels amongst groups. Yet, ObFO revealed lower levels of total cholesterol (TC; 30%) and triacylglycerol (TG; 33%) compared to Ob. Finally, since exposed to insulin, ObFO skeletal muscle revealed an increase of 10% in lactate production, 38% in glycogen synthesis and 39% in oxidation of glucose compared to Ob. Conclusions Low dose of fish oil supplementation (1 g/kg/day) was able to reduce TC and TG levels, in addition to improved systemic and muscle insulin sensitivity. These results lend credence to the benefits of n-3 fatty acids upon the deleterious effects of insulin resistance mechanisms. PMID:21526994

  6. Insulin resistance modifies the association between obesity and current asthma in adults.

    PubMed

    Cardet, Juan Carlos; Ash, Samuel; Kusa, Tope; Camargo, Carlos A; Israel, Elliot

    2016-08-01

    Insulin resistance potentiates the association between obesity and childhood asthma, but this relationship appears inconsistent in relatively small studies of adults. We investigated effect modification in adults using the National Health and Nutrition Examination Survey 2003-2012, a large, nationally representative database.Insulin resistance and a history of physician-diagnosed current asthma were obtained from 12 421 adults, ages 18-85 years. We used logistic regression to determine associations between obesity and current asthma, adjusting for age, sex, race/ethnicity, poverty income ratio and smoking status. An interaction term evaluated effect modification by insulin resistance of the obesity-asthma association.As expected, obesity was positively associated with current asthma. Insulin resistance modified this association, with obesity measured as body mass index, waist circumference or waist-to-height ratio. The relationship between obesity and current asthma was stronger with increasing insulin resistance tertiles (OR 2.05, 95% CI 2.76-3.00; p-value for interaction 0.03). This association was robust to adjustments for other components of the metabolic syndrome (hypertriglyceridaemia, hypertension, hyperglycaemia and systemic inflammation). None of these components were themselves effect modifiers of the obesity-asthma association.In this large, nationally representative sample, insulin resistance modified the association between obesity and current asthma in adults. Targeting insulin resistance may represent a novel therapeutic strategy for obese patients with asthma. PMID:27103388

  7. Effects of stevioside on glucose transport activity in insulin-sensitive and insulin-resistant rat skeletal muscle.

    PubMed

    Lailerd, Narissara; Saengsirisuwan, Vitoon; Sloniger, Julie A; Toskulkao, Chaivat; Henriksen, Erik J

    2004-01-01

    Stevioside (SVS), a natural sweetener extracted from Stevia rebaudiana, has been used as an antihyperglycemic agent. However, little is known regarding its potential action on skeletal muscle, the major site of glucose disposal. Therefore, the purpose of the present study was to determine the effect of SVS treatment on skeletal muscle glucose transport activity in both insulin-sensitive lean (Fa/-) and insulin-resistant obese (fa/fa) Zucker rats. SVS was administered (500 mg/kg body weight by gavage) 2 hours before an oral glucose tolerance test (OGTT). Whereas the glucose incremental area under the curve (IAUC(glucose)) was not affected by SVS in lean Zucker rats, the insulin incremental area under the curve (IAUC(insulin)) and the glucose-insulin index (product of glucose and insulin IAUCs and inversely related to whole-body insulin sensitivity) were decreased (P<.05) by 42% and 45%, respectively. Interestingly, in the obese Zucker rat, SVS also reduced the IAUC(insulin) by 44%, and significantly decreased the IAUC(glucose) (30%) and the glucose-insulin index (57%). Muscle glucose transport was assessed following in vitro SVS treatment. In lean Zucker rats, basal glucose transport in type I soleus and type IIb epitrochlearis muscles was not altered by 0.01 to 0.1 mmol/L SVS. In contrast, 0.1 mmol/L SVS enhanced insulin-stimulated (2 mU/mL) glucose transport in both epitrochlearis (15%) and soleus (48%). At 0.5 mmol/L or higher, the SVS effect was reversed. Similarly, basal glucose transport in soleus and epitrochlearis muscles in obese Zucker rats was not changed by lower doses of SVS (0.01 to 0.1 mmol/L). However, these lower doses of SVS significantly increased insulin-stimulated glucose transport in both obese epitrochlearis and soleus (15% to 20%). In conclusion, acute oral SVS increased whole-body insulin sensitivity, and low concentrations of SVS (0.01 to 0.1 mmol/L) modestly improved in vitro insulin action on skeletal muscle glucose transport in both lean

  8. A Health Threat to Bystanders Living in the Homes of Smokers: How Smoke Toxins Deposited on Surfaces Can Cause Insulin Resistance

    PubMed Central

    Adhami, Neema; Starck, Shelley R.; Flores, Cristina; Martins Green, Manuela

    2016-01-01

    Thirdhand smoke (THS) is the accumulation of secondhand smoke on environmental surfaces. THS is found on the clothing and hair of smokers as well as on surfaces in homes and cars of smokers. Exposure occurs by ingestion, inhalation and dermal absorption. Children living in homes of smokers are at highest risk because they crawl on the floor, touch parents’ clothing/hair and household objects. Using mice exposed to THS under conditions that mimic exposure of humans, we show that THS increases cellular oxidative stress by increasing superoxide dismutase (SOD) activity and hydrogen peroxide (H2O2) levels while reducing the activity of antioxidant enzymes catalase and glutathione peroxidase (GPx) that break down H2O2 into H2O and O2. This results in lipid peroxidation, protein nitrosylation and DNA damage. Consequences of these cell and molecular changes are hyperglycemia and insulinemia. Indeed, we found reduced levels of insulin receptor, PI3K, AKT, all important molecules in insulin signaling and glucose uptake by cells. To determine whether these effects on THS-induced insulin resistance are due to increase in oxidative stress, we treated mice exposed to THS with the antioxidants N-acetyl cysteine (NAC) and alpha-tocopherol (alpha-toc) and showed that the oxidative stress, the molecular damage, and the insulin resistance, were significantly reversed. Conversely, feeding the mice with chow that mimics “western diet”, which is known to increase oxidative stress, while exposing the mice to THS, further increased the oxidative stress and aggravated hyperglycemia and insulinemia. In conclusion, THS exposure results in insulin resistance in the form of non-obese type II diabetes (NODII) through oxidative stress. If confirmed in humans, these studies could have a major impact on how people view exposure to environmental tobacco toxins, in particular to children, elderly and workers in environments where tobacco smoke has taken place. PMID:26934053

  9. A Health Threat to Bystanders Living in the Homes of Smokers: How Smoke Toxins Deposited on Surfaces Can Cause Insulin Resistance.

    PubMed

    Adhami, Neema; Starck, Shelley R; Flores, Cristina; Martins Green, Manuela

    2016-01-01

    Thirdhand smoke (THS) is the accumulation of secondhand smoke on environmental surfaces. THS is found on the clothing and hair of smokers as well as on surfaces in homes and cars of smokers. Exposure occurs by ingestion, inhalation and dermal absorption. Children living in homes of smokers are at highest risk because they crawl on the floor, touch parents' clothing/hair and household objects. Using mice exposed to THS under conditions that mimic exposure of humans, we show that THS increases cellular oxidative stress by increasing superoxide dismutase (SOD) activity and hydrogen peroxide (H2O2) levels while reducing the activity of antioxidant enzymes catalase and glutathione peroxidase (GPx) that break down H2O2 into H2O and O2. This results in lipid peroxidation, protein nitrosylation and DNA damage. Consequences of these cell and molecular changes are hyperglycemia and insulinemia. Indeed, we found reduced levels of insulin receptor, PI3K, AKT, all important molecules in insulin signaling and glucose uptake by cells. To determine whether these effects on THS-induced insulin resistance are due to increase in oxidative stress, we treated mice exposed to THS with the antioxidants N-acetyl cysteine (NAC) and alpha-tocopherol (alpha-toc) and showed that the oxidative stress, the molecular damage, and the insulin resistance, were significantly reversed. Conversely, feeding the mice with chow that mimics "western diet", which is known to increase oxidative stress, while exposing the mice to THS, further increased the oxidative stress and aggravated hyperglycemia and insulinemia. In conclusion, THS exposure results in insulin resistance in the form of non-obese type II diabetes (NODII) through oxidative stress. If confirmed in humans, these studies could have a major impact on how people view exposure to environmental tobacco toxins, in particular to children, elderly and workers in environments where tobacco smoke has taken place. PMID:26934053

  10. Severe Injury Is Associated With Insulin Resistance, Endoplasmic Reticulum Stress Response, and Unfolded Protein Response

    PubMed Central

    Jeschke, Marc G.; Finnerty, Celeste C.; Herndon, David N.; Song, Juquan; Boehning, Darren; Tompkins, Ronald G.; Baker, Henry V.; Gauglitz, Gerd G.

    2012-01-01

    Objective We determined whether postburn hyperglycemia and insulin resistance are associated with endoplasmic reticulum (ER) stress/unfolded protein response (UPR) activation leading to impaired insulin receptor signaling. Background Inflammation and cellular stress, hallmarks of severely burned and critically ill patients, have been causally linked to insulin resistance in type 2 diabetes via induction of ER stress and the UPR. Methods Twenty severely burned pediatric patients were compared with 36 nonburned children. Clinical markers, protein, and GeneChip analysis were used to identify transcriptional changes in ER stress and UPR and insulin resistance–related signaling cascades in peripheral blood leukocytes, fat, and muscle at admission and up to 466 days postburn. Results Burn-induced inflammatory and stress responses are accompanied by profound insulin resistance and hyperglycemia. Genomic and protein analysis revealed that burn injury was associated with alterations in the signaling pathways that affect insulin resistance, ER/sarcoplasmic reticulum stress, inflammation, and cell growth/apoptosis up to 466 days postburn. Conclusion Burn-induced insulin resistance is associated with persistent ER/sarcoplasmic reticulum stress/UPR and subsequent suppressed insulin receptor signaling over a prolonged period of time. PMID:22241293

  11. Pharyngeal collapsibility during sleep is elevated in insulin-resistant females with morbid obesity.

    PubMed

    Llanos, Oscar L; Galiatsatos, Panagis; Guzmán-Vélez, Edmarie; Patil, Susheel P; Smith, Philip L; Magnuson, Thomas; Schweitzer, Michael; Steele, Kimberley; Polotsky, Vsevolod Y; Schwartz, Alan R

    2016-06-01

    Insulin resistance is associated with sleep apnoea, leading us to hypothesise that it is also associated with elevations in pharyngeal collapsibility, even in the absence of sleep apnoea.90 bariatric patients were characterised for sleep apnoea, pharyngeal collapsibility and insulin resistance. Patients with a respiratory disturbance index (RDI) >10 events·h(-1), diabetes mellitus, tonsillar hypertrophy and pulmonary disease were excluded. The remaining 14 females underwent collapsibility measurements (passive critical pressure, Pcritp ) during non-rapid eye movement sleep. The homeostasis model assessment (HOMA) index, a measure of insulin resistance, was derived from measurements of fasting glucose and insulin levels, and compared to Pcritp Groups with high Pcritp compared to low Pcritp did not differ in age, body mass index or RDI. HOMA and insulin were elevated in the high Pcritp group compared to the low Pcritp group (p<0.02). Pcritp correlated with HOMA (Spearman's ρ=0.565, 95% CI 0.104-0.862; p=0.035) and insulin (Spearman's ρ=0.609 95% CI 0.196-0.835; p=0.021).Obese insulin-resistant subjects without frank diabetes or sleep apnoea demonstrate preclinical elevations in pharyngeal collapsibility, which may increase their susceptibility to sleep apnoea. Our findings suggest that insulin resistance could play a significant role in sleep apnoea pathogenesis by generating requisite elevations in pharyngeal collapsibility. PMID:27103392

  12. Correlations between surrogate measures of insulin resistance and cardiovascular risk factors in obese and overweight patients.

    PubMed

    Lerman, Israel; Villa, Antonio R; Ríos Torres, Juan Manuel; Tamez, Laura Elena; Gómez Pérez, Francisco; del Villar Velasco, Sonia Luna; Rull Rodrigo, Juan Antonio

    2003-01-01

    There are different equations to estimate insulin sensitivity by using OGTT with a reasonable approximation to whole body sensitivity obtained with the glucose clamp. Further work is needed to address their role in clinical practice as markers of the metabolic syndrome and predictors for cardiovascular disease. In the present study, we determined plasma glucose and insulin values during an OGTT test in 144 overweight and obese individuals. We assessed insulin resistance by the use of different equations and established their relationship with cardiovascular risk factors associated to the insulin resistance syndrome. Distributed the patients by quintiles of body mass index (BMI), the different surrogate measures clearly demonstrated that the more obese individuals were the most insulin resistant, a similar but not significant trend was observed related to the other cardiovascular risk factors. Efforts to use both fasting and post-load glucose and insulin concentrations to create indexes for routine use in clinical practice do not seem to be particularly useful in overweight or obese patients, as most of these patients will be insulin-resistant and insulin resistance is closely linked but not equal to the metabolic syndrome. PMID:12614971

  13. Effects of dipeptidyl peptidase-4 inhibitor in insulin-resistant rats with myocardial infarction.

    PubMed

    Apaijai, Nattayaporn; Inthachai, Tharnwimol; Lekawanvijit, Suree; Chattipakorn, Siriporn C; Chattipakorn, Nipon

    2016-06-01

    Adverse cardiac remodeling after myocardial infarction (MI) leads to progressive heart failure. Obese-insulin resistance increases risks of MI and heart failure. Although dipeptidyl peptidase-4 (DPP4) inhibitor is known to exert cardioprotection, its effects on adverse remodeling after MI in obese-insulin-resistant rats are unclear. We hypothesized that DPP4 inhibitor reduces adverse left ventricular (LV) remodeling and LV dysfunction in obese-insulin-resistant rats with MI. Rats were fed either normal diet (ND) or high-fat diet (HFD) for 12 weeks to induce obese-insulin resistance, followed by left anterior descending coronary artery ligation to induce MI. Then, rats in each dietary group were divided into five subgroups to receive vehicle, enalapril (10mg/kg/day), metformin (30mg/kg/day), DPP4 inhibitor vildagliptin (3mg/kg/day), or combined metformin and vildagliptin for 8 weeks. Heart rate variability (HRV), LV function, pathological and biochemical studies for LV remodeling, and cardiomyocyte apoptosis were determined. Obese-insulin-resistant rats had severe insulin resistance and LV dysfunction. HFD rats had a higher mortality rate than ND rats, and all treatments reduced the mortality rate in obese-insulin-resistant rats. Although all drugs improved insulin resistance, HRV, LV function as well as reduced cardiac hypertrophy and fibrosis, vildagliptin effectively reduced cardiomyocyte cross-sectional areas more than enalapril and was related to markedly decreased ERK1/2 phosphorylation. In ND rats with MI, metformin neither improved LV ejection fraction nor reduced cardiac fibrosis. The infarct size and transforming growth factor-β expression were not different among groups. In obese-insulin-resistant rats with chronic MI, DPP4 inhibitor vildagliptin exerts better cardioprotection than enalapril in attenuating adverse LV remodeling. PMID:27044778

  14. Investigation of the Relationship Between Chronic Stress and Insulin Resistance in a Chinese Population

    PubMed Central

    Yan, Yu-Xiang; Xiao, Huan-Bo; Wang, Si-Si; Zhao, Jing; He, Yan; Wang, Wei; Dong, Jing

    2016-01-01

    Background Chronic stress may facilitate the development of metabolic diseases. Insulin resistance is present long before the clinical manifestations of individual metabolic abnormalities. To explore whether chronic stress is an independent risk factor of insulin resistance, we investigated the relationship between the stress system, selected parameters of energy homeostasis, and insulin resistance in a Chinese population. Methods We recruited 766 workers employed at four companies in Beijing. The degree of insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR). The highest quartile of HOMA-IR among all study subjects was further defined as insulin resistance in our study. The short standard version of the Copenhagen Psychosocial Questionnaire (COPSOQ) was used to assess job-related psychosocial stress. Pearson’s correlation coefficients were calculated between cortisol level and HOMA-IR and components of metabolic syndrome, with stratification by gender. The relationship between cortisol and HOMA-IR independent of obesity was analyzed using a linear mixed model with company as a cluster unit. Results The values of the two scales of COPSOQ, including “demands at work” and “insecurity at work”, were significantly associated with insulin resistance and cortisol concentration (P < 0.05). Cortisol was significantly positively correlated with glucose, HOMA-IR, and waist circumference in males and females (P < 0.05). After adjusting for potential confounders, cortisol was an independent positive predictor for HOMA-IR (P < 0.05). Conclusions These findings showed that chronic stress was associated with insulin resistance and may contribute to the development of insulin resistance. PMID:26830350

  15. Effect of Phosphodiesterase Inhibition on Insulin Resistance in Obese Individuals

    PubMed Central

    Ho, Jennifer E.; Arora, Pankaj; Walford, Geoffrey A.; Ghorbani, Anahita; Guanaga, Derek P.; Dhakal, Bishnu P.; Nathan, Daniel I.; Buys, Emmanuel S.; Florez, Jose C.; Newton‐Cheh, Christopher; Lewis, Gregory D.; Wang, Thomas J.

    2014-01-01

    Background Obesity is associated with cardiometabolic disease, including insulin resistance (IR) and diabetes. Cyclic guanosine monophosphate (cGMP) signaling affects energy balance, IR, and glucose metabolism in experimental models. We sought to examine effects of phosphodiesterase‐5 inhibition with tadalafil on IR in a pilot study of obese nondiabetic individuals. Methods and Results We conducted a randomized, double‐blinded, placebo‐controlled trial of adults age 18 to 50 years with obesity and elevated fasting insulin levels (≥10 μU/mL). Participants were randomized to tadalafil 20 mg daily or placebo for 3 months. Oral glucose tolerance tests were performed, and the effect of tadalafil on IR was examined. A total of 53 participants (mean age, 33 years; body mass index [BMI], 38 kg/m2) were analyzed, 25 randomized to tadalafil and 28 to placebo. In the overall sample, measures of IR did not differ between tadalafil and placebo groups at 3 months. However, in individuals with severe obesity (BMI ≥36.2 kg/m2), tadalafil use was associated with improved IR (homeostatic model assessment for IR), compared to placebo (P=0.02, respectively). Furthermore, one measure of β‐cell compensation for IR (oral disposition index) improved with tadalafil in the overall sample (P=0.009) and in the subgroup with severe obesity (P=0.01). Conclusion Results of this pilot study did not show improvements in IR with tadalafil, compared to placebo. However, tadalafil may have favorable effects on β‐cell compensation, particularly in individuals with severe obesity. Future studies evaluating the potential metabolic benefits of cGMP modulation in obesity are warranted. Clinical Trial Registration URL: ClinicalTrials.gov. Unique Identifier: NCT01444651. PMID:25213566

  16. Adipose Cell Size and Regional Fat Deposition as Predictors of Metabolic Response to Overfeeding in Insulin-Resistant and Insulin-Sensitive Humans.

    PubMed

    McLaughlin, Tracey; Craig, Colleen; Liu, Li-Fen; Perelman, Dalia; Allister, Candice; Spielman, Daniel; Cushman, Samuel W

    2016-05-01

    Obesity is associated with insulin resistance, but significant variability exists between similarly obese individuals, pointing to qualitative characteristics of body fat as potential mediators. To test the hypothesis that obese, insulin-sensitive (IS) individuals possess adaptive adipose cell/tissue responses, we measured subcutaneous adipose cell size, insulin suppression of lipolysis, and regional fat responses to short-term overfeeding in BMI-matched overweight/obese individuals classified as IS or insulin resistant (IR). At baseline, IR subjects exhibited significantly greater visceral adipose tissue (VAT), intrahepatic lipid (IHL), plasma free fatty acids, adipose cell diameter, and percentage of small adipose cells. With weight gain (3.1 ± 1.4 kg), IR subjects demonstrated no significant change in adipose cell size, VAT, or insulin suppression of lipolysis and only 8% worsening of insulin-mediated glucose uptake (IMGU). Alternatively, IS subjects demonstrated significant adipose cell enlargement; decrease in the percentage of small adipose cells; increase in VAT, IHL, and lipolysis; 45% worsening of IMGU; and decreased expression of lipid metabolism genes. Smaller baseline adipose cell size and greater enlargement with weight gain predicted decline in IMGU, as did increase in IHL and VAT and decrease in insulin suppression of lipolysis. Weight gain in IS humans causes maladaptive changes in adipose cells, regional fat distribution, and insulin resistance. The correlation between development of insulin resistance and changes in adipose cell size, VAT, IHL, and insulin suppression of lipolysis highlight these factors as potential mediators between obesity and insulin resistance. PMID:26884438

  17. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage.

    PubMed

    Muniyappa, Ranganath; Lee, Sihoon; Chen, Hui; Quon, Michael J

    2008-01-01

    Insulin resistance contributes to the pathophysiology of diabetes and is a hallmark of obesity, metabolic syndrome, and many cardiovascular diseases. Therefore, quantifying insulin sensitivity/resistance in humans and animal models is of great importance for epidemiological studies, clinical and basic science investigations, and eventual use in clinical practice. Direct and indirect methods of varying complexity are currently employed for these purposes. Some methods rely on steady-state analysis of glucose and insulin, whereas others rely on dynamic testing. Each of these methods has distinct advantages and limitations. Thus, optimal choice and employment of a specific method depends on the nature of the studies being performed. Established direct methods for measuring insulin sensitivity in vivo are relatively complex. The hyperinsulinemic euglycemic glucose clamp and the insulin suppression test directly assess insulin-mediated glucose utilization under steady-state conditions that are both labor and time intensive. A slightly less complex indirect method relies on minimal model analysis of a frequently sampled intravenous glucose tolerance test. Finally, simple surrogate indexes for insulin sensitivity/resistance are available (e.g., QUICKI, HOMA, 1/insulin, Matusda index) that are derived from blood insulin and glucose concentrations under fasting conditions (steady state) or after an oral glucose load (dynamic). In particular, the quantitative insulin sensitivity check index (QUICKI) has been validated extensively against the reference standard glucose clamp method. QUICKI is a simple, robust, accurate, reproducible method that appropriately predicts changes in insulin sensitivity after therapeutic interventions as well as the onset of diabetes. In this Frontiers article, we highlight merits, limitations, and appropriate use of current in vivo measures of insulin sensitivity/resistance. PMID:17957034

  18. Fine-mapping diabetes-related traits, including insulin resistance, in heterogeneous stock rats.

    PubMed

    Solberg Woods, Leah C; Holl, Katie L; Oreper, Daniel; Xie, Yuying; Tsaih, Shirng-Wern; Valdar, William

    2012-11-01

    Type 2 diabetes (T2D) is a disease of relative insulin deficiency resulting from both insulin resistance and beta cell failure. We have previously used heterogeneous stock (HS) rats to fine-map a locus for glucose tolerance. We show here that glucose intolerance in the founder strains of the HS colony is mediated by different mechanisms: insulin resistance in WKY and an insulin secretion defect in ACI, and we demonstrate a high degree of variability for measures of insulin resistance and insulin secretion in HS rats. As such, our goal was to use HS rats to fine-map several diabetes-related traits within a region on rat chromosome 1. We measured blood glucose and plasma insulin levels after a glucose tolerance test in 782 male HS rats. Using 97 SSLP markers, we genotyped a 68 Mb region on rat chromosome 1 previously implicated in glucose and insulin regulation. We used linkage disequilibrium mapping by mixed model regression with inferred descent to identify a region from 198.85 to 205.9 that contains one or more quantitative trait loci (QTL) for fasting insulin and a measure of insulin resistance, the quantitative insulin sensitivity check index. This region also encompasses loci identified for fasting glucose and Insulin_AUC (area under the curve). A separate <3 Mb QTL was identified for body weight. Using a novel penalized regression method we then estimated effects of alternative haplotype pairings under each locus. These studies highlight the utility of HS rats for fine-mapping genetic loci involved in the underlying causes of T2D. PMID:22947656

  19. Impact of obesity and insulin-resistance on cirrhosis and portal hypertension.

    PubMed

    Berzigotti, Annalisa; Abraldes, Juan G

    2013-10-01

    Obesity is sharply rising worldwide and is increasingly recognized in patients with cirrhosis. This review summarizes the available data documenting a detrimental role of obesity and insulin-resistance on the risk of appearance of clinical events in patients with cirrhosis. Molecular pathways explaining the harmful effect of obesity and insulin resistance in the natural history of cirrhosis are largely unknown. Increasing knowledge of mechanisms leading to white adipose tissue dysfunction on one side, and to portal hypertension on the other side, allow hypothesizing that a link between the pathophysiology of obesity, insulin resistance and portal hypertension in cirrhosis exists. Mechanisms likely involved in this interplay are discussed in this article. PMID:23731977

  20. Heterozygous caveolin-3 mice show increased susceptibility to palmitate-induced insulin resistance.

    PubMed

    Talukder, M A Hassan; Preda, Marilena; Ryzhova, Larisa; Prudovsky, Igor; Pinz, Ilka M

    2016-03-01

    Insulin resistance and diabetes are comorbidities of obesity and affect one in 10 adults in the United States. Despite the high prevalence, the mechanisms of cardiac insulin resistance in obesity are still unclear. We test the hypothesis that the insulin receptor localizes to caveolae and is regulated through binding to caveolin-3 (CAV3). We further test whether haploinsufficiency forCAV3 increases the susceptibility to high-fat-induced insulin resistance. We used in vivo and in vitro studies to determine the effect of palmitate exposure on global insulin resistance, contractile performance of the heart in vivo, glucose uptake in the heart, and on cellular signaling downstream of theIR We show that haploinsufficiency forCAV3 increases susceptibility to palmitate-induced global insulin resistance and causes cardiomyopathy. On the basis of fluorescence energy transfer (FRET) experiments, we show thatCAV3 andIRdirectly interact in cardiomyocytes. Palmitate impairs insulin signaling by a decrease in insulin-stimulated phosphorylation of Akt that corresponds to an 87% decrease in insulin-stimulated glucose uptake inHL-1 cardiomyocytes. Despite loss of Akt phosphorylation and lower glucose uptake, palmitate increased insulin-independent serine phosphorylation ofIRS-1 by 35%. In addition, we found lipid induced downregulation ofCD36, the fatty acid transporter associated with caveolae. This may explain the problem the diabetic heart is facing with the simultaneous impairment of glucose uptake and lipid transport. Thus, these findings suggest that loss ofCAV3 interferes with downstream insulin signaling and lipid uptake, implicatingCAV3 as a regulator of theIRand regulator of lipid uptake in the heart. PMID:27033451

  1. Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training

    PubMed Central

    Roberts, Christian K.; Hevener, Andrea L.; Barnard, R. James

    2014-01-01

    Metabolic syndrome (MS) is a collection of cardiometabolic risk factors that includes obesity, insulin resistance, hypertension, and dyslipidemia. Although there has been significant debate regarding the criteria and concept of the syndrome, this clustering of risk factors is unequivocally linked to an increased risk of developing type 2 diabetes and cardiovascular disease. Regardless of the true definition, based on current population estimates, nearly 100 million have MS. It is often characterized by insulin resistance, which some have suggested is a major underpinning link between physical inactivity and MS. The purpose of this review is to: (i) provide an overview of the history, causes and clinical aspects of MS, (ii) review the molecular mechanisms of insulin action and the causes of insulin resistance, and (iii) discuss the epidemiological and intervention data on the effects of exercise on MS and insulin sensitivity. PMID:23720280

  2. The Role of PTP1B O-GlcNAcylation in Hepatic Insulin Resistance

    PubMed Central

    Zhao, Yun; Tang, Zhuqi; Shen, Aiguo; Tao, Tao; Wan, Chunhua; Zhu, Xiaohui; Huang, Jieru; Zhang, Wanlu; Xia, Nana; Wang, Suxin; Cui, Shiwei; Zhang, Dongmei

    2015-01-01

    Protein tyrosine phosphatase 1B (PTP1B), which can directly dephosphorylate both the insulin receptor and insulin receptor substrate 1 (IRS-1), thereby terminating insulin signaling, reportedly plays an important role in insulin resistance. Accumulating evidence has demonstrated that O-GlcNAc modification regulates functions of several important components of insulin signal pathway. In this study, we identified that PTP1B is modified by O-GlcNAcylation at three O-GlcNAc sites (Ser104, Ser201, and Ser386). Palmitate acid (PA) impaired the insulin signaling, indicated by decreased phosphorylation of both serine/threonine-protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK3β) following insulin administration, and upregulated PTP1B O-GlcNAcylation in HepG2 cells. Compared with the wild-type, intervention PTP1B O-GlcNAcylation by site-directed gene mutation inhibited PTP1B phosphatase activity, resulted in a higher level of phosphorylated Akt and GSK3β, recovered insulin sensitivity, and improved lipid deposition in HepG2 cells. Taken together, our research showed that O-GlcNAcylation of PTP1B can influence insulin signal transduction by modulating its own phosphatase activity, which participates in the process of hepatic insulin resistance. PMID:26402673

  3. Unaltered Prion Pathogenesis in a Mouse Model of High-Fat Diet-Induced Insulin Resistance

    PubMed Central

    Zhu, Caihong; Schwarz, Petra; Abakumova, Irina; Aguzzi, Adriano

    2015-01-01

    Epidemiological, clinical, and experimental animal studies suggest a strong correlation between insulin resistance and Alzheimer’s disease. In fact, type-2 diabetes is considered an important risk factor of developing Alzheimer’s disease. In addition, impaired insulin signaling in the Alzheimer’s disease brain may promote Aβ production, impair Aβ clearance and induce tau hyperphosphorylation, thereby leading to deterioration of the disease. The pathological prion protein, PrPSc, deposits in the form of extracellular aggregates and leads to dementia, raising the question as to whether prion pathogenesis may also be affected by insulin resistance. We therefore established high-fat diet-induced insulin resistance in tga20 mice, which overexpress the prion protein. We then inoculated the insulin-resistant mice with prions. We found that insulin resistance in tga20 mice did not affect prion disease progression, PrPSc deposition, astrogliosis or microglial activation, and had no effect on survival. Our study demonstrates that in a mouse model, insulin resistance does not significantly contribute to prion pathogenesis. PMID:26658276

  4. Insulin Resistance in Human iPS Cells Reduces Mitochondrial Size and Function

    PubMed Central

    Burkart, Alison M.; Tan, Kelly; Warren, Laura; Iovino, Salvatore; Hughes, Katelyn J.; Kahn, C. Ronald; Patti, Mary-Elizabeth

    2016-01-01

    Insulin resistance, a critical component of type 2 diabetes (T2D), precedes and predicts T2D onset. T2D is also associated with mitochondrial dysfunction. To define the cause-effect relationship between insulin resistance and mitochondrial dysfunction, we compared mitochondrial metabolism in induced pluripotent stem cells (iPSC) from 5 healthy individuals and 4 patients with genetic insulin resistance due to insulin receptor mutations. Insulin-resistant iPSC had increased mitochondrial number and decreased mitochondrial size. Mitochondrial oxidative function was impaired, with decreased citrate synthase activity and spare respiratory capacity. Simultaneously, expression of multiple glycolytic enzymes was decreased, while lactate production increased 80%. These perturbations were accompanied by an increase in ADP/ATP ratio and 3-fold increase in AMPK activity, indicating energetic stress. Insulin-resistant iPSC also showed reduced catalase activity and increased susceptibility to oxidative stress. Thus, insulin resistance can lead to mitochondrial dysfunction with reduced mitochondrial size, oxidative activity, and energy production. PMID:26948272

  5. Effect of a p38 MAPK inhibitor on FFA-induced hepatic insulin resistance in vivo

    PubMed Central

    Pereira, S; Yu, W Q; Moore, J; Mori, Y; Tsiani, E; Giacca, A

    2016-01-01

    The mechanisms whereby prolonged plasma free fatty acids elevation, as found in obesity, causes hepatic insulin resistance are not fully clarified. We herein investigated whether inhibition of p38 mitogen-activated protein kinase (MAPK) prevented hepatic insulin resistance following prolonged lipid infusion. Chronically cannulated rats were subdivided into one of four intravenous (i.v.) treatments that lasted 48 h: Saline (5.5 μl min−1), Intralipid plus heparin (IH, 20% Intralipid+20 U ml−1 heparin; 5.5 μl min−1), IH+p38 MAPK inhibitor (SB239063) and SB239063 alone. During the last 2 h of treatment, a hyperinsulinemic (5 mU kg−1 min−1) euglycemic clamp together with [3-3H] glucose methodology was carried out to distinguish hepatic from peripheral insulin sensitivity. We found that SB239063 prevented IH-induced hepatic insulin resistance, but not peripheral insulin resistance. SB239063 also prevented IH-induced phosphorylation of activating transcription factor 2 (ATF2), a marker of p38 MAPK activity, in the liver. Moreover, in another lipid infusion model in mice, SB239063 prevented hepatic but not peripheral insulin resistance caused by 48 h combined ethyloleate plus ethylpalmitate infusion. Our results suggest that inhibition of p38 MAPK may be a useful strategy in alleviating hepatic insulin resistance in obesity-associated disorders. PMID:27136448

  6. Effect of a p38 MAPK inhibitor on FFA-induced hepatic insulin resistance in vivo.

    PubMed

    Pereira, S; Yu, W Q; Moore, J; Mori, Y; Tsiani, E; Giacca, A

    2016-01-01

    The mechanisms whereby prolonged plasma free fatty acids elevation, as found in obesity, causes hepatic insulin resistance are not fully clarified. We herein investigated whether inhibition of p38 mitogen-activated protein kinase (MAPK) prevented hepatic insulin resistance following prolonged lipid infusion. Chronically cannulated rats were subdivided into one of four intravenous (i.v.) treatments that lasted 48 h: Saline (5.5 μl min(-1)), Intralipid plus heparin (IH, 20% Intralipid+20 U ml(-1) heparin; 5.5 μl min(-1)), IH+p38 MAPK inhibitor (SB239063) and SB239063 alone. During the last 2 h of treatment, a hyperinsulinemic (5 mU kg(-1) min(-1)) euglycemic clamp together with [3-(3)H] glucose methodology was carried out to distinguish hepatic from peripheral insulin sensitivity. We found that SB239063 prevented IH-induced hepatic insulin resistance, but not peripheral insulin resistance. SB239063 also prevented IH-induced phosphorylation of activating transcription factor 2 (ATF2), a marker of p38 MAPK activity, in the liver. Moreover, in another lipid infusion model in mice, SB239063 prevented hepatic but not peripheral insulin resistance caused by 48 h combined ethyloleate plus ethylpalmitate infusion. Our results suggest that inhibition of p38 MAPK may be a useful strategy in alleviating hepatic insulin resistance in obesity-associated disorders. PMID:27136448

  7. Inhibition of Carnitine Palmitoyltransferase-1 Activity Alleviates Insulin Resistance in Diet-Induced Obese Mice

    PubMed Central

    Keung, Wendy; Ussher, John R.; Jaswal, Jagdip S.; Raubenheimer, Monique; Lam, Victoria H.M.; Wagg, Cory S.; Lopaschuk, Gary D.

    2013-01-01

    Impaired skeletal muscle fatty acid oxidation has been suggested to contribute to insulin resistance and glucose intolerance. However, increasing muscle fatty acid oxidation may cause a reciprocal decrease in glucose oxidation, which might impair insulin sensitivity and glucose tolerance. We therefore investigated what effect inhibition of mitochondrial fatty acid uptake has on whole-body glucose tolerance and insulin sensitivity in obese insulin-resistant mice. C57BL/6 mice were fed a high-fat diet (60% calories from fat) for 12 weeks to develop insulin resistance. Subsequent treatment of mice for 4 weeks with the carnitine palmitoyltransferase-1 inhibitor, oxfenicine (150 mg/kg i.p. daily), resulted in improved whole-body glucose tolerance and insulin sensitivity. Exercise capacity was increased in oxfenicine-treated mice, which was accompanied by an increased respiratory exchange ratio. In the gastrocnemius muscle, oxfenicine increased pyruvate dehydrogenase activity, membrane GLUT4 content, and insulin-stimulated Akt phosphorylation. Intramyocellular levels of lipid intermediates, including ceramide, long-chain acyl CoA, and diacylglycerol, were also decreased. Our results demonstrate that inhibition of mitochondrial fatty acid uptake improves insulin sensitivity in diet-induced obese mice. This is associated with increased carbohydrate utilization and improved insulin signaling in the skeletal muscle, suggestive of an operating Randle Cycle in muscle. PMID:23139350

  8. Inhibition of carnitine palmitoyltransferase-1 activity alleviates insulin resistance in diet-induced obese mice.

    PubMed

    Keung, Wendy; Ussher, John R; Jaswal, Jagdip S; Raubenheimer, Monique; Lam, Victoria H M; Wagg, Cory S; Lopaschuk, Gary D

    2013-03-01

    Impaired skeletal muscle fatty acid oxidation has been suggested to contribute to insulin resistance and glucose intolerance. However, increasing muscle fatty acid oxidation may cause a reciprocal decrease in glucose oxidation, which might impair insulin sensitivity and glucose tolerance. We therefore investigated what effect inhibition of mitochondrial fatty acid uptake has on whole-body glucose tolerance and insulin sensitivity in obese insulin-resistant mice. C57BL/6 mice were fed a high-fat diet (60% calories from fat) for 12 weeks to develop insulin resistance. Subsequent treatment of mice for 4 weeks with the carnitine palmitoyltransferase-1 inhibitor, oxfenicine (150 mg/kg i.p. daily), resulted in improved whole-body glucose tolerance and insulin sensitivity. Exercise capacity was increased in oxfenicine-treated mice, which was accompanied by an increased respiratory exchange ratio. In the gastrocnemius muscle, oxfenicine increased pyruvate dehydrogenase activity, membrane GLUT4 content, and insulin-stimulated Akt phosphorylation. Intramyocellular levels of lipid intermediates, including ceramide, long-chain acyl CoA, and diacylglycerol, were also decreased. Our results demonstrate that inhibition of mitochondrial fatty acid uptake improves insulin sensitivity in diet-induced obese mice. This is associated with increased carbohydrate utilization and improved insulin signaling in the skeletal muscle, suggestive of an operating Randle Cycle in muscle. PMID:23139350

  9. Muscle-specific vascular endothelial growth factor deletion induces muscle capillary rarefaction creating muscle insulin resistance.

    PubMed

    Bonner, Jeffrey S; Lantier, Louise; Hasenour, Clinton M; James, Freyja D; Bracy, Deanna P; Wasserman, David H

    2013-02-01

    Muscle insulin resistance is associated with a reduction in vascular endothelial growth factor (VEGF) action and muscle capillary density. We tested the hypothesis that muscle capillary rarefaction critically contributes to the etiology of muscle insulin resistance in chow-fed mice with skeletal and cardiac muscle VEGF deletion (mVEGF(-/-)) and wild-type littermates (mVEGF(+/+)) on a C57BL/6 background. The mVEGF(-/-) mice had an ~60% and ~50% decrease in capillaries in skeletal and cardiac muscle, respectively. The mVEGF(-/-) mice had augmented fasting glucose turnover. Insulin-stimulated whole-body glucose disappearance was blunted in mVEGF(-/-) mice. The reduced peripheral glucose utilization during insulin stimulation was due to diminished in vivo cardiac and skeletal muscle insulin action and signaling. The decreased insulin-stimulated muscle glucose uptake was independent of defects in insulin action at the myocyte, suggesting that the impairment in insulin-stimulated muscle glucose uptake was due to poor muscle perfusion. The deletion of VEGF in cardiac muscle did not affect cardiac output. These studies emphasize the importance for novel therapeutic approaches that target the vasculature in the treatment of insulin-resistant muscle. PMID:23002035

  10. Resveratrol improves insulin signaling in a tissue-specific manner under insulin-resistant conditions only: in vitro and in vivo experiments in rodents.

    PubMed

    Kang, Wonyoung; Hong, Hyun Ju; Guan, Jian; Kim, Dong Geon; Yang, Eun-Jin; Koh, Gwanpyo; Park, Doekbae; Han, Chang Hoon; Lee, Young-Jae; Lee, Dae-Ho

    2012-03-01

    Resveratrol (RSV) has various metabolic effects, especially with relatively high-dose therapy. However, the ability of RSV to modulate insulin signaling has not been completely evaluated. Here, we determined whether RSV alters insulin signaling in insulin-responsive cells and tissues. The effects of RSV on insulin signaling in 3T3-L1 adipocytes under both insulin-sensitive and insulin-resistant states and in insulin-sensitive tissues of high fat-fed diet-induced obese (DIO) mice were investigated. Insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation (Y612) was suppressed in RSV-treated adipocytes compared with untreated adipocytes, as was the insulin-stimulated Akt phosphorylation (Ser473). However, under an insulin-resistant condition that was made by incubating 3T3-L1 adipocytes in the conditioned medium from lipopolysaccharide-stimulated LAW264.7 cells, RSV reduced inducible nitric oxide synthase expression and IκBα protein degradation and improved insulin-stimulated Akt phosphorylation (Ser473). In DIO mice, relatively low-dose RSV (30 mg/kg daily for 2 weeks) therapy lowered fasting blood glucose level and serum insulin, increased hepatic glycogen content, and ameliorated fatty liver without change in body weight. The insulin-stimulated Akt phosphorylation was decreased in the liver and white adipose tissue of DIO mice, but it was completely normalized by RSV treatment. However, in the skeletal muscle of DIO mice, insulin signaling was not improved by RSV treatment, whereas the phosphorylation of adenosine monophosphate-activated protein kinase α (Thr172) was improved by it. Our results show that RSV enhances insulin action only under insulin-resistant conditions and suggest that the effect of RSV may depend on the type of tissue being targeted and its metabolic status. PMID:21945106

  11. Hepatic NF-κB essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis

    PubMed Central

    Wunderlich, F. Thomas; Luedde, Tom; Singer, Stephan; Schmidt-Supprian, Marc; Baumgartl, Julia; Schirmacher, Peter; Pasparakis, Manolis; Brüning, Jens C.

    2008-01-01

    Development of obesity-associated insulin resistance and diabetes mellitus type 2 has been linked to activation of proinflammatory pathways in the liver, leading to impaired insulin signal transduction. To further define the role of hepatic NF-κB activation in this process, we have analyzed glucose metabolism in mice with liver-specific inactivation of the NF-κB essential modulator gene (NEMOL-KO mice) exposed to a high-fat diet (HFD). These animals are protected from the development of obesity-associated insulin resistance, highlighting the importance of hepatic NF-κB activation in this context. However, hepatic NEMO deficiency synergizes with HFD in the development of liver steatosis as a consequence of decreased peroxisome proliferator-activated receptor (PPAR-α) and increased PPAR-γ expression. Steatosis interacts with increased inflammation, causing elevated apoptosis in the livers of these mice under HFD. These changes result in liver tumorigenesis of NEMOL-KO mice under normal diet, a process that is largely aggravated when these mice are exposed to HFD. These data directly demonstrate the interaction of hepatic inflammation, dietary composition, and metabolism in the development of liver tumorigenesis. PMID:18216263

  12. Effect of folic acid on homocysteine and insulin resistance of overweight and obese children and adolescents

    PubMed Central

    Dehkordi, Elham Hashemi; Sedehi, Morteza; Shahraki, Zohre Gholipour; Najafi, Reza

    2016-01-01

    Background: Considering the increasing trend of childhood obesity and subsequent burden of the disease in Iran and other countries and importance of early life intervention for achieving sustained effect on health of children and adolescents, this study aimed to investigate the effect of two different dose of folic acid on homocysteine (Hcy) level and insulin resistance of obese children. Materials and Methods: In this randomized, double-blind controlled clinical trial study, 60 obese and overweight children aged 5–12 years were enrolled. Selected obese children randomly allocated in two interventional (1 mg/day folic acid and 5 mg/day folic acid, for 8 weeks) and one control groups. Biochemical measurements including folic acid, Hcy, insulin and insulin resistance were measured between and within groups before and after trial. Results: In each group, 20 obese children were studied. The three groups were age and sex matched. After folic acid administration, mean of Hcy, insulin resistance and insulin decreased significantly in two groups which folic acid administrated with two different doses (P < 0.05). The reduction in studied biochemical variables was similar in two interventional groups (1 and 5 mg folic acid daily) (P > 0.05). Mean differences for Hcy, insulin resistance and insulin, in two intervention groups were significantly higher than the control group (P < 0.0001). Mean differences of Hcy, insulin resistance and insulin, in two intervention groups were not different significantly (P > 0.05). Conclusion: The findings of current trial showed that folic acid in two studied doses could be a safe and effective supplement for obese children to reduce Hcy level and insulin resistance, which consequently could prevent obesity-related complications including cardiovascular and metabolic disorders. PMID:27274503

  13. Insulin resistance for glucose metabolism in disused soleus muscle of mice

    NASA Technical Reports Server (NTRS)

    Seider, M. J.; Nicholson, W. F.; Booth, F. W.

    1981-01-01

    Results of this study on mice provide the first direct evidence of insulin resistance for glucose metabolism in skeletal muscle that has undergone a previous period of reduced muscle usage. This lack of responsiveness to insulin developed in one day and in the presence of hypoinsulinemia. Future studies will utilize the model of hindlimb immobilization to determine the causes of these changes.

  14. Gamma-carboxylation of osteocalcin and insulin resistance in older men and women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Context: The uncarboxylated form of osteocalcin (OC), a protein synthesized in bone, may influence glucose and insulin metabolism. Objective: Our purpose was to examine the cross-sectional associations between circulating ucOC and measures of insulin resistance and inflammation in humans. Design , ...

  15. PI3-kinase mutation linked to insulin and growth factor resistance in vivo.

    PubMed

    Winnay, Jonathon N; Solheim, Marie H; Dirice, Ercument; Sakaguchi, Masaji; Noh, Hye-Lim; Kang, Hee Joon; Takahashi, Hirokazu; Chudasama, Kishan K; Kim, Jason K; Molven, Anders; Kahn, C Ronald; Njølstad, Pål R

    2016-04-01

    The phosphatidylinositol 3-kinase (PI3K) signaling pathway is central to the action of insulin and many growth factors. Heterozygous mutations in the gene encoding the p85α regulatory subunit of PI3K (PIK3R1) have been identified in patients with SHORT syndrome - a disorder characterized by short stature, partial lipodystrophy, and insulin resistance. Here, we evaluated whether SHORT syndrome-associated PIK3R1 mutations account for the pathophysiology that underlies the abnormalities by generating knockin mice that are heterozygous for the Pik3r1Arg649Trp mutation, which is homologous to the mutation found in the majority of affected individuals. Similar to the patients, mutant mice exhibited a reduction in body weight and length, partial lipodystrophy, and systemic insulin resistance. These derangements were associated with a reduced capacity of insulin and other growth factors to activate PI3K in liver, muscle, and fat; marked insulin resistance in liver and fat of mutation-harboring animals; and insulin resistance in vitro in cells derived from these mice. In addition, mutant mice displayed defective insulin secretion and GLP-1 action on islets in vivo and in vitro. These data demonstrate the ability of this heterozygous mutation to alter PI3K activity in vivo and the central role of PI3K in insulin/growth factor action, adipocyte function, and glucose metabolism. PMID:26974159

  16. Odontella aurita-enriched diet prevents high fat diet-induced liver insulin resistance.

    PubMed

    Amine, Hamza; Benomar, Yacir; Haimeur, Adil; Messaouri, Hafida; Meskini, Nadia; Taouis, Mohammed

    2016-01-01

    The beneficial effect of polyunsaturated omega-3 fatty acid (w-3 FA) consumption regarding cardiovascular diseases, insulin resistance and inflammation has been widely reported. Fish oil is considered as the main source of commercialized w-3 FAs, and other alternative sources have been reported such as linseed or microalgae. However, despite numerous reports, the underlying mechanisms of action of w-3 FAs on insulin resistance are still not clearly established, especially those from microalgae. Here, we report that Odontella aurita, a microalga rich in w-3 FAs eicosapentaenoic acid, prevents high fat diet-induced insulin resistance and inflammation in the liver of Wistar rats. Indeed, a high fat diet (HFD) increased plasma insulin levels associated with the impairment of insulin receptor signaling and the up-regulation of toll-like receptor 4 (TLR4) expressions. Importantly, Odontella aurita-enriched HFD (HFOA) reduces body weight and plasma insulin levels and maintains normal insulin receptor expression and responsiveness. Furthermore, HFOA decreased TLR4 expression, JNK/p38 phosphorylation and pro-inflammatory factors. In conclusion, we demonstrate for the first time, to our knowledge, that diet supplementation with whole Ondontella aurita overcomes HFD-induced insulin resistance through the inhibition of TLR4/JNK/p38 MAP kinase signaling pathways. PMID:26459640

  17. Evidence of Insulin Resistance in Adult Uncomplicated Malaria: Result of a Two-Year Prospective Study

    PubMed Central

    Acquah, Samuel; Boampong, Johnson Nyarko; Eghan Jnr, Benjamin Ackon; Eriksson, Magdalena

    2014-01-01

    The study aimed at investigating the effects of adult uncomplicated malaria on insulin resistance. Fasting levels of blood glucose (FBG), glycosylated hemoglobin (HbA1c), and serum insulin were measured in 100 diabetics and 100 age-matched controls before and during Plasmodium falciparum malaria. Insulin resistance and beta cell function were computed by homeostatic models assessment of insulin resistance (HOMAIR) and beta cell function (HOMAB) formulae, respectively. Body mass index (BMI) was computed. At baseline, diabetics had significantly (P < 0.05) higher levels of BMI, FBG, HbA1c, and HOMAIR but lower level of HOMAB than controls. Baseline insulin levels were comparable (P > 0.05) between the two study groups. During malaria, diabetics maintained significantly (P < 0.05) higher levels of BMI, FBG, and HbA1c but lower levels of insulin and HOMAB than controls. Malaria-induced HOMAIR levels were comparable (P > 0.05) between the two study groups but higher than baseline levels. Apart from BMI and HOMAB, mean levels of all the remaining parameters increased in malaria-infected controls. In malaria-infected diabetics, significant (P < 0.05) increase was only observed for insulin and HOMAIR but not the other measured parameters. Uncomplicated malaria increased insulin resistance in diabetics and controls independent of BMI. This finding may have implications for the evolution of T2DM in malaria-endemic regions. PMID:25587486

  18. The effect of cinnamon extract on insulin resistance parameters in polycystic ovary syncrome: a pilot study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: To evaluate the effects of oral cinnamon extract on insulin resistance parameters. Methods: 15 women with polycystic ovary syndrome were enrolled in a prospective, randomized, placebo-controlled, double-blinded clinical trial. Fasting glucose and insulin levels, homeostasis model insu...

  19. Quantitative secretome and glycome of primary human adipocytes during insulin resistance

    PubMed Central

    2014-01-01

    Adipose tissue is both an energy storage depot and an endocrine organ. The impaired regulation of the secreted proteins of adipose tissue, known as adipocytokines, observed during obesity contributes to the onset of whole-body insulin resistance and the pathobiology of type 2 diabetes mellitus (T2DM). In addition, the global elevation of the intracellular glycosylation of proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) via either genetic or pharmacological methods is sufficient to induce insulin resistance in both cultured cells and animal models. The elevation of global O-GlcNAc levels is associated with the altered expression of many adipocytokines. We have previously characterized the rodent adipocyte secretome during insulin sensitive and insulin resistant conditions. Here, we characterize and quantify the secretome and glycome of primary human adipocytes during insulin responsive and insulin resistant conditions generated by the classical method of hyperglycemia and hyperinsulinemia or by the pharmacological manipulation of O-GlcNAc levels. Using a proteomic approach, we identify 190 secreted proteins and report a total of 20 up-regulated and 6 down-regulated proteins that are detected in both insulin resistant conditions. Moreover, we apply glycomic techniques to examine (1) the sites of N-glycosylation on secreted proteins, (2) the structures of complex N- and O-glycans, and (3) the relative abundance of complex N- and O-glycans structures in insulin responsive and insulin resistant conditions. We identify 91 N-glycosylation sites derived from 51 secreted proteins, as well as 155 and 29 released N- and O-glycans respectively. We go on to quantify many of the N- and O-glycan structures between insulin responsive and insulin resistance conditions demonstrating no significant changes in complex glycosylation in the time frame for the induction of insulin resistance. Thus, our data support that the O-GlcNAc modification is involved in the regulation of

  20. Insulin and GLP-1 infusions demonstrate the onset of adipose-specific insulin resistance in a large fasting mammal: potential glucogenic role for GLP-1.

    PubMed

    Viscarra, Jose A; Rodriguez, Ruben; Vazquez-Medina, Jose Pablo; Lee, Andrew; Tift, Michael S; Tavoni, Stephen K; Crocker, Daniel E; Ortiz, Rudy M

    2013-08-01

    Prolonged food deprivation increases lipid oxidation and utilization, which may contribute to the onset of the insulin resistance associated with fasting. Because insulin resistance promotes the preservation of glucose and oxidation of fat, it has been suggested to be an adaptive response to food deprivation. However, fasting mammals exhibit hypoinsulinemia, suggesting that the insulin resistance-like conditions they experience may actually result from reduced pancreatic sensitivity to glucose/capacity to secrete insulin. To determine whether fasting results in insulin resistance or in pancreatic dysfunction, we infused early- and late-fasted seals (naturally adapted to prolonged fasting) with insulin (0.065 U/kg), and a separate group of late-fasted seals with low (10 pM/kg) or high (100 pM/kg) dosages of glucagon-like peptide-1 (GLP-1) immediately following a glucose bolus (0.5g/kg), and measured the systemic and cellular responses. Because GLP-1 facilitates glucose-stimulated insulin secretion, these infusions provide a method to assess pancreatic insulin-secreting capacity. Insulin infusions increased the phosphorylation of insulin receptor and Akt in adipose and muscle of early and late fasted seals; however the timing of the signaling response was blunted in adipose of late fasted seals. Despite the dose-dependent increases in insulin and increased glucose clearance (high dose), both GLP-1 dosages produced increases in plasma cortisol and glucagon, which may have contributed to the glucogenic role of GLP-1. Results suggest that fasting induces adipose-specific insulin resistance in elephant seal pups, while maintaining skeletal muscle insulin sensitivity, and therefore suggests that the onset of insulin resistance in fasting mammals is an evolved response to cope with prolonged food deprivation. PMID:23997935

  1. Insulin

    MedlinePlus

    ... pump is connected to your body by a flexible tube that has a tip that sticks under your skin. A cartridge of insulin is put in the pump. The insulin flows through the tube into your body. The pump controls how much insulin goes into your body. The ...

  2. S961, an insulin receptor antagonist causes hyperinsulinemia, insulin-resistance and depletion of energy stores in rats

    SciTech Connect

    Vikram, Ajit; Jena, Gopabandhu

    2010-07-23

    Research highlights: {yields}Insulin receptor antagonist S961 causes hyperglycemia, hyperinsulinemia and insulin resistance in rats. {yields}Peroxysome-proliferator-activated-receptor-gamma agonist pioglitazone improves S961 induced hyperglycemia and glucose intolerance. {yields}Long term treatment with insulin receptor antagonist S961 results in the decreased adiposity and hepatic glycogen content. {yields}Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. -- Abstract: Impairment in the insulin receptor signaling and insulin mediated effects are the key features of type 2 diabetes. Here we report that S961, a peptide insulin receptor antagonist induces hyperglycemia, hyperinsulinemia ({approx}18-fold), glucose intolerance and impairment in the insulin mediated glucose disposal in the Sprague-Dawley rats. Further, long-term S961 treatment (15 day, 10 nM/kg/day) depletes energy storage as evident from decrease in the adiposity and hepatic glycogen content. However, peroxysome-proliferator-activated-receptor-gamma (PPAR{gamma}) agonist pioglitazone significantly (P < 0.001) restored S961 induced hyperglycemia (196.73 {+-} 16.32 vs. 126.37 {+-} 27.07 mg/dl) and glucose intolerance ({approx}78%). Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. Further, results of the present study reconfirms and provide direct evidence to the crucial role of insulin receptor signaling in the glucose homeostasis and fuel metabolism.

  3. Decreased irisin secretion contributes to muscle insulin resistance in high-fat diet mice

    PubMed Central

    Yang, Zaigang; Chen, Xu; Chen, Yujuan; Zhao, Qian

    2015-01-01

    Aims: Recent studies have revealed the relationship between irisin and insulin signaling, while positive associations of muscle FNDC5 with insulin resistance is observed. However, the functional mechanism of irisin on muscle insulin resistance is still obscure. This study aims to investigate the effect of irisin on muscle insulin action. Methods: Diabetic mouse model was established by high fat diet (HFD) induced obesity in C57BL/6 mice. Body indexes and serum levels of triglyceride (TG), blood glucose and insulin were record. Oral glucose tolerance test (OGTT) was performed before being killed. Circulating irisin level was also detected, while FNDC5/irisin expression was determined by RT-PCR and western blot analysis in both muscle and adipose tissues. Insulin action was further evaluated by the phosphorylation of AKT and Erk, and palmitic acid treated muscle cells were introduced for mimicking diabetic status in vitro. Results: Obvious obese feathers associated with type 2 diabetes were observed in HFD feeding mice, with decreased circulating irisin level and FNDC5/irisin secretion in adipose tissues. Although FNDC5/irisin expression showed little change in skeletal muscle, the insulin action was inhibited significantly. Moreover, palmitic acid treated muscle cells showed similar inhibition of insulin action, and FNDC5/irisin expression change. Besides, insulin action could be reversed by irisin addition in muscle cells. Conclusion: HFD induced obese mice showed decreased irisin secretion from adipose tissues, which might contribute to muscle insulin resistance. Furthermore, irisin addition could recover insulin action in palmitic acid treated muscle cells, indicating the importance of irisin for preserving insulin signaling. PMID:26261526

  4. Combination of Alcohol and Fructose Exacerbates Metabolic Imbalance in Terms of Hepatic Damage, Dyslipidemia, and Insulin Resistance in Rats

    PubMed Central

    Schultze, Frank Christian; Wilting, Jörg; Mihm, Sabine; Raddatz, Dirk; Ramadori, Giuliano

    2014-01-01

    Although both alcohol and fructose are particularly steatogenic, their long-term effect in the development of a metabolic syndrome has not been studied in vivo. Consumption of fructose generally leads to obesity, whereas ethanol can induce liver damage in the absence of overweight. Here, Sprague-Dawley rats were fed ad libitum for 28 days on five diets: chow (control), liquid Lieber-DeCarli (LDC) diet, LDC +30%J of ethanol (L-Et) or fructose (L-Fr), and LDC combined with 30%J ethanol and 30%J fructose (L-EF). Body weight (BW) and liver weight (LW) were measured. Blood and liver samples were harvested and subjected to biochemical tests, histopathological examinations, and RT-PCR. Alcohol-containing diets substantially reduced the food intake and BW (≤3rd week), whereas fructose-fed animals had higher LW than controls (P<0.05). Additionally, leukocytes, plasma AST and leptin levels were the highest in the fructose-administered rats. Compared to the chow and LDC diets, the L-EF diet significantly elevated blood glucose, insulin, and total-cholesterol levels (also vs. the L-Et group). The albumin and Quick-test levels were the lowest, whereas ALT activity was the highest in the L-EF group. Moreover, the L-EF diet aggravated plasma triglyceride and reduced HDL-cholesterol levels more than 2.7-fold compared to the sum of the effects of the L-Et and L-Fr diets. The decreased hepatic insulin clearance in the L-EF group vs. control and LDC groups was reflected by a significantly decreased C-peptide:insulin ratio. All diets except the control caused hepatosteatosis, as evidenced by Nile red and H&E staining. Hepatic transcription of insulin receptor substrate-1/2 was mainly suppressed by the L-Fr and L-EF diets. The L-EF diet did not enhance the mitochondrial β-oxidation of fatty acids (Cpt1α and Ppar-α expressions) compared to the L-Et or L-Fr diet. Together, our data provide evidence for the coaction of ethanol and fructose with a high-fat-diet on dyslipidemia and

  5. Chenodeoxycholic acid, an endogenous FXR ligand alters adipokines and reverses insulin resistance.

    PubMed

    Shihabudeen, Mohamed Sham; Roy, Debasish; James, Joel; Thirumurugan, Kavitha

    2015-10-15

    Adipose tissue secretes adipokines that regulate insulin sensitivity in adipocytes and other peripheral tissues critical to glucose metabolism. Insulin resistance is associated with severe alterations in adipokines characterized by release of increased pro-inflammatory cytokines and decreased anti-inflammatory cytokines from adipose tissue. The role of Farnesoid X receptor (FXR) activation on adipokines in relation to adipose tissue inflammation and insulin resistance is not completely explored. For the first time, we have evaluated the ability of Chenodeoxycholic acid (CDCA), an endogenous FXR ligand, in restoring the disturbance in adipokine secretion and insulin resistance in palmitate treated 3T3-L1 cells and adipose tissues of High fat diet (HFD) rats. CDCA suppressed several of the tested pro-inflammatory adipokines (TNF-α, MCP-1, IL-6, Chemerin, PAI, RBP4, resistin, vaspin), and enhanced the major anti-inflammatory and insulin sensitizing adipokines (adiponectin, leptin). CDCA suppressed the activation of critical inflammatory regulators such as NF-κB and IKKβ which are activated by palmitate treatment in differentiated cells and HFD in rats. We show the altered adipokines in insulin resistance, its association with inflammatory regulators, and the role of CDCA in amelioration of insulin resistance by modulation of adipokines. PMID:26188168

  6. Insulin Resistance, Ceramide Accumulation, and Endoplasmic Reticulum Stress in Human Chronic Alcohol-Related Liver Disease

    PubMed Central

    Longato, Lisa; Ripp, Kelsey; Setshedi, Mashiko; Dostalek, Miroslav; Akhlaghi, Fatemeh; Branda, Mark; Wands, Jack R.; de la Monte, Suzanne M.

    2012-01-01

    Background. Chronic alcohol-related liver disease (ALD) is mediated by insulin resistance, mitochondrial dysfunction, inflammation, oxidative stress, and DNA damage. Recent studies suggest that dysregulated lipid metabolism with accumulation of ceramides, together with ER stress potentiate hepatic insulin resistance and may cause steatohepatitis to progress. Objective. We examined the degree to which hepatic insulin resistance in advanced human ALD is correlated with ER stress, dysregulated lipid metabolism, and ceramide accumulation. Methods. We assessed the integrity of insulin signaling through the Akt pathway and measured proceramide and ER stress gene expression, ER stress signaling proteins, and ceramide profiles in liver tissue. Results. Chronic ALD was associated with increased expression of insulin, IGF-1, and IGF-2 receptors, impaired signaling through IGF-1R and IRS1, increased expression of multiple proceramide and ER stress genes and proteins, and higher levels of the C14, C16, C18, and C20 ceramide species relative to control. Conclusions. In human chronic ALD, persistent hepatic insulin resistance is associated with dysregulated lipid metabolism, ceramide accumulation, and striking upregulation of multiple ER stress signaling molecules. Given the role of ceramides as mediators of ER stress and insulin resistance, treatment with ceramide enzyme inhibitors may help reverse or halt progression of chronic ALD. PMID:22577490

  7. (-)-Epicatechin mitigates high fructose-associated insulin resistance by modulating redox signaling and endoplasmic reticulum stress

    PubMed Central

    Bettaieb, Ahmed; Vazquez Prieto, Marcela A.; Rodriguez Lanzi, Cecilia; Miatello, Roberto M.; Haj, Fawaz G.; Fraga, César G.; Oteiza, Patricia I.

    2014-01-01

    We investigated the capacity of dietary (-)-epicatechin (EC) to mitigate insulin resistance through the modulation of redox-regulated mechanisms in a rat model of metabolic syndrome (MetS). Adolescent rats were fed a regular chow diet without or with high fructose (HFr) (10% (w/v)) in drinking water for 8 weeks, and a group of HFr-fed rats was supplemented with EC in the diet. HFr-fed rats developed insulin resistance which was mitigated by EC supplementation. Accordingly, the activation of components of the insulin signaling cascade (insulin receptor (IR), IRS-1, Akt and ERK1/2) was impaired, while negative regulators (PKC, IKK, JNK and PTP1B) were upregulated in the liver and adipose tissue of HFr rats. These alterations were partially or totally prevented by EC supplementation. In addition, EC inhibited events which contribute to insulin resistance: HFr-associated increased expression and activity of NADPH oxidase, activation of redox-sensitive signals, expression of NF-κB-regulated pro-inflammatory cytokines and chemokines, and some sub-arms of endoplasmic reticulum stress signaling. Collectively, these findings indicate that EC supplementation can mitigate HFr-induced insulin resistance and are relevant to define interventions that can prevent/mitigate MetS-associated insulin resistance. PMID:24746618

  8. Insulin Resistance and Endothelial Dysfunction Constitute a Common Therapeutic Target in Cardiometabolic Disorders

    PubMed Central

    Mazur, G.

    2016-01-01

    Insulin resistance and other risk factors for atherosclerosis, such as hypertension and hypercholesterolemia, promote endothelial dysfunction and lead to development of metabolic syndrome which constitutes an introduction to cardiovascular disease. The insulin resistance and endothelial dysfunction cross talk between each other by numerous metabolic pathways. Hence, targeting one of these pathologies with pleiotropic treatment exerts beneficial effect on another one. Combined and expletive treatment of hypertension, lipid disorders, and insulin resistance with nonpharmacological interventions and conventional pharmacotherapy may inhibit the transformation of metabolic disturbances to fully developed cardiovascular disease. This paper summarises the common therapeutic targets for insulin resistance, endothelial dysfunction, and vascular inflammatory reaction at molecular level and analyses the potential pleiotropic effects of drugs used currently in management of cardiovascular disease, metabolic syndrome, and diabetes. PMID:27413253

  9. Perilipin polymorphism interacts with saturated fat and carbohydrates to modulate insulin resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Macronutrient intakes and genetic variants have been shown to interact to alter insulin resistance, but replications of gene-nutrient interactions across independent populations are rare, despite their critical importance in establishing credibility. We aimed to investigate a previously demonstrated...

  10. Link between insulin resistance and hypertension: What is the evidence from evolutionary biology?

    PubMed

    Zhou, Ming-Sheng; Wang, Aimei; Yu, Hong

    2014-01-01

    Insulin resistance and hypertension are considered as prototypical "diseases of civilization" that are manifested in the modern environment as plentiful food and sedentary life. The human propensity for insulin resistance and hypertension is a product, at least in part, of our evolutionary history. Adaptation to ancient lifestyle characterized by a low sodium, low-calorie food supply and physical stress to injury response has driven our evolution to shape and preserve a thrifty genotype, which is favorite with energy-saving and sodium conservation. As our civilization evolved, a sedentary lifestyle and sodium- and energy-rich diet, the thrifty genotype is no longer advantageous, and may be maladaptive to disease phenotype, such as hypertension, obesity and insulin resistance syndrome. This article reviews human evolution and the impact of the modern environment on hypertension and insulin resistance. PMID:24485020

  11. Link between insulin resistance and hypertension: What is the evidence from evolutionary biology?

    PubMed Central

    2014-01-01

    Insulin resistance and hypertension are considered as prototypical “diseases of civilization” that are manifested in the modern environment as plentiful food and sedentary life. The human propensity for insulin resistance and hypertension is a product, at least in part, of our evolutionary history. Adaptation to ancient lifestyle characterized by a low sodium, low-calorie food supply and physical stress to injury response has driven our evolution to shape and preserve a thrifty genotype, which is favorite with energy-saving and sodium conservation. As our civilization evolved, a sedentary lifestyle and sodium- and energy-rich diet, the thrifty genotype is no longer advantageous, and may be maladaptive to disease phenotype, such as hypertension, obesity and insulin resistance syndrome. This article reviews human evolution and the impact of the modern environment on hypertension and insulin resistance. PMID:24485020

  12. Pid1 induces insulin resistance in both human and mouse skeletal muscle during obesity.

    PubMed

    Bonala, Sabeera; McFarlane, Craig; Ang, Jackie; Lim, Radiance; Lee, Marcus; Chua, Hillary; Lokireddy, Sudarsanareddy; Sreekanth, Patnam; Leow, Melvin Khee Shing; Meng, Khoo Chin; Shyong, Tai E; Lee, Yung Seng; Gluckman, Peter D; Sharma, Mridula; Kambadur, Ravi

    2013-09-01

    Obesity is associated with insulin resistance and abnormal peripheral tissue glucose uptake. However, the mechanisms that interfere with insulin signaling and glucose uptake in human skeletal muscle during obesity are not fully characterized. Using microarray, we have identified that the expression of Pid1 gene, which encodes for a protein that contains a phosphotyrosine-interacting domain, is increased in myoblasts established from overweight insulin-resistant individuals. Molecular analysis further validated that both Pid1 mRNA and protein levels are increased in cell culture models of insulin resistance. Consistent with these results, overexpression of phosphotyrosine interaction domain-containing protein 1 (PID1) in human myoblasts resulted in reduced insulin signaling and glucose uptake, whereas knockdown of PID1 enhanced glucose uptake and insulin signaling in human myoblasts and improved the insulin sensitivity following palmitate-, TNF-α-, or myostatin-induced insulin resistance in human myoblasts. Furthermore, the number of mitochondria in myoblasts that ectopically express PID1 was significantly reduced. In addition to overweight humans, we find that Pid1 levels are also increased in all 3 peripheral tissues (liver, skeletal muscle, and adipose tissue) in mouse models of diet-induced obesity and insulin resistance. An in silico search for regulators of Pid1 expression revealed the presence of nuclear factor-κB (NF-κB) binding sites in the Pid1 promoter. Luciferase reporter assays and chromatin immunoprecipitation studies confirmed that NF-κB is sufficient to transcriptionally up-regulate the Pid1 promoter. Furthermore, we find that myostatin up-regulates Pid1 expression via an NF-κB signaling mechanism. Collectively these results indicate that Pid1 is a potent intracellular inhibitor of insulin signaling pathway during obesity in humans and mice. PMID:23927930

  13. Prolonged Fasting Identifies Skeletal Muscle Mitochondrial Dysfunction as Consequence Rather Than Cause of Human Insulin Resistance

    PubMed Central

    Hoeks, Joris; van Herpen, Noud A.; Mensink, Marco; Moonen-Kornips, Esther; van Beurden, Denis; Hesselink, Matthijs K.C.; Schrauwen, Patrick

    2010-01-01

    OBJECTIVE Type 2 diabetes and insulin resistance have been associated with mitochondrial dysfunction, but it is debated whether this is a primary factor in the pathogenesis of the disease. To test the concept that mitochondrial dysfunction is secondary to the development of insulin resistance, we employed the unique model of prolonged fasting in humans. Prolonged fasting is a physiologic condition in which muscular insulin resistance develops in the presence of increased free fatty acid (FFA) levels, increased fat oxidation and low glucose and insulin levels. It is therefore anticipated that skeletal muscle mitochondrial function is maintained to accommodate increased fat oxidation unless factors secondary to insulin resistance exert negative effects on mitochondrial function. RESEARCH DESIGN AND METHODS While in a respiration chamber, twelve healthy males were subjected to a 60 h fast and a 60 h normal fed condition in a randomized crossover design. Afterward, insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp, and mitochondrial function was quantified ex vivo in permeabilized muscle fibers using high-resolution respirometry. RESULTS Indeed, FFA levels were increased approximately ninefold after 60 h of fasting in healthy male subjects, leading to elevated intramuscular lipid levels and decreased muscular insulin sensitivity. Despite an increase in whole-body fat oxidation, we observed an overall reduction in both coupled state 3 respiration and maximally uncoupled respiration in permeabilized skeletal muscle fibers, which could not be explained by changes in mitochondrial density. CONCLUSIONS These findings confirm that the insulin-resistant state has secondary negative effects on mitochondrial function. Given the low insulin and glucose levels after prolonged fasting, hyperglycemia and insulin action per se can be excluded as underlying mechanisms, pointing toward elevated plasma FFA and/or intramuscular fat accumulation as possible

  14. Diabetes, Insulin Resistance, and Metabolic Syndrome in Horses

    PubMed Central

    Johnson, Philip J.; Wiedmeyer, Charles E.; LaCarrubba, Alison; Ganjam, V. K. (Seshu); Messer, Nat T.

    2012-01-01

    Analogous to the situation in human medicine, contemporary practices in horse management, which incorporate lengthy periods of physical inactivity coupled with provision of nutritional rations characterized by inappropriately high sugar and starch, have led to obesity being more commonly recognized by practitioners of equine veterinary practice. In many of these cases, obesity is associated with insulin resistance (IR) and glucose intolerance. An equine metabolic syndrome (MS) has been described that is similar to the human MS in that both IR and aspects of obesity represent cornerstones of its definition. Unlike its human counterpart, identification of the equine metabolic syndrome (EMS) portends greater risk for development of laminitis, a chronic, crippling affliction of the equine hoof. When severe, laminitis sometimes necessitates euthanasia. Unlike the human condition, the risk of developing type 2 diabetes mellitus and many other chronic conditions, for which the risk is recognized as increased in the face of MS, is less likely in horses. The equine veterinary literature has been replete with reports of scientific investigations regarding the epidemiology, pathophysiology, and treatment of EMS. PMID:22768883

  15. Does Inflammation Mediate the Association Between Obesity and Insulin Resistance?

    PubMed

    Adabimohazab, Razieh; Garfinkel, Amanda; Milam, Emily C; Frosch, Olivia; Mangone, Alexander; Convit, Antonio

    2016-06-01

    In adult obesity, low-grade systemic inflammation is considered an important step in the pathogenesis of insulin resistance (IR). The association between obesity and inflammation is less well established in adolescents. Here, we ascertain the importance of inflammation in IR among obese adolescents by utilizing either random forest (RF) classification or mediation analysis approaches. The inflammation balance score, composed of eight pro- and anti-inflammatory makers, as well as most of the individual inflammatory markers differed significantly between lean and overweight/obese. In contrast, adiponectin was the only individual marker selected as a predictor of IR by RF, and the balance score only revealed a medium-to-low importance score. Neither adiponectin nor the inflammation balance score was found to mediate the relationship between obesity and IR. These findings do not support the premise that low-grade systemic inflammation is a key for the expression of IR in the human. Prospective longitudinal studies should confirm these findings. PMID:26956471

  16. Obesity, insulin resistance and comorbidities – Mechanisms of association

    PubMed Central

    Castro, Ana Valeria B.; Kolka, Cathryn M.; Kim, Stella P.; Bergman, Richard N.

    2015-01-01

    Overall excess of fat, usually defined by the body mass index, is associated with metabolic (e.g. glucose intolerance, type 2 diabetes mellitus (T2DM), dyslipidemia) and non-metabolic disorders (e.g. neoplasias, polycystic ovary syndrome, non-alcoholic fat liver disease, glomerulopathy, bone fragility etc.). However, more than its total amount, the distribution of adipose tissue throughout the body is a better predictor of the risk to the development of those disorders. Fat accumulation in the abdominal area and in non-adipose tissue (ectopic fat), for example, is associated with increased risk to develop metabolic and non-metabolic derangements. On the other hand, observations suggest that individuals who present peripheral adiposity, characterized by large hip and thigh circumferences, have better glucose tolerance, reduced incidence of T2DM and of metabolic syndrome. Insulin resistance (IR) is one of the main culprits in the association between obesity, particularly visceral, and metabolic as well as non-metabolic diseases. In this review we will highlight the current pathophysiological and molecular mechanisms possibly involved in the link between increased VAT, ectopic fat, IR and comorbidities. We will also provide some insights in the identification of these abnormalities. PMID:25211442

  17. Obesity-related insulin resistance: implications for the surgical patient.

    PubMed

    Tewari, N; Awad, S; Macdonald, I A; Lobo, D N

    2015-11-01

    In healthy surgical patients, preoperative fasting and major surgery induce development of insulin resistance (IR). IR can be present in up to 41% of obese patients without diabetes and this can rise in the postoperative period, leading to an increased risk of postoperative complications. Inflammation is implicated in the aetiology of IR. This review examines obesity-associated IR and its implications for the surgical patient. Searches of the Medline and Science Citation Index databases were performed using various key words in combinations with the Boolean operators AND, OR and NOT. Key journals, nutrition and metabolism textbooks and the reference lists of key articles were also hand searched. Adipose tissue has been identified as an active endocrine organ and the chemokines secreted as a result of macrophage infiltration have a role in the pathogenesis of IR. Visceral adipose tissue appears to be the most metabolically active, although results across studies are not consistent. Results from animal and human studies often provide conflicting results, which has rendered the pursuit of a common mechanistic pathway challenging. Obesity-associated IR appears, in part, to be related to inflammatory changes associated with increased adiposity. Postoperatively, the surgical patient is in a proinflammatory state, so this finding has important implications for the obese surgical patient. PMID:26028059

  18. Endogenous epinephrine protects against obesity induced insulin resistance.

    PubMed

    Ziegler, Michael G; Milic, Milos; Sun, Ping; Tang, Chih-Min; Elayan, Hamzeh; Bao, Xuping; Cheung, Wai Wilson; O'Connor, Daniel T

    2011-07-01

    Epinephrine (E) is a hormone released from the adrenal medulla in response to low blood sugar and other stresses. E and related β2-adrenergic agonists are used to treat asthma, but a side effect is high blood sugar. C57BL/6 mice prone to overfeeding induced type II diabetes had the PNMT gene knocked out to prevent E synthesis. These E deficient mice were very similar to control animals on a 14% fat diet. On a 40.6% fat diet they gained 20 to 33% more weight than control animals and increased their blood glucose response to a glucose tolerance test because they became resistant to insulin. Although the short term effect of β2-agonists such as E is to raise blood glucose, some long acting β2-agonists improve muscle glucose uptake. Endogenous E protects against overfeeding induced diabetes. Since adrenal E release can be impaired with aging and diabetes, endogenous E may help prevent adult onset diabetes. PMID:21354376

  19. Human obesity and insulin resistance: lessons from experiments of nature.

    PubMed

    O'Rahilly, Stephen

    2007-01-01

    The past decade or so has seen the adipocyte catapulted from a position of relative obscurity onto the centre stage of biomedical science. Having long been viewed largely as a passive storage depot for energy in times of plenty and a fuel reservoir called upon in times of need, the discovery that the adipocyte is an active participant in the control mechanisms for both energy balance and intermediary metabolism represents one of the most stunning paradigm shifts in modern mammalian biology. The normal control of energy homeostasis is now known to be highly dependent on the adipocyte-secreted hormone, leptin. Defects in the leptin signalling pathway, both inherited and acquired, are now known to contribute to the important clinical problem of obesity. Dysfunction of adipocytes, in both obesity and lipodystrophies, is now considered to be critically involved in the pathogenesis of insulin resistance, the metabolic syndrome and type 2 diabetes. The range of metabolites, steroids and bioactive peptides now known to be actively produced by adipocytes and influencing organs as diverse as brain, muscle, liver and pancreatic islet has increased dramatically. Our understanding of how these are co-ordinated to regulate normal metabolism and are dysregulated in metabolic disease is still in its infancy. However what is clear is that the adipocyte, until recently the 'Cinderella Cell' of metabolism, has rapidly become the 'Belle of the Ball'. PMID:18269171

  20. [Oxidative stress in adipose tissue as a primary link in pathogenesis of insulin resistance].

    PubMed

    Kuzmenko, D I; Udintsev, S N; Klimentyeva, T K; Serebrov, V Yu

    2016-01-01

    Obesity is a leading risk factor of diabetes mellitus type 2, impairments of lipid metabolism and cardiovascular diseases. Dysfunctions of the accumulating weight of the visceral fat are primarily linked to pathogenesis of systemic insulin resistance. The review considers modern views about biochemical mechanisms underlying formation of oxidative stress in adipocytes at obesity, as one of key elements of impairments of their metabolism triggering formation of systemic insulin resistance. PMID:26973182

  1. Insulin resistance and delayed clearance of peptide hormones in cirrhotic rat liver.

    PubMed

    Shankar, T P; Drake, S; Solomon, S S

    1987-06-01

    Clearance of porcine insulin, glucagon, and human growth hormone was measured in intact perfused cirrhotic and normal rat livers. Binding and degradation of 125I-insulin by hepatocytes isolated from cirrhotic and normal livers were also studied. The half-lives (t1/2) of immunoreactive insulin and glucagon were 14.0 +/- 3.1 and 9.6 +/- 2.1 min in normal livers and 26.0 +/- 6.1 and 25.0 +/- 7.1 min in cirrhotic livers (P less than 0.001). Insulin binding and degradation by hepatocytes from control and cirrhotic livers showed no significant differences. Intraportal insulin infusion in perfusion studies suppressed glucagon-stimulated increases in glucose output from control livers but failed to suppress glucose production by cirrhotic livers, suggesting the presence of hepatic insulin resistance in cirrhosis. Impaired clearance of insulin and glucagon by the intact cirrhotic liver and normal binding and degradation of insulin by isolated hepatocytes suggest that factors such as intrahepatic fibrosis and shunting and postbinding defects may be responsible for the impaired hormone clearance and hepatic insulin resistance. PMID:3296781

  2. PPARδ agonist attenuates alcohol-induced hepatic insulin resistance and improves liver injury and repair

    PubMed Central

    Pang, Maoyin; de la Monte, Suzanne M.; Longato, Lisa; Tong, Ming; He, Jiman; Chaudhry, Rajeeve; Duan, Kevin; Ouh, Jiyun; Wands, Jack R.

    2009-01-01

    Background/Aims Chronic ethanol exposure impairs liver regeneration due to inhibition of insulin signaling and oxidative injury. PPAR agonists function as insulin sensitizers and anti-inflammatory agents. We investigated whether treatment with a PPARδ agonist could restore hepatic insulin sensitivity, survival signaling, and regenerative responses vis-a-vis chronic ethanol feeding. Methods Adult rats were fed isocaloric liquid diets containing 0% or 37% ethanol, and administered a PPARδ agonist by i.p. injection. We used liver tissue to examine histopathology, gene expression, oxidative stress, insulin signaling, and regenerative responses to 2/3 hepatectomy. Results Chronic ethanol feeding caused insulin resistance, increased oxidative stress, lipid peroxidation, DNA damage, and hepatocellular injury in liver. These effects were associated with reduced insulin receptor binding and affinity, impaired survival signaling through PI3K/Akt/GSK3β, and reduced expression of insulin responsive genes mediating energy metabolism and tissue remodeling. PPARδ agonist treatment reduced ethanol-mediated hepatic injury, oxidative stress, lipid peroxidation, and insulin resistance, increased signaling through PI3K/Akt/GSK3β, and enhanced the regenerative response to partial hepatectomy. Conclusions PPARδ agonist administration may attenuate the severity of chronic ethanol-induced liver injury and ethanol’s adverse effects on the hepatic repair by restoring insulin responsiveness, even in the context of continued high-level ethanol consumption. PMID:19398227

  3. Insulin resistance and delayed clearance of peptide hormones in cirrhotic rat liver

    SciTech Connect

    Shankar, T.P.; Drake, S.; Solomon, S.S.

    1987-06-01

    Clearance of porcine insulin, glucagon, and human growth hormone was measured in intact perfused cirrhotic and normal rat livers. Binding and degradation of /sup 125/I-insulin by hepatocytes isolated from cirrhotic and normal livers were also studied. The half-lives (t/sub 1/2/) of immunoreactive insulin and glucagon were 14.0 +/- 3.1 and 9.6 +/- 2.1 min in normal livers and 26.0 +/- 6.1 and 25.0 +/- 7.1 min in cirrhotic livers. Insulin binding and degradation by hepatocytes from control and cirrhotic livers showed no significant differences. Intraportal insulin infusion in perfusion studies suppressed glucagon-stimulated increases in glucose output from control livers but failed to suppress glucose production by cirrhotic livers, suggesting the presence of hepatic insulin resistance in cirrhosis. Impaired clearance of insulin and glucagon by the intact cirrhotic liver and normal binding and degradation of insulin by isolated hepatocytes suggest that factors such as intrahepatic fibrosis and shunting and postbinding defects may be responsible for the impaired hormone clearance and hepatic insulin resistance.

  4. Estrogen Treatment After Ovariectomy Protects Against Fatty Liver and May Improve Pathway-Selective Insulin Resistance

    PubMed Central

    Zhu, Lin; Brown, William C.; Cai, Qing; Krust, Andrée; Chambon, Pierre; McGuinness, Owen P.; Stafford, John M.

    2013-01-01

    Pathway-selective insulin resistance where insulin fails to suppress hepatic glucose production but promotes liver fat storage may underlie glucose and lipid abnormalities after menopause. We tested the mechanisms by which estrogen treatment may alter the impact of a high-fat diet (HFD) when given at the time of ovariectomy (OVX) in mice. Female C57BL/6J mice underwent sham operation, OVX, or OVX with estradiol (E2) treatment and were fed an HFD. Hyperinsulinemic-euglycemic clamps were used to assess insulin sensitivity, tracer incorporation into hepatic lipids, and liver triglyceride export. OVX mice had increased adiposity that was prevented with E2 at the time of OVX. E2 treatment increased insulin sensitivity with OVX and HFD. In sham and OVX mice, HFD feeding induced fatty liver, and insulin reduced hepatic apoB100 and liver triglyceride export. E2 treatment reduced liver lipid deposition and prevented the decrease in liver triglyceride export during hyperinsulinemia. In mice lacking the liver estrogen receptor α, E2 after OVX limited adiposity but failed to improve insulin sensitivity, to limit liver lipid deposition, and to prevent insulin suppression of liver triglyceride export. In conclusion, estrogen treatment may reverse aspects of pathway-selective insulin resistance by promoting insulin action on glucose metabolism but limiting hepatic lipid deposition. PMID:22966069

  5. Relationship of insulin resistance and hyperinsulinemia to blood pressure during pregnancy.

    PubMed

    Cioffi, F J; Amorosa, L F; Vintzileos, A M; Lai, Y L; Lake, M F; Gregory, P M; Rifici, V A

    1997-01-01

    The purpose of our study was to examine the relationship between insulin resistance and blood pressure during pregnancy and to determine to what extent insulin resistance is related to the subsequent development of pregnancy-induced hypertension. The study population consisted of 292 women who had serum insulin, glucose and insulin-glucose ratios determined at 26-28 weeks gestation in a fasting state and 1 hr after a 50-g oral glucose challenge. These were compared with blood pressures at 26-28 weeks gestation and in the late third trimester. A statistically significant correlation exists overall between (1) blood pressure at 26-28 weeks gestation and both fasting insulin and insulin-glucose ratios, as well as (2) systolic blood pressure at term and fasting insulin levels. However, when controlled for confounding variables including body mass index, race and age, no statistically significant relationship remained. The metabolic variables in patients with pregnancy-induced hypertension were not statistically different from the normotensive patients. In conclusion, this study demonstrates that insulin resistance and hyperinsulinemia are not major determinants of blood pressure during pregnancy. PMID:9172061

  6. The Insulin/IGF System in Colorectal Cancer Development and Resistance to Therapy

    PubMed Central

    Vigneri, Paolo Giovanni; Tirrò, Elena; Pennisi, Maria Stella; Massimino, Michele; Stella, Stefania; Romano, Chiara; Manzella, Livia

    2015-01-01

    The insulin/insulin-like growth factor (IGF) system is a major determinant in the pathogenesis and progression of colorectal cancer (CRC). Indeed, several components of this signaling network, including insulin, IGF-1, IGF-2, the IGF-binding proteins, the insulin receptor (IR), the IGF-1 receptor (IGF-1R), and IR substrate proteins 1 and 2 contribute to the transformation of normal colon epithelial cells. Moreover, the insulin/IGF system is also implicated in the development of resistance to both chemotherapeutic drugs and epidermal growth factor receptor targeted agents. The identification of hybrid receptors comprising both the IR and IGF-1R adds further complexity to this signaling network. Thus, a comprehensive understanding of the biological functions performed by each component of the insulin/IGF system is required to design successful drugs for the treatment of CRC patients. PMID:26528439

  7. Insulin resistance: site of the primary defect or how the current and the emerging therapies work.

    PubMed

    Kolaczynski, J W; Caro, J F

    1998-01-01

    Insulin resistance is one of the cardinal pathophysiological components of the metabolic syndrome, type 2 diabetes, and frequently co-exists with essential hypertension. Although insulin resistance is defined as inadequate target organ (muscle, liver and fat) responsiveness and/or sensitivity to insulin, the primary defect may be located in the target organs themselves or at their remote controller--the central nervous system. One of the ways of resolving this dilemma is studying the mechanisms of action of drugs that have insulin-sensitizing properties. In this brief review we discuss how the known and potential insulin sensitizers: metformin, appetite suppressants, thiazolidinediones, and the new class of centrally acting antihypertensive drugs, I1-receptor agonists, may work. PMID:10212839

  8. Umbelliferone attenuates unpredictable chronic mild stress induced-insulin resistance in rats.

    PubMed

    Su, Qiang; Tao, Weiwei; Wang, Hanqing; Chen, Yanyan; Huang, Huang; Chen, Gang

    2016-05-01

    The aim of this study was to investigate whether umbelliferone (Umb) could attenuate insulin resistance in unpredictable chronic mild stress (CUMS)-induced rats. Behavioral changes were evaluated through sucrose preference test (SPT), open-field test, forced swimming test, and tail suspension test (TST), suggesting that Umb (20 and 40 mg/kg) could effectively improve depression symptoms. Oral glucose tolerance test and serum insulin indicated that Umb attributed to the control of blood glucose levels. The phosphorylation of insulin receptor, insulin receptor substrate (IRS)-1, glycogen synthase kinase-3β, PI3K, and Akt was increased in Umb (20 and 40 mg/kg) treatment according to Western blot analysis. Taken together, the current results suggested the ameliorative effect of Umb against insulin resistance in the CUMS-induced rats. © 2016 IUBMB Life, 68(5):403-409, 2016. PMID:27027512

  9. The role of uric acid in the insulin resistance in children and adolescents with obesity

    PubMed Central

    de Miranda, Josiane Aparecida; Almeida, Guilherme Gomide; Martins, Raissa Isabelle Leão; Cunha, Mariana Botrel; Belo, Vanessa Almeida; dos Santos, José Eduardo Tanus; Mourão-Júnior, Carlos Alberto; Lanna, Carla Márcia Moreira

    2015-01-01

    Objective: To investigate the association between serum uric acid levels and insulin resistance in children and adolescents with obesity. Methods: Cross-sectional study with 245 children and adolescents (134 obese and 111 controls), aged 8-18 years. The anthropometric variables (weight, height and waist circumference), blood pressure and biochemical parameters were collected. The clinical characteristics of the groups were analyzed by t-test or chi-square test. To evaluate the association between uric acid levels and insulin resistance the Pearson's test and logistic regression were applied. Results: The prevalence of insulin resistance was 26.9%. The anthropometric variables, systolic and diastolic blood pressure and biochemical variables were significantly higher in the obese group (p<0.001), except for the high-density-lipoprotein cholesterol. There was a positive and significant correlation between anthropometric variables and uric acid with HOMA-IR in the obese and in the control groups, which was higher in the obese group and in the total sample. The logistic regression model that included age, gender and obesity, showed an odds ratio of uric acid as a variable associated with insulin resistance of 1.91 (95%CI 1.40-2.62; p<−0.001). Conclusions: The increase in serum uric acid showed a positive statistical correlation with insulin resistance and it is associated with and increased risk of insulin resistance in obese children and adolescents. PMID:26300523

  10. Does Diacylglycerol Accumulation in Fatty Liver Disease Cause Hepatic Insulin Resistance?

    PubMed Central

    Finck, Brian N.; Hall, Angela M.

    2015-01-01

    Numerous studies conducted on obese humans and various rodent models of obesity have identified a correlation between hepatic lipid content and the development of insulin resistance in liver and other tissues. Despite a large body of the literature on this topic, the cause and effect relationship between hepatic steatosis and insulin resistance remains controversial. If, as many believe, lipid aggregation in liver drives insulin resistance and other metabolic abnormalities, there are significant unanswered questions as to which lipid mediators are causative in this cascade. Several published papers have now correlated levels of diacylglycerol (DAG), the penultimate intermediate in triglyceride synthesis, with development of insulin resistance and have postulated that this occurs via activation of protein kinase C signaling. Although many studies have confirmed this relationship, many others have reported a disconnect between DAG content and insulin resistance. It has been postulated that differences in methods for DAG measurement, DAG compartmentalization within the cell, or fatty acid composition of the DAG may explain these discrepancies. The purpose of this review is to compare and contrast some of the relevant findings in this area and to discuss a number of unanswered questions regarding the relationship between DAG and insulin resistance. PMID:26273583

  11. Lipid-Overloaded Enlarged Adipocytes Provoke Insulin Resistance Independent of Inflammation

    PubMed Central

    Kim, Jong In; Huh, Jin Young; Sohn, Jee Hyung; Choe, Sung Sik; Lee, Yun Sok; Lim, Chun Yan; Jo, Ala; Park, Seung Bum; Han, Weiping

    2015-01-01

    In obesity, adipocyte hypertrophy and proinflammatory responses are closely associated with the development of insulin resistance in adipose tissue. However, it is largely unknown whether adipocyte hypertrophy per se might be sufficient to provoke insulin resistance in obese adipose tissue. Here, we demonstrate that lipid-overloaded hypertrophic adipocytes are insulin resistant independent of adipocyte inflammation. Treatment with saturated or monounsaturated fatty acids resulted in adipocyte hypertrophy, but proinflammatory responses were observed only in adipocytes treated with saturated fatty acids. Regardless of adipocyte inflammation, hypertrophic adipocytes with large and unilocular lipid droplets exhibited impaired insulin-dependent glucose uptake, associated with defects in GLUT4 trafficking to the plasma membrane. Moreover, Toll-like receptor 4 mutant mice (C3H/HeJ) with high-fat-diet-induced obesity were not protected against insulin resistance, although they were resistant to adipose tissue inflammation. Together, our in vitro and in vivo data suggest that adipocyte hypertrophy alone may be crucial in causing insulin resistance in obesity. PMID:25733684

  12. JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity.

    PubMed

    Solinas, Giovanni; Vilcu, Cristian; Neels, Jaap G; Bandyopadhyay, Gautam K; Luo, Jun-Li; Naugler, Willscott; Grivennikov, Sergei; Wynshaw-Boris, Anthony; Scadeng, Miriam; Olefsky, Jerrold M; Karin, Michael

    2007-11-01

    Obesity-induced insulin resistance is a major factor in the etiology of type 2 diabetes, and Jun kinases (JNKs) are key negative regulators of insulin sensitivity in the obese state. Activation of JNKs (mainly JNK1) in insulin target cells results in phosphorylation of insulin receptor substrates (IRSs) at serine and threonine residues that inhibit insulin signaling. JNK1 activation is also required for accumulation of visceral fat. Here we used reciprocal adoptive transfer experiments to determine whether JNK1 in myeloid cells, such as macrophages, also contributes to insulin resistance and central adiposity. Our results show that deletion of Jnk1 in the nonhematopoietic compartment protects mice from high-fat diet (HFD)-induced insulin resistance, in part through decreased adiposity. By contrast, Jnk1 removal from hematopoietic cells has no effect on adiposity but confers protection against HFD-induced insulin resistance by decreasing obesity-induced inflammation. PMID:17983584

  13. Hypochlorous acid via peroxynitrite activates protein kinase Cθ and insulin resistance in adipocytes

    PubMed Central

    Zhou, Jun; Wang, Qilong; Ding, Ye; Zou, Ming-Hui

    2015-01-01

    We recently reported that genetic deletion of myeloperoxidase (MPO) alleviates obesity-related insulin resistance in mice in vivo. How MPO impairs insulin sensitivity in adipocytes is poorly characterized. As hypochlorous acid (HOCl) is a principal oxidant product generated by MPO, we evaluated the effects of HOCl on insulin signaling in adipocytes differentiated from 3T3-L1 cells. Exposure of 3T3-L1 adipocytes to exogenous HOCl (200 μmol/l) attenuated insulin-stimulated 2-deoxyglucose uptake, GLUT4 translocation, and insulin signals, including tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) and phosphorylation of Akt. Furthermore, treatment with HOCl induced phosphorylation of IRS1 at serine 307, inhibitor κB kinase (IKK), c-Jun NH2-terminal kinase (JNK), and phosphorylation of PKCθ (PKCθ). In addition, genetic and pharmacological inhibition of IKK and JNK abolished serine phosphorylation of IRS1 and impairment of insulin signaling by HOCl. Furthermore, knockdown of PKCθ using siRNA transfection suppressed phosphorylation of IKK and JNK and consequently attenuated the HOCl-impaired insulin signaling pathway. Moreover, activation of PKCθ by peroxynitrite was accompanied by increased phosphorylation of IKK, JNK, and IRS1-serine 307. In contrast, ONOO− inhibitors abolished HOCl-induced phosphorylation of PKCθ, IKK, JNK, and IRS1-serine 307, as well as insulin resistance. Finally, high-fat diet (HFD)-induced insulin resistance was associated with enhanced phosphorylation of PKCθ, IKK, JNK, and IRS1 at serine 307 in white adipose tissues from WT mice, all of which were not found in Mpo knockout mice fed HFDs. We conclude that HOCl impairs insulin signaling pathway by increasing ONOO− mediated phosphorylation of PKCθ, resulting in phosphorylation of IKK/JNK and consequent serine phosphorylation of IRS1 in adipocytes. PMID:25381390

  14. Ultrastructure of the liver microcirculation influences hepatic and systemic insulin activity and provides a mechanism for age-related insulin resistance.

    PubMed

    Mohamad, Mashani; Mitchell, Sarah Jayne; Wu, Lindsay Edward; White, Melanie Yvonne; Cordwell, Stuart James; Mach, John; Solon-Biet, Samantha Marie; Boyer, Dawn; Nines, Dawn; Das, Abhirup; Catherine Li, Shi-Yun; Warren, Alessandra; Hilmer, Sarah Nicole; Fraser, Robin; Sinclair, David Andrew; Simpson, Stephen James; de Cabo, Rafael; Le Couteur, David George; Cogger, Victoria Carroll

    2016-08-01

    While age-related insulin resistance and hyperinsulinemia are usually considered to be secondary to changes in muscle, the liver also plays a key role in whole-body insulin handling and its role in age-related changes in insulin homeostasis is largely unknown. Here, we show that patent pores called 'fenestrations' are essential for insulin transfer across the liver sinusoidal endothelium and that age-related loss of fenestrations causes an impaired insulin clearance and hyperinsulinemia, induces hepatic insulin resistance, impairs hepatic insulin signaling, and deranges glucose homeostasis. To further define the role of fenestrations in hepatic insulin signaling without any of the long-term adaptive responses that occur with aging, we induced acute defenestration using poloxamer 407 (P407), and this replicated many of the age-related changes in hepatic glucose and insulin handling. Loss of fenestrations in the liver sinusoidal endothelium is a hallmark of aging that has previously been shown to cause deficits in hepatic drug and lipoprotein metabolism and now insulin. Liver defenestration thus provides a new mechanism that potentially contributes to age-related insulin resistance. PMID:27095270

  15. Why can insulin resistance be a natural consequence of thyroid dysfunction?

    PubMed

    Brenta, Gabriela

    2011-01-01

    Evidence for a relationship between T4 and T3 and glucose metabolism appeared over 100 years ago when the influence of thyroid hormone excess in the deterioration of glucose metabolism was first noticed. Since then, it has been known that hyperthyroidism is associated with insulin resistance. More recently, hypothyroidism has also been linked to decreased insulin sensitivity. The explanation to this apparent paradox may lie in the differential effects of thyroid hormones at the liver and peripheral tissues level. The purpose of this paper is to explore the effects of thyroid hormones in glucose metabolism and analyze the mechanisms whereby alterations of thyroid hormones lead to insulin resistance. PMID:21941681

  16. Why Can Insulin Resistance Be a Natural Consequence of Thyroid Dysfunction?

    PubMed Central

    Brenta, Gabriela

    2011-01-01

    Evidence for a relationship between T4 and T3 and glucose metabolism appeared over 100 years ago when the influence of thyroid hormone excess in the deterioration of glucose metabolism was first noticed. Since then, it has been known that hyperthyroidism is associated with insulin resistance. More recently, hypothyroidism has also been linked to decreased insulin sensitivity. The explanation to this apparent paradox may lie in the differential effects of thyroid hormones at the liver and peripheral tissues level. The purpose of this paper is to explore the effects of thyroid hormones in glucose metabolism and analyze the mechanisms whereby alterations of thyroid hormones lead to insulin resistance. PMID:21941681

  17. High Fat Diet Produces Brain Insulin Resistance, Synaptodendritic Abnormalities and Altered Behavior in Mice

    PubMed Central

    Arnold, Steven E.; Lucki, Irwin; Brookshire, Bethany R.; Carlson, Gregory C.; Browne, Carolyn A.; Kazi, Hala; Bang, Sookhee; Choi, Bo-Ran; Chen, Yong; McMullen, Mary F.; Kim, Sangwon F.

    2014-01-01

    Insulin resistance and other features of the metabolic syndrome are increasingly recognized for their effects on cognitive health. To ascertain mechanisms by which this occurs, we fed mice a very high fat diet (60% kcal by fat) for 17 days or a moderate high fat diet (HFD, 45% kcal by fat) for 8 weeks and examined changes in brain insulin signaling responses, hippocampal synaptodendritic protein expression, and spatial working memory. Compared to normal control diet mice, cerebral cortex tissues of HFD mice were insulin-resistant as evidenced by failed activation of Akt, S6 and GSK3β with ex-vivo insulin stimulation. Importantly, we found that expression of brain IPMK, which is necessary for mTOR/Akt signaling, remained decreased in HFD mice upon activation of AMPK. HFD mouse hippocampus exhibited increased expression of serine-phosphorylated insulin receptor substrate 1 (IRS1-pS616), a marker of insulin resistance, as well as decreased expression of PSD-95, a scaffolding protein enriched in post-synaptic densities, and synaptopodin, an actin-associated protein enriched in spine apparatuses. Spatial working memory was impaired as assessed by decreased spontaneous alternation in a T-maze. These findings indicate that HFD is associated with telencephalic insulin resistance and deleterious effects on synaptic integrity and cognitive behaviors. PMID:24686304

  18. Exercise Intensity Modulates Glucose-Stimulated Insulin Secretion when Adjusted for Adipose, Liver and Skeletal Muscle Insulin Resistance

    PubMed Central

    Malin, Steven K.; Rynders, Corey A.; Weltman, Judy Y.; Barrett, Eugene J.; Weltman, Arthur

    2016-01-01

    Little is known about the effects of exercise intensity on compensatory changes in glucose-stimulated insulin secretion (GSIS) when adjusted for adipose, liver and skeletal muscle insulin resistance (IR). Fifteen participants (8F, Age: 49.9±3.6yr; BMI: 31.0±1.5kg/m2; VO2peak: 23.2±1.2mg/kg/min) with prediabetes (ADA criteria, 75g OGTT and/or HbA1c) underwent a time-course matched Control, and isocaloric (200kcal) exercise at moderate (MIE; at lactate threshold (LT)), and high-intensity (HIE; 75% of difference between LT and VO2peak). A 75g OGTT was conducted 1 hour post-exercise/Control, and plasma glucose, insulin, C-peptide and free fatty acids were determined for calculations of skeletal muscle (1/Oral Minimal Model; SMIR), hepatic (HOMAIR), and adipose (ADIPOSEIR) IR. Insulin secretion rates were determined by deconvolution modeling for GSIS, and disposition index (DI; GSIS/IR; DISMIR, DIHOMAIR, DIADIPOSEIR) calculations. Compared to Control, exercise lowered SMIR independent of intensity (P<0.05), with HIE raising HOMAIR and ADIPOSEIR compared with Control (P<0.05). GSIS was not reduced following exercise, but DIHOMAIR and DIADIPOSEIR were lowered more following HIE compared with Control (P<0.05). However, DISMIR increased in an intensity based manner relative to Control (P<0.05), which corresponded with lower post-prandial blood glucose levels. Taken together, pancreatic insulin secretion adjusts in an exercise intensity dependent manner to match the level of insulin resistance in skeletal muscle, liver and adipose tissue. Further work is warranted to understand the mechanism by which exercise influences the cross-talk between tissues that regulate blood glucose in people with prediabetes. PMID:27111219

  19. Novel adiponectin-resistin (AR) and insulin resistance (IRAR) indexes are useful integrated diagnostic biomarkers for insulin resistance, type 2 diabetes and metabolic syndrome: a case control study

    PubMed Central

    2011-01-01

    Background Adiponectin and resistin are adipokines which modulate insulin action, energy, glucose and lipid homeostasis. Meta-analyses showed that hypoadiponectinemia and hyperresistinemia are strongly associated with increased risk of insulin resistance, type 2 diabetes (T2DM), metabolic syndrome (MS) and cardiovascular disease. The aim of this study was to propose a novel adiponectin-resistin (AR) index by taking into account both adiponectin and resistin levels to povide a better indicator of the metabolic homeostasis and metabolic disorders. In addition, a novel insulin resistance (IRAR) index was proposed by integration of the AR index into an existing insulin resistance index to provide an improved diagnostic biomarker of insulin sensitivity. Methods In this case control study, anthropometric clinical and metabolic parameters including fasting serum total adiponectin and resistin levels were determined in 809 Malaysian men (208 controls, 174 MS without T2DM, 171 T2DM without MS, 256 T2DM with MS) whose ages ranged between 40-70 years old. Significant differences in continuous variables among subject groups were confirmed by ANCOVA or MANCOVA test using 1,000 stratified bootstrap samples with bias corrected and accelerated (BCa) 95% CI. Spearman's rho rank correlation test was used to test the correlation between two variables. Results The AR index was formulated as 1+log10(R0)-log10(A0). The AR index was more strongly associated with increased risk of T2DM and MS than hypoadiponectinemia and hyperresistinemia alone. The AR index was more strongly correlated with the insulin resistance indexes and key metabolic endpoints of T2DM and MS than adiponectin and resistin levels alone. The AR index was also correlated with a higher number of MS components than adiponectin and resistin levels alone. The IRAR index was formulated as log10(I0G0)+log10(I0G0)log10(R0/A0). The normal reference range of the IRAR index for insulin sensitive individuals was between 3.265 and

  20. FOXO1 Mediates Vitamin D Deficiency-induced Insulin Resistance in Skeletal Muscle

    PubMed Central

    Chen, Songcang; Villalta, Armando; Agrawal, Devendra K.

    2015-01-01

    Prospective epidemiological studies have consistently shown a relationship between vitamin D deficiency, insulin resistance, and type 2 diabetes mellitus (DM2). This is supported by recent trials showing that vitamin D supplementation in prediabetic or insulin-resistant patients with inadequate vitamin D levels improves insulin sensitivity. However, the molecular mechanisms underlying vitamin D deficiency-induced insulin resistance and DM2 remain unknown. Skeletal muscle insulin resistance is a primary defect in the majority of patients with DM2. While sustained activation of forkhead box O1 (FOXO1) in skeletal muscle causes insulin resistance, a relationship between vitamin D deficiency and FOXO1 activation in muscle is unknown. We generated skeletal muscle-specific vitamin D receptor (VDR)-null mice and discovered that these mice developed insulin resistance and glucose intolerance accompanied by increased expression and activity of FOXO1. We also found sustained FOXO1 activation in the skeletal muscle of global VDR-null mice. Treatment of C2C12 muscle cells with 1,25-dihydroxyvitamin D (VD3) reduced FOXO1 expression, nuclear translocation, and activity. The VD3-dependent suppression of FOXO1 activation disappeared by knockdown of VDR, indicating that it is VDR-dependent. Taken together, these results suggest that FOXO1 is a critical target mediating VDR-null signaling in skeletal muscle. The novel findings provide the conceptual support that persistent FOXO1 activation may be responsible for insulin resistance and impaired glucose metabolism in vitamin D signaling-deficient mice, as well as evidence for the utility of vitamin D supplementation for intervention in DM2. PMID:26462119

  1. Molecular Targets Related to Inflammation and Insulin Resistance and Potential Interventions

    PubMed Central

    Hirabara, Sandro M.; Gorjão, Renata; Vinolo, Marco A.; Rodrigues, Alice C.; Nachbar, Renato T.; Curi, Rui

    2012-01-01

    Inflammation and insulin resistance are common in several chronic diseases, such as obesity, type 2 diabetes mellitus, metabolic syndrome, cancer, and cardiovascular diseases. Various studies show a relationship between these two factors, although the mechanisms involved are not completely understood yet. Here, we discuss the molecular basis of insulin resistance and inflammation and the molecular aspects on inflammatory pathways interfering in insulin action. Moreover, we explore interventions based on molecular targets for preventing or treating correlated disorders, advances for a better characterization, and understanding of the mechanisms and mediators involved in the different inflammatory and insulin resistance conditions. Finally, we address biotechnological studies for the development of new potential therapies and interventions. PMID:23049242

  2. Mesenteric Fat Lipolysis Mediates Obesity-Associated Hepatic Steatosis and Insulin Resistance.

    PubMed

    Wueest, Stephan; Item, Flurin; Lucchini, Fabrizio C; Challa, Tenagne D; Müller, Werner; Blüher, Matthias; Konrad, Daniel

    2016-01-01

    Hepatic steatosis and insulin resistance are among the most prevalent metabolic disorders and are tightly associated with obesity and type 2 diabetes. However, the underlying mechanisms linking obesity to hepatic lipid accumulation and insulin resistance are incompletely understood. Glycoprotein 130 (gp130) is the common signal transducer of all interleukin 6 (IL-6) cytokines. We provide evidence that gp130-mediated adipose tissue lipolysis promotes hepatic steatosis and insulin resistance. In obese mice, adipocyte-specific gp130 deletion reduced basal lipolysis and enhanced insulin's ability to suppress lipolysis from mesenteric but not epididymal adipocytes. Consistently, free fatty acid levels were reduced in portal but not in systemic circulation of obese knockout mice. Of note, adipocyte-specific gp130 knockout mice were protected from high-fat diet-induced hepatic steatosis as well as from insulin resistance. In humans, omental but not subcutaneous IL-6 mRNA expression correlated positively with liver lipid accumulation (r = 0.31, P < 0.05) and negatively with hyperinsulinemic-euglycemic clamp glucose infusion rate (r = -0.28, P < 0.05). The results show that IL-6 cytokine-induced lipolysis may be restricted to mesenteric white adipose tissue and that it contributes to hepatic insulin resistance and steatosis. Therefore, blocking IL-6 cytokine signaling in (mesenteric) adipocytes may be a novel approach to blunting detrimental fat-liver crosstalk in obesity. PMID:26384383

  3. Stressful life events are associated with insulin resistance among Chinese immigrant women in the United States

    PubMed Central

    Fang, Carolyn Y.; Boden, Guenther; Siu, Philip T.; Tseng, Marilyn

    2015-01-01

    Background Chinese immigrants experience increased chronic disease risk following migration to the US. Although the impact of lifestyle changes (e.g., diet) on disease risk has been extensively studied, associations of psychosocial stress and disease risk have attracted less attention. Thus, the objective of the present study was to examine associations between stress and insulin resistance in foreign-born Chinese American women. Methods From October, 2005 to April, 2008, 423 women recruited from southeastern Pennsylvania completed questionnaires reporting stressful life events. Blood samples were analyzed for fasting insulin and fasting glucose levels, which were used to estimate insulin resistance according to the homeostasis model assessment (HOMAIR). Results In logistic regression analyses, a greater number of negative life events were associated with insulin resistance (OR = 1.17, 95% CI = 1.02–1.34), controlling for age, level of acculturation, marital status, body mass index, and waist circumference. Similarly, greater negative life event impact ratings were also associated with insulin resistance (OR = 1.08, 95% CI = 1.01–1.16) controlling for relevant covariates. Conclusions This is one of the first studies to examine the associations between psychosocial stress and insulin resistance in Chinese immigrant women. These findings contribute to a growing body of literature on stress and diabetes risk in an immigrant population. PMID:26346575

  4. Adipose tissue inflammation: a cause or consequence of obesity-related insulin resistance?

    PubMed

    Blüher, Matthias

    2016-09-01

    The worldwide obesity epidemic has become a major health concern, because it contributes to higher mortality due to an increased risk for noncommunicable diseases including cardiovascular diseases, type 2 diabetes, musculoskeletal disorders and some cancers. Insulin resistance may link accumulation of adipose tissue in obesity to metabolic diseases, although the underlying mechanisms are not completely understood. In the past decades, data from human studies and transgenic animal models strongly suggested correlative, but also causative associations between activation of proinflammatory pathways and insulin resistance. Particularly chronic inflammation in adipose tissue seems to play an important role in the development of obesity-related insulin resistance. On the other hand, adipose tissue inflammation has been shown to be essential for healthy adipose tissue expansion and remodelling. However, whether adipose tissue inflammation represents a consequence or a cause of impaired insulin sensitivity remains an open question. A better understanding of the molecular pathways linking excess adipose tissue storage to chronic inflammation and insulin resistance may provide the basis for the future development of anti-inflammatory treatment strategies to improve adverse metabolic consequences of obesity. In this review, potential mechanisms of adipose tissue inflammation and how adipose tissue inflammation may cause insulin resistance are discussed. PMID:27503945

  5. Myeloperoxidase Deletion Prevents High-Fat Diet–Induced Obesity and Insulin Resistance

    PubMed Central

    Wang, Qilong; Xie, Zhonglin; Zhang, Wencheng; Zhou, Jun; Wu, Yue; Zhang, Miao; Zhu, Huaiping

    2014-01-01

    Activation of myeloperoxidase (MPO), a heme protein primarily expressed in granules of neutrophils, is associated with the development of obesity. However, whether MPO mediates high-fat diet (HFD)-induced obesity and obesity-associated insulin resistance remains to be determined. Here, we found that consumption of an HFD resulted in neutrophil infiltration and enhanced MPO expression and activity in epididymal white adipose tissue, with an increase in body weight gain and impaired insulin signaling. MPO knockout (MPO−/−) mice were protected from HFD-enhanced body weight gain and insulin resistance. The MPO inhibitor 4-aminobenzoic acid hydrazide reduced peroxidase activity of neutrophils and prevented HFD-enhanced insulin resistance. MPO deficiency caused high body temperature via upregulation of uncoupling protein-1 and mitochondrial oxygen consumption in brown adipose tissue. Lack of MPO also attenuated HFD-induced macrophage infiltration and expression of proinflammatory cytokines. We conclude that activation of MPO in adipose tissue contributes to the development of obesity and obesity-associated insulin resistance. Inhibition of MPO may be a potential strategy for prevention and treatment of obesity and insulin resistance. PMID:25024373

  6. Endoplasmic reticulum stress regulates inflammation and insulin resistance in skeletal muscle from pregnant women.

    PubMed

    Liong, Stella; Lappas, Martha

    2016-04-15

    Sterile inflammation and infection are key mediators of inflammation and peripheral insulin resistance associated with gestational diabetes mellitus (GDM). Studies have shown endoplasmic reticulum (ER) stress to induce inflammation and insulin resistance associated with obesity and type 2 diabetes, however is paucity of studies investigating the effects of ER stress in skeletal muscle on inflammation and insulin resistance associated with GDM. ER stress proteins IRE1α, GRP78 and XBP-1s were upregulated in skeletal muscle of obese pregnant women, whereas IRE1α was increased in GDM women. Suppression of ER stress, using ER stress inhibitor tauroursodeoxycholic acid (TUDCA) or siRNA knockdown of IRE1α and GRP78, significantly downregulated LPS-, poly(I:C)- or IL-1β-induced production of IL-6, IL-8, IL-1β and MCP-1. Furthermore, LPS-, poly(I:C)- or TNF-α-induced insulin resistance was improved following suppression of ER stress, by increasing insulin-stimulated phosphorylation of IR-β, IRS-1, GLUT-4 expression and glucose uptake. In summary, our inducible obesity and GDM-like models suggests that the development of GDM may be involved in activating ER stress-induced inflammation and insulin resistance in human skeletal muscle. PMID:26902174

  7. Paraoxonase-1 is not affected in polycystic ovary syndrome without metabolic syndrome and insulin resistance, but oxidative stress is altered.

    PubMed

    Torun, Ayse Nur; Vural, Mehmet; Cece, Hasan; Camuzcuoglu, Hakan; Toy, Harun; Aksoy, Nurten

    2011-12-01

    Paraoxonase-1 (PON1) activity is decreased in polycystic ovary syndrome (PCOS) having metabolic syndrome (MetS) or insulin resistance (IR). We aimed to assess PON1 activity and oxidative stress in PCOS without MetS or IR. Metabolic and hormonal parameters, high-sensitive C-reactive protein (hs-CRP), oxidative stress parameters (total antioxidant status (TAS), total oxidative stress (TOS), oxidative stress index (OSI), lipid hydroperoxide (LOOH), total free sulfhydryl (--SH) groups), PON and arylesterase were analyzed in 30 normal weighed patients with PCOS without MetS or IR and 20 normal controls. Hs-CRP, PON, arylesterase, and TAS levels of PCOS and control groups were similar. LOOH, TOS, and OSI of PCOS group were higher than in the controls (p < 0.05; p < 0.001, and p < 0.001, respectively). - SH group levels showed a positive correlation with free testosterone (fT). TOS positively correlated with free androgen index (FAI), body mass index (BMI), waist-to-hip ratio (WHR), LOOH, and OSI. This study showed that oxidative stress is increased in PCOS even in the absence of MetS or IR. PON1 activity appears not to be affected in PCOS without MetS and IR. Several metabolic and antropometric risk factors may aggravate this altered oxidative state in PCOS. PMID:21557696

  8. Activation of Proteinase 3 Contributes to Nonalcoholic Fatty Liver Disease and Insulin Resistance

    PubMed Central

    Toonen, Erik JM; Mirea, Andreea-Manuela; Tack, Cees J; Stienstra, Rinke; Ballak, Dov B; van Diepen, Janna A; Hijmans, Anneke; Chavakis, Triantafyllos; Dokter, Wim H; Pham, Christine TN; Netea, Mihai G; Dinarello, Charles A; Joosten, Leo AB

    2016-01-01

    Activation of inflammatory pathways is known to accompany development of obesity-induced nonalcoholic fatty liver disease (NAFLD), insulin resistance and type 2 diabetes. In addition to caspase-1, the neutrophil serine proteases proteinase 3, neutrophil elastase and cathepsin G are able to process the inactive proinflammatory mediators interleukin (IL)-1β and IL-18 to their bioactive forms, thereby regulating inflammatory responses. In this study, we investigated whether proteinase 3 is involved in obesity-induced development of insulin resistance and NAFLD. We investigated the development of NAFLD and insulin resistance in mice deficient for neutrophil elastase/proteinase 3 and neutrophil elastase/cathepsin G and in wild-type mice treated with the neutrophil serine proteinase inhibitor human α-1 antitrypsin. Expression profiling of metabolically relevant tissues obtained from insulin-resistant mice showed that expression of proteinase 3 was specifically upregulated in the liver, whereas neutrophil elastase, cathepsin G and caspase-1 were not. Neutrophil elastase/proteinase 3-deficient mice showed strongly reduced levels of lipids in the liver after being fed a high-fat diet. Moreover, these mice were resistant to high–fat–diet-induced weight gain, inflammation and insulin resistance. Injection of proteinase 3 exacerbated insulin resistance in caspase-1–/– mice, indicating that proteinase 3 acts independently of caspase-1. Treatment with α-1 antitrypsin during the last 10 d of a 16-wk high-fat diet reduced hepatic lipid content and decreased fasting glucose levels. We conclude that proteinase 3 is involved in NAFLD and insulin resistance and that inhibition of proteinase 3 may have therapeutic potential. PMID:27261776

  9. The relationship between rosacea and insulin resistance and metabolic syndrome.

    PubMed

    Akin Belli, Asli; Ozbas Gok, Seyran; Akbaba, Gulhan; Etgu, Fatma; Dogan, Gursoy

    2016-06-01

    Rosacea is a chronic inflammatory skin disease affecting the face. A positive correlation has been found between rosacea and cardiovascular diseases. We sought to investigate the relation between rosacea and metabolic syndrome (MS) and insulin resistance (IR). Between January and June 2015, a case-control study including 47 age-, gender-, and body mass index (BMI)-matched rosacea patients and 50 controls was conducted. Demographic data, clinical features of rosacea patients, anthropometric measures, laboratory findings, blood pressure levels, BMI, smoking history, alcohol consumption, sports life, family history of cardiovascular disease, and presence of MS and IR were recorded. Forty-seven rosacea patients (12 men and 35 women; age range: 35-68 years) and 50 controls (11 men and 39 women; age range: 38-78 years) were included in our study. Of 47 rosacea patients, 24 had erythematotelangiectatic type, 22 had papulopustular type, and one had phymatous type. Whereas the rate of IR was significantly higher in the rosacea group, there was no significant difference in the rate of MS between rosacea and the control group (p = 0.009 and p = 0.186, respectively). In addition, the rosacea group had significantly higher fasting blood glucose, total cholesterol, and systolic and diastolic blood pressure levels (p<0.05). Mean levels of LDL, triglyceride, total cholesterol and CRP were significantly higher than in the control group (p<0.05). Our findings suggest that there is a relationship between rosacea and IR and some parameters of cardiovascular risk factors. We recommend investigation of IR in rosacea patients. PMID:27328660

  10. Insulin Resistance, Diabetes Mellitus, and Brain Structure in Bipolar Disorders

    PubMed Central

    Hajek, Tomas; Calkin, Cynthia; Blagdon, Ryan; Slaney, Claire; Uher, Rudolf; Alda, Martin

    2014-01-01

    Type 2 diabetes mellitus (T2DM) damages the brain, especially the hippocampus, and frequently co-occurs with bipolar disorders (BD). Reduced hippocampal volumes are found only in some studies of BD subjects and may thus be secondary to the presence of certain clinical variables. Studying BD patients with abnormal glucose metabolism could help identify preventable risk factors for hippocampal atrophy in BD. We compared brain structure using optimized voxel-based morphometry of 1.5T MRI scans in 33 BD subjects with impaired glucose metabolism (19 with insulin resistance/glucose intolerance (IR/GI), 14 with T2DM), 15 euglycemic BD participants and 11 euglycemic, nonpsychiatric controls. The group of BD patients with IR, GI or T2DM had significantly smaller hippocampal volumes than the euglycemic BD participants (corrected p=0.02) or euglycemic, nonpsychiatric controls (corrected p=0.004). Already the BD subjects with IR/GI had smaller hippocampal volumes than euglycemic BD participants (t(32)=−3.15, p=0.004). Age was significantly more negatively associated with hippocampal volumes in BD subjects with IR/GI/T2DM than in the euglycemic BD participants (F(2, 44)=9.96, p=0.0003). The gray matter reductions in dysglycemic subjects extended to the cerebral cortex, including the insula. In conclusion, this is the first study demonstrating that T2DM or even prediabetes may be risk factors for smaller hippocampal and cortical volumes in BD. Abnormal glucose metabolism may accelerate the age-related decline in hippocampal volumes in BD. These findings raise the possibility that improving diabetes care among BD subjects and intervening already at the level of prediabetes could slow brain aging in BD. PMID:25074491

  11. Telmisartan aggravates pustular psoriasis

    PubMed Central

    Keerthi, Subramaniam; Rangaraj, Murugaiyan; Karthikeyan, Kaliaperumal

    2015-01-01

    Pustular psoriasis is characterized by abrupt onset of macroscopic pustules associated with erythema and symptoms of burning pain and constitutional symptoms. There are several precipitating factors, both physiological such as pregnancy and routinely prescribed drugs like antihypertensives, antifungals, corticosteroids and progesterone. We present a case of a 50-year-old male patient with pustular psoriasis, well controlled on oral methotrexate, who presented with sudden exacerbation of pustular psoriasis following the use of telmisartan. This case is presented due to the absence of prior reports of telmisartan aggravating pustular psoriasis. PMID:25969662

  12. Impaired Translocation of GLUT4 Results in Insulin Resistance of Atrophic Soleus Muscle

    PubMed Central

    Xu, Peng-Tao; Song, Zhen; Zhang, Wen-Cheng; Jiao, Bo; Yu, Zhi-Bin

    2015-01-01

    Whether or not the atrophic skeletal muscle induces insulin resistance and its mechanisms are not resolved now. The antigravity soleus muscle showed a progressive atrophy in 1-week, 2-week, and 4-week tail-suspended rats. Hyperinsulinemic-euglycemic clamp showed that the steady-state glucose infusion rate was lower in 4-week tail-suspended rats than that in the control rats. The glucose uptake rates under insulin- or contraction-stimulation were significantly decreased in 4-week unloaded soleus muscle. The key protein expressions of IRS-1, PI3K, and Akt on the insulin-dependent pathway and of AMPK, ERK, and p38 on the insulin-independent pathway were unchanged in unloaded soleus muscle. The unchanged phosphorylation of Akt and p38 suggested that the activity of two signal pathways was not altered in unloaded soleus muscle. The AS160 and GLUT4 expression on the common downstream pathway also was not changed in unloaded soleus muscle. But the GLUT4 translocation to sarcolemma was inhibited during insulin stimulation in unloaded soleus muscle. The above results suggest that hindlimb unloading in tail-suspended rat induces atrophy in antigravity soleus muscle. The impaired GLUT4 translocation to sarcolemma under insulin stimulation may mediate insulin resistance in unloaded soleus muscle and further affect the insulin sensitivity of whole body in tail-suspended rats. PMID:25713812

  13. Impaired translocation of GLUT4 results in insulin resistance of atrophic soleus muscle.

    PubMed

    Xu, Peng-Tao; Song, Zhen; Zhang, Wen-Cheng; Jiao, Bo; Yu, Zhi-Bin

    2015-01-01

    Whether or not the atrophic skeletal muscle induces insulin resistance and its mechanisms are not resolved now. The antigravity soleus muscle showed a progressive atrophy in 1-week, 2-week, and 4-week tail-suspended rats. Hyperinsulinemic-euglycemic clamp showed that the steady-state glucose infusion rate was lower in 4-week tail-suspended rats than that in the control rats. The glucose uptake rates under insulin- or contraction-stimulation were significantly decreased in 4-week unloaded soleus muscle. The key protein expressions of IRS-1, PI3K, and Akt on the insulin-dependent pathway and of AMPK, ERK, and p38 on the insulin-independent pathway were unchanged in unloaded soleus muscle. The unchanged phosphorylation of Akt and p38 suggested that the activity of two signal pathways was not altered in unloaded soleus muscle. The AS160 and GLUT4 expression on the common downstream pathway also was not changed in unloaded soleus muscle. But the GLUT4 translocation to sarcolemma was inhibited during insulin stimulation in unloaded soleus muscle. The above results suggest that hindlimb unloading in tail-suspended rat induces atrophy in antigravity soleus muscle. The impaired GLUT4 translocation to sarcolemma under insulin stimulation may mediate insulin resistance in unloaded soleus muscle and further affect the insulin sensitivity of whole body in tail-suspended rats. PMID:25713812

  14. Pharmacological TLR4 Inhibition Protects against Acute and Chronic Fat-Induced Insulin Resistance in Rats

    PubMed Central

    Zhang, Ning; Liang, Hanyu; Farese, Robert V.; Li, Ji

    2015-01-01

    Aims To evaluate whether pharmacological TLR4 inhibition protects against acute and chronic fat-induced insulin resistance in rats. Materials and Methods For the acute experiment, rats received a TLR4 inhibitor [TAK-242 or E5564 (2x5 mg/kg i.v. bolus)] or vehicle, and an 8-h Intralipid (20%, 8.5 mg/kg/min) or saline infusion, followed by a two-step hyperinsulinemic-euglycemic clamp. For the chronic experiment, rats were subcutaneously implanted with a slow-release pellet of TAK-242 (1.5 mg/d) or placebo. Rats then received a high fat diet (HFD) or a low fat control diet (LFD) for 10 weeks, followed by a two-step insulin clamp. Results Acute experiment; the lipid-induced reduction (18%) in insulin-stimulated glucose disposal (Rd) was attenuated by TAK-242 and E5564 (the effect of E5564 was more robust), suggesting improved peripheral insulin action. Insulin was able to suppress hepatic glucose production (HGP) in saline- but not lipid-treated rats. TAK-242, but not E5564, partially restored this effect, suggesting improved HGP. Chronic experiment; insulin-stimulated Rd was reduced ~30% by the HFD, but completely restored by TAK-242. Insulin could not suppress HGP in rats fed a HFD and TAK-242 had no effect on HGP. Conclusions Pharmacological TLR4 inhibition provides partial protection against acute and chronic fat-induced insulin resistance in vivo. PMID:26196892

  15. Swimming improves high-fat induced insulin resistance by regulating lipid and energy metabolism and the insulin pathway in rats.

    PubMed

    Song, An; Wang, Chao; Ren, Luping; Zhao, Jiajun

    2014-06-01

    In this study, we aimed to determine the preventive and therapeutic effects of swimming on insulin resistance in high-fat-fed rats. Sprague-Dawley rats were divided into 4 groups and fed for 8 weeks as follows: i) the control (Con) group fed a control diet; ii) the high-fat (HF) group fed a high-fat diet; iii) the treatment (ST) group fed a high-fat diet and trained with swimming from the 4th week; and iv) the prevention (SP) group fed a high-fat diet and trained with swimming from the 1st week of the experiment. A hyperinsulinemic-euglycemic clamp was used to evaluate the insulin sensitivity of the rats. The ultrastructure of the liver cells was observed by electron microscopy. Hepatic lipid accumulation was observed by Oil Red O staining. Quantitative RT-PCR and western blot analysis were performed to detect the expression of proteins related to lipid metabolism, energy metabolism and insulin signaling transduction. After 8 weeks of feeding, compared with the Con group, the glucose infusion rate (GIR) was significantly decreased; a significant lipid accumulation was observed in the liver, while the ultrastructure of the liver cells was damaged in the HF group. Proteins related to lipid metabolism in the liver and skeletal muscle, including FAT and FABP were upregulated, while CPT1 and PPAR levels were downregulated in the HF group. The levels of the energy-metabolism-related molecules, AMPKα2, PGC1α, PGC1β and MFN2 were downregulated in skeletal muscle in the HF group. The expression levels of insulin signaling transduction molecules, INSR, IRS1, PI3K/p85, AKT2 and GLUT4, as well as the phosphorylation levels of INSR, IRS1, PI3K/p85 and AKT2 were lower in skeletal muscles in the HF rats. Compared with HF group, the GIR levels were significantly increased in the ST and SP groups. Lipid accumulation and damage to the ultrastructure of the liver cells were improved in both groups. The expression of molecules related to lipid metabolism in the liver and skeletal

  16. Carnitine Palmitoyltransferase 1b Deficient Mice Develop Severe Insulin Resistance After Prolonged High Fat Diet Feeding

    PubMed Central

    Kim, Teayoun; Moore, John F; Sharer, Jon D; Yang, Kevin; Wood, Philip A; Yang, Qinglin

    2014-01-01

    Background Carnitine palmitoyltransferase 1 (CPT1) is the rate-limiting enzyme governing the entry of long-chain acyl-CoAs into mitochondria. Treatments with CPT1 inhibitors protect against insulin resistance in short-term preclinical animal studies. We recently reported that mice with muscle isoform CPT1b deficiency demonstrated improved insulin sensitivity when fed a High Fat-Diet (HFD) for up to 5 months. In this follow up study, we further investigated whether the insulin sensitizing effects of partial CPT1b deficiency could be maintained under a prolonged HFD feeding condition. Methods We investigated the effects of CPT1b deficiency on HFD-induced insulin resistance using heterozygous CPT1b deficient (Cpt1b+/−) mice compared with Wild Type (WT) mice fed a HFD for a prolonged period of time (7 months). We assessed insulin sensitivity using hyperinsulinemic-euglycemic clamps. We also examined body composition, skeletal muscle lipid profile, and changes in the insulin signaling pathways of skeletal muscle, liver, and adipose tissue. Results We found that Cpt1b+/− mice became severely insulin resistant after 7 months of HFD feeding. Cpt1b+/− mice exhibited a substantially reduced glucose infusion rate and skeletal muscle glucose uptake. While Cpt1b+/− mice maintained a slower weight gain with less fat mass than WT mice, accumulation of lipid intermediates became evident in the muscle of Cpt1b+/− but not WT mice after 7 months of HFD feeding. Insulin signaling was impaired in the Cpt1b+/− as compared to the WT muscles. Conclusion Partial CPT1b deficiency, mimicking CPT1b inhibition, may lead to impaired insulin signaling and insulin sensitivity under a prolonged HFD feeding condition. Therefore, further studies on the potential detrimental effects of prolonged therapy with CPT1 inhibition are necessary in the development of this potential therapeutic strategy. PMID:25580367

  17. Altered Skeletal Muscle Lipase Expression and Activity Contribute to Insulin Resistance in Humans

    PubMed Central

    Badin, Pierre-Marie; Louche, Katie; Mairal, Aline; Liebisch, Gerhard; Schmitz, Gerd; Rustan, Arild C.; Smith, Steven R.; Langin, Dominique; Moro, Cedric

    2011-01-01

    OBJECTIVE Insulin resistance is associated with elevated content of skeletal muscle lipids, including triacylglycerols (TAGs) and diacylglycerols (DAGs). DAGs are by-products of lipolysis consecutive to TAG hydrolysis by adipose triglyceride lipase (ATGL) and are subsequently hydrolyzed by hormone-sensitive lipase (HSL). We hypothesized that an imbalance of ATGL relative to HSL (expression or activity) may contribute to DAG accumulation and insulin resistance. RESEARCH DESIGN AND METHODS We first measured lipase expression in vastus lateralis biopsies of young lean (n = 9), young obese (n = 9), and obese-matched type 2 diabetic (n = 8) subjects. We next investigated in vitro in human primary myotubes the impact of altered lipase expression/activity on lipid content and insulin signaling. RESULTS Muscle ATGL protein was negatively associated with whole-body insulin sensitivity in our population (r = −0.55, P = 0.005), whereas muscle HSL protein was reduced in obese subjects. We next showed that adenovirus-mediated ATGL overexpression in human primary myotubes induced DAG and ceramide accumulation. ATGL overexpression reduced insulin-stimulated glycogen synthesis (−30%, P < 0.05) and disrupted insulin signaling at Ser1101 of the insulin receptor substrate-1 and downstream Akt activation at Ser473. These defects were fully rescued by nonselective protein kinase C inhibition or concomitant HSL overexpression to restore a proper lipolytic balance. We show that selective HSL inhibition induces DAG accumulation and insulin resistance. CONCLUSIONS Altogether, the data indicate that altered ATGL and HSL expression in skeletal muscle could promote DAG accumulation and disrupt insulin signaling and action. Targeting skeletal muscle lipases may constitute an interesting strategy to improve insulin sensitivity in obesity and type 2 diabetes. PMID:21498783

  18. The Role of Skeletal Muscle Sphingolipids in the Development of Insulin Resistance

    PubMed Central

    Straczkowski, Marek; Kowalska, Irina

    2008-01-01

    Insulin resistance is an important risk factor for type 2 diabetes, obesity, cardiovascular disease, polycystic ovary syndrome and other diseases. The most important stage in the development of insulin resistance is impairment of insulin-stimulated skeletal muscle glucose uptake. There is evidence that intramyocellular lipids might be responsible for this process through inhibition of insulin signaling. One of the important intracellular lipid pools is associated with the sphingomyelin signaling pathway. The second messenger in this pathway is ceramide. In vitro data indicate that ceramide inhibits insulin signaling, mainly through inactivation of protein kinase B. In vivo data suggest that ceramide accumulation within muscle cells might be associated with the development of insulin resistance. In this review, we discuss both in vitro and in vivo evidence for the role of muscle ceramide in the impairment of insulin action with particular focus on the question whether findings from animal studies are applicable to humans. We describe problems that are unresolved so far and topics of potential interest for future research. PMID:18548166

  19. Adaptation of β-Cell and Endothelial Function to Carbohydrate Loading: Influence of Insulin Resistance.

    PubMed

    Hurwitz, Barry E; Schneiderman, Neil; Marks, Jennifer B; Mendez, Armando J; Gonzalez, Alex; Llabre, Maria M; Smith, Steven R; Bizzotto, Roberto; Santini, Eleonora; Manca, Maria Laura; Skyler, Jay S; Mari, Andrea; Ferrannini, Ele

    2015-07-01

    High-carbohydrate diets have been associated with β-cell strain, dyslipidemia, and endothelial dysfunction. We examined how β-cell and endothelial function adapt to carbohydrate overloading and the influence of insulin resistance. On sequential days in randomized order, nondiabetic subjects (classified as insulin-sensitive [IS] [n = 64] or insulin-resistant [IR] [n = 79] by euglycemic clamp) received four mixed meals over 14 h with either standard (300 kcal) or double carbohydrate content. β-Cell function was reconstructed by mathematical modeling; brachial artery flow-mediated dilation (FMD) was measured before and after each meal. Compared with IS, IR subjects showed higher glycemia and insulin hypersecretion due to greater β-cell glucose and rate sensitivity; potentiation of insulin secretion, however, was impaired. Circulating free fatty acids (FFAs) were less suppressed in IR than IS subjects. Baseline FMD was reduced in IR, and postprandial FMD attenuation occurred after each meal, particularly with high carbohydrate, similarly in IR and IS. Throughout the two study days, higher FFA levels were significantly associated with lower (incretin-induced) potentiation and impaired FMD. In nondiabetic individuals, enhanced glucose sensitivity and potentiation upregulate the insulin secretory response to carbohydrate overloading. With insulin resistance, this adaptation is impaired. Defective suppression of endogenous FFA is one common link between impaired potentiation and vascular endothelial dysfunction. PMID:25754957

  20. Adaptation of β-Cell and Endothelial Function to Carbohydrate Loading: Influence of Insulin Resistance

    PubMed Central

    Hurwitz, Barry E.; Schneiderman, Neil; Marks, Jennifer B.; Mendez, Armando J.; Gonzalez, Alex; Llabre, Maria M.; Smith, Steven R.; Bizzotto, Roberto; Santini, Eleonora; Manca, Maria Laura; Skyler, Jay S.; Mari, Andrea

    2015-01-01

    High-carbohydrate diets have been associated with β-cell strain, dyslipidemia, and endothelial dysfunction. We examined how β-cell and endothelial function adapt to carbohydrate overloading and the influence of insulin resistance. On sequential days in randomized order, nondiabetic subjects (classified as insulin-sensitive [IS] [n = 64] or insulin-resistant [IR] [n = 79] by euglycemic clamp) received four mixed meals over 14 h with either standard (300 kcal) or double carbohydrate content. β-Cell function was reconstructed by mathematical modeling; brachial artery flow-mediated dilation (FMD) was measured before and after each meal. Compared with IS, IR subjects showed higher glycemia and insulin hypersecretion due to greater β-cell glucose and rate sensitivity; potentiation of insulin secretion, however, was impaired. Circulating free fatty acids (FFAs) were less suppressed in IR than IS subjects. Baseline FMD was reduced in IR, and postprandial FMD attenuation occurred after each meal, particularly with high carbohydrate, similarly in IR and IS. Throughout the two study days, higher FFA levels were significantly associated with lower (incretin-induced) potentiation and impaired FMD. In nondiabetic individuals, enhanced glucose sensitivity and potentiation upregulate the insulin secretory response to carbohydrate overloading. With insulin resistance, this adaptation is impaired. Defective suppression of endogenous FFA is one common link between impaired potentiation and vascular endothelial dysfunction. PMID:25754957

  1. Insulin Resistance in PCOS Patients Enhances Oxidative Stress and Leukocyte Adhesion: Role of Myeloperoxidase

    PubMed Central

    Victor, Victor M.; Rovira-Llopis, Susana; Bañuls, Celia; Diaz-Morales, Noelia; Martinez de Marañon, Arantxa; Rios-Navarro, Cesar; Alvarez, Angeles; Gomez, Marcelino; Rocha, Milagros; Hernández-Mijares, Antonio

    2016-01-01

    Cardiovascular diseases and oxidative stress are related to polycystic ovary syndrome (PCOS) and insulin resistance (IR). We have evaluated the relationship between myeloperoxidase (MPO) and leukocyte activation in PCOS patients according to homeostatic model assessment of IR (HOMA-IR), and have explored a possible correlation between these factors and endocrine and inflammatory parameters. This was a prospective controlled study conducted in an academic medical center. The study population consisted of 101 PCOS subjects and 105 control subjects. We divided PCOS subjects into PCOS non-IR (HOMA-IR<2.5) and PCOS IR (HOMA-IR>2.5). Metabolic and anthropometric parameters, total and mitochondrial reactive oxygen species (ROS) production, MPO levels, interactions between human umbilical vein endothelial cells and leukocytes, adhesion molecules (E-selectin, ICAM-1 and VCAM-1) and proinflammatory cytokines (IL-6 and TNF-α) were evaluated. Oxidative stress was observed in PCOS patients, in whom there was an increase in total and mitochondrial ROS production and MPO levels. Enhanced rolling flux and adhesion, and a decrease in polymorphonuclear cell rolling velocity were also detected in PCOS subjects. Increases in IL-6 and TNF-α and adhesion molecules (E-selectin, ICAM-1 and VCAM-1) were also observed, particularly in the PCOS IR group, providing evidence that inflammation and oxidative stress are related in PCOS patients. HOMA-IR was positively correlated with hsCRP (p<0.001, r = 0.304), ROS production (p<0.01, r = 0.593), leukocyte rolling flux (p<0.05, r = 0.446), E-selectin (p<0.01, r = 0.436) and IL-6 (p<0.001, r = 0.443). The results show an increase in the rate of ROS and MPO levels in PCOS patients in general, and particularly in those with IR. Inflammation in PCOS induces leukocyte-endothelium interactions and a simultaneous increase in IL-6, TNF-α, E-selectin, ICAM-1 and VCAM-1. These conditions are aggravated by the presence of IR. PMID:27007571

  2. Genipin ameliorates age-related insulin resistance through inhibiting hepatic oxidative stress and mitochondrial dysfunction.

    PubMed

    Guan, Lili; Feng, Haiyan; Gong, Dezheng; Zhao, Xu; Cai, Li; Wu, Qiong; Yuan, Bo; Yang, Mei; Zhao, Jie; Zou, Yuan

    2013-12-01

    Insulin resistance (IR) increases with age and plays a key role in the pathogenesis of type 2 diabetes mellitus. Oxidative stress and mitochondrial dysfunction are supposed to be major factors leading to age-related IR. Genipin, an extract from Gardenia jasminoides Ellis fruit, has been reported to stimulate insulin secretion in pancreatic islet cells by regulating mitochondrial function. In this study, we first investigated the effects of genipin on insulin sensitivity and the potential mitochondrial mechanisms in the liver of aging rats. The rats were randomly assigned to receive intraperitoneal injections of either 25mg/kg genipin or vehicle once daily for 12days. The aging rats showed hyperinsulinemia and hyperlipidemia, and insulin resistance as examined by the decreased glucose decay constant rate during insulin tolerance test (kITT). The hepatic tissues showed steatosis and reduced glycogen content. Hepatic malondialdehyde level and mitochondrial reactive oxygen species (ROS) were higher, and levels of mitochondrial membrane potential (MMP) and ATP were lower as compared with the normal control rats. Administration of genipin ameliorated systemic and hepatic insulin resistance, alleviated hyperinsulinemia, hyperglyceridemia and hepatic steatosis, relieved hepatic oxidative stress and mitochondrial dysfunction in aging rats. Furthermore, genipin not only improved insulin sensitivity by promoting insulin-stimulated glucose consumption and glycogen synthesis, inhibited cellular ROS overproduction and alleviated the reduction of levels of MMP and ATP, but also reversed oxidative stress-associated JNK hyperactivation and reduced Akt phosphorylation in palmitate-treated L02 hepatocytes. In conclusion, genipin ameliorates age-related insulin resistance through inhibiting hepatic oxidative stress and mitochondrial dysfunction. PMID:24041487

  3. Lipocalin-2 inhibits autophagy and induces insulin resistance in H9c2 cells.

    PubMed

    Chan, Yee Kwan; Sung, Hye Kyoung; Jahng, James Won Suk; Kim, Grace Ha Eun; Han, Meng; Sweeney, Gary

    2016-07-15

    Lipocalin-2 (Lcn2; also known as neutrophil gelatinase associated lipocalin, NGAL) levels are increased in obesity and diabetes and associate with insulin resistance. Correlations exist between Lcn2 levels and various forms or stages of heart failure. Insulin resistance and autophagy both play well-established roles in cardiomyopathy. However, little is known about the impact of Lcn2 on insulin signaling in cardiomyocytes. In this study, we treated H9c2 cells with recombinant Lcn2 for 1 h followed by dose- and time-dependent insulin treatment and found that Lcn2 attenuated insulin signaling assessed via phosphorylation of Akt and p70S6K. We used multiple assays to demonstrate that Lcn2 reduced autophagic flux. First, Lcn2 reduced pULK1 S555, increased pULK1 S757 and reduced LC3-II levels determined by Western blotting. We validated the use of DQ-BSA to assess autolysosomal protein degradation and this together with MagicRed cathepsin B assay indicated that Lcn2 reduced lysosomal degradative activity. Furthermore, we generated H9c2 cells stably expressing tandem fluorescent RFP/GFP-LC3 and this approach verified that Lcn2 decreased autophagic flux. We also created an autophagy-deficient H9c2 cell model by overexpressing a dominant-negative Atg5 mutant and found that reduced autophagy levels also induced insulin resistance. Adding rapamycin after Lcn2 could stimulate autophagy and recover insulin sensitivity. In conclusion, our study indicated that acute Lcn2 treatment caused insulin resistance and use of gain and loss of function approaches elucidated a causative link between autophagy inhibition and regulation of insulin sensitivity by Lcn2. PMID:27090568

  4. ABDOMINAL OBESITY, MUSCLE COMPOSITION, AND INSULIN RESISTANCE IN PREMENOPAUSAL WOMEN

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The independent relationships between visceral and abdominal subcutaneous adipose tissue (AT) depots, muscle composition, and insulin sensitivity were examined in 40 abdominally obese, premenopausal women. Measurements included glucose disposal by euglycemic clamp, muscle composition by computed to...

  5. Transient receptor potential vanilloid type-1 channel regulates diet-induced obesity, insulin resistance, and leptin resistance.

    PubMed

    Lee, Eunjung; Jung, Dae Young; Kim, Jong Hun; Patel, Payal R; Hu, Xiaodi; Lee, Yongjin; Azuma, Yoshihiro; Wang, Hsun-Fan; Tsitsilianos, Nicholas; Shafiq, Umber; Kwon, Jung Yeon; Lee, Hyong Joo; Lee, Ki Won; Kim, Jason K

    2015-08-01

    Insulin resistance is a major characteristic of obesity and type 2 diabetes, but the underlying mechanism is unclear. Recent studies have shown a metabolic role of capsaicin that may be mediated via the transient receptor potential vanilloid type-1 (TRPV1) channel. In this study, TRPV1 knockout (KO) and wild-type (WT) mice (as controls) were fed a high-fat diet (HFD), and metabolic studies were performed to measure insulin and leptin action. The TRPV1 KO mice became more obese than the WT mice after HFD, partly attributed to altered energy balance and leptin resistance in the KO mice. The hyperinsulinemic-euglycemic clamp experiment showed that the TRPV1 KO mice were more insulin resistant after HFD because of the ∼40% reduction in glucose metabolism in the white and brown adipose tissue, compared with that in the WT mice. Leptin treatment failed to suppress food intake, and leptin-mediated hypothalamic signal transducer and activator of transcription (STAT)-3 activity was blunted in the TRPV1 KO mice. We also found that the TRPV1 KO mice were more obese and insulin resistant than the WT mice at 9 mo of age. Taken together, these results indicate that lacking TRPV1 exacerbates the obesity and insulin resistance associated with an HFD and aging, and our findings further suggest that TRPV1 has a major role in regulating glucose metabolism and hypothalamic leptin's effects in obesity. PMID:25888600

  6. Surgical removal of visceral fat reverses hepatic insulin resistance.

    PubMed

    Barzilai, N; She, L; Liu, B Q; Vuguin, P; Cohen, P; Wang, J; Rossetti, L

    1999-01-01

    We directly examined whether visceral fat (VF) modulates hepatic insulin action by randomizing moderately obese (body wt approximately 400 g) Sprague-Dawley rats to either surgical removal of epididymal and perinephric fat pads (VF-; n = 9) or a sham operation (VF+; n = 11). Three weeks later, total VF was fourfold increased (8.5 +/- 1.2 vs. 2.1 +/- 0.3 g, P < 0.001) in the VF+ compared with the VF- group, but whole-body fat mass (determined using 3H2O) was not significantly different. The rates of insulin infusion required to maintain plasma glucose levels and basal hepatic glucose production in the presence of hepatic-pancreatic clamp were markedly decreased in VF- compared with VF+ rats (0.57 +/- 0.02 vs. 1.22 +/- 0.19 mU x kg(-1) x min(-1), P < 0.001). Similarly, plasma insulin levels were more than twofold higher in the VF+ group (P < 0.001). The heightened hepatic insulin sensitivity is supported by the decrease in gene expression of both glucose-6-phosphatase and PEPCK and by physiological hyperinsulinemia in VF- but not VF+ rats. The improvement in hepatic insulin sensitivity in VF- rats was also supported by a approximately 70% decrease in the plasma levels of insulin-like growth factor binding protein-1, a marker of insulin's transcription regulation in the liver. The removal of VF pads also resulted in marked decreases in the gene expression of tumor necrosis factor-alpha (by 72%) and leptin (by 60%) in subcutaneous fat. We conclude that visceral fat is a potent modulator of insulin action on hepatic glucose production and gene expression. PMID:9892227

  7. Genistein reduced insulin resistance index through modulating lipid metabolism in ovariectomized rats.

    PubMed

    Choi, Joo Sun; Koh, In-Uk; Song, Jihyun

    2012-11-01

    Postmenopausal women are at higher risk for obesity and insulin resistance due to the decline of estrogen, but genistein, a phytoestrogen, may reduce the risks of these diet-related diseases. In this study, we hypothesized that supplemental genistein has beneficial effects on insulin resistance in an ovariectomized rat model by modulating lipid metabolism. Three weeks after a sham surgery (sham) or an ovariectomy (OVX), ovariectomized Sprague-Dawley rats were placed on a diet containing 0 (OVX group) or 0.1% genistein for 4 weeks. The sham rats were fed a high-fat diet containing 0% genistein and served as the control group (sham group). The ovariectomized rats showed increases in body weight and insulin resistance index, but genistein reduced insulin resistance index and the activity of hepatic fatty acid synthetase. Genistein was also associated with increased activity of succinate dehydrogenase and carnitine palmitoyltransferase and the rate of β-oxidation in the fat tissue of rats. The ovariectomized rats given genistein had smaller-sized adipocytes. Using gene-set enrichment analysis (GSEA) of microarray data, we found that a number of gene sets of fatty acid metabolism, insulin resistance, and oxidative stress were differentially expressed by OVX and reversed by genistein. This systemic approach of GSEA enables the identification of such consensus between the gene expression changes and phenotypic changes caused by OVX and genistein supplementation. Genistein treatment could help reduce insulin resistance through the amelioration of OVX-induced metabolic dysfunction, and the GSEA approach may be useful in proposing putative targets related to insulin resistance. PMID:23176795

  8. Triglyceride Is a Useful Surrogate Marker for Insulin Resistance in Korean Women with Polycystic Ovary Syndrome

    PubMed Central

    Park, So Yun; Cho, Yeon Jean; Lee, Sa Ra; Chung, Hyewon

    2015-01-01

    Purpose To evaluate lipid profiles and liver enzymes as surrogate markers used for recognizing insulin resistance in Korean women with polycystic ovary syndrome (PCOS). Materials and Methods 458 women with PCOS were divided into two groups: non-obese with a body mass index (BMI)<25.0 kg/m2 and obese with a BMI≥25.0 kg/m2. Anthropometric measures and blood sampling for hormone assay, liver enzymes, lipid profiles and 75 g oral glucose tolerance test were performed. Insulin resistance was defined as homeostasis model assessment of insulin resistance (HOMA-IR)≥2.5. Areas under the receiver operating characteristic (ROC) curves were used to compare the power of serum markers. Multiple linear regression analysis was used to evaluate the contribution of each confounding factor for HOMA-IR. Results In non-obese and obese groups, the ROC curve analyses demonstrated that the best marker for insulin resistance was triglyceride (TG), with the areas under the ROC curve of 0.617 and 0.837, respectively. Low-density lipoprotein cholesterol (LDL-C) was the significant marker for insulin resistance with areas under the ROC curve of 0.698 in obese group, but not significant in non-obese group. TG and LDL-C were significantly associated with HOMA-IR in both non-obese and obese PCOS women by multiple linear regression analysis. The optimal cut-off points of TG≥68.5 was a marker for predicting insulin resistance in non-obese PCOS patients and TG≥100.5 in obese group. Conclusion TG can be used as a useful marker for insulin resistance in Korean women with PCOS, especially for obese patients. PMID:25837186

  9. Gut Microbiota Is a Key Modulator of Insulin Resistance in TLR 2 Knockout Mice

    PubMed Central

    Caricilli, Andréa M.; Picardi, Paty K.; de Abreu, Lélia L.; Ueno, Mirian; Prada, Patrícia O.; Ropelle, Eduardo R.; Hirabara, Sandro Massao; Castoldi, Ângela; Vieira, Pedro; Camara, Niels O. S.; Curi, Rui; Carvalheira, José B.; Saad, Mário J. A.

    2011-01-01

    Environmental factors and host genetics interact to control the gut microbiota, which may have a role in the development of obesity and insulin resistance. TLR2-deficient mice, under germ-free conditions, are protected from diet-induced insulin resistance. It is possible that the presence of gut microbiota could reverse the phenotype of an animal, inducing insulin resistance in an animal genetically determined to have increased insulin sensitivity, such as the TLR2 KO mice. In the present study, we investigated the influence of gut microbiota on metabolic parameters, glucose tolerance, insulin sensitivity, and signaling of TLR2-deficient mice. We investigated the gut microbiota (by metagenomics), the metabolic characteristics, and insulin signaling in TLR2 knockout (KO) mice in a non-germ free facility. Results showed that the loss of TLR2 in conventionalized mice results in a phenotype reminiscent of metabolic syndrome, characterized by differences in the gut microbiota, with a 3-fold increase in Firmicutes and a slight increase in Bacteroidetes compared with controls. These changes in gut microbiota were accompanied by an increase in LPS absorption, subclinical inflammation, insulin resistance, glucose intolerance, and later, obesity. In addition, this sequence of events was reproduced in WT mice by microbiota transplantation and was also reversed by antibiotics. At the molecular level the mechanism was unique, with activation of TLR4 associated with ER stress and JNK activation, but no activation of the IKKβ-IκB-NFκB pathway. Our data also showed that in TLR2 KO mice there was a reduction in regulatory T cell in visceral fat, suggesting that this modulation may also contribute to the insulin resistance of these animals. Our results emphasize the role of microbiota in the complex network of molecular and cellular interactions that link genotype to phenotype and have potential implications for common human disorders involving obesity, diabetes, and even other

  10. Fucoidan from sea cucumber may improve hepatic inflammatory response and insulin resistance in mice.

    PubMed

    Wang, Jinhui; Hu, Shiwei; Jiang, Wei; Song, Wendong; Cai, Lu; Wang, Jingfeng

    2016-02-01

    Nutrition excess-induced inflammation positively contributed to insulin resistance. Fucoidan from sea cucumber can increase glucose translocation in skeletal muscle. However, its effects on inflammation-associated insulin resistance are not understood. We investigated fucoidan from Isostichopus badionotus (Ib-FUC)-alleviated inflammatory response and signaling as well as -improved insulin resistance in the liver of obesity mice. The results showed that Ib-FUC reduced body weight and glucose levels, increased insulin sensitivity, and inhibited serum lipid concentrations. Meanwhile, Hepatic glycogen synthesis was promoted by Ib-FUC via activation of the PI3K/PKB/GSK-3β signaling and regulation of glucose metabolism-related enzymatic activities. Ib-FUC regulated serum inflammatory cytokines and their mRNA expression in the liver. Ib-FUC-induced inactivation of the JNK and IKKβ/NFκB pathways was involved in the activation of insulin signal cascade and inflammatory factor production. These findings suggested that Ib-FUC supplementary-induced alleviation of inflammatory response could be a mechanism responsible for its beneficial effects against hepatic insulin resistance. PMID:26690975

  11. Serum Autotaxin/ENPP2 Correlates with Insulin Resistance in Older Humans with Obesity

    PubMed Central

    Reeves, Valerie L.; Trybula, Joy S.; Wills, Rachel C.; Goodpaster, Bret H.; Dubé, John J.; Kienesberger, Petra C.; Kershaw, Erin E.

    2015-01-01

    Objective Autotaxin (ATX) is an adipocyte-derived lysophospholipase D that generates the lipid signaling molecule lysophosphatidic acid (LPA). The ATX/LPA pathway in adipose tissue has recently been implicated in obesity and insulin resistance in animal models, but the role of circulating ATX in humans remains unclear. The aim of the present study was to determine the relationship between serum ATX and insulin resistance. Methods In this retrospective study, older (60–75 years), non-diabetic human participants with overweight or obesity (BMI 25–37 kg/m2), were characterized for metabolic phenotype including measures of energy, glucose, and lipid homeostasis. The relationship between serum ATX and metabolic parameters was then determined using correlative and predictive statistics. Results Serum ATX was higher in females than in males. After controlling for sex, serum ATX correlated with multiple measures of adiposity and glucose homeostasis/insulin action. Serum ATX and BMI also independently predicted glucose infusion rate during a hyperinsulinemic euglycemic clamp and homeostatic model assessment of insulin resistance after controlling for sex and medication use. Conclusion Serum ATX correlates with and predicts measures of glucose homeostasis and insulin sensitivity in older humans, suggesting that it may be a potential pathogenic factor and/or diagnostic/therapeutic target for insulin resistance in this population. PMID:26727116

  12. Insulin resistance and clinical aspects of non-alcoholic steatohepatitis (NASH).

    PubMed

    Agarwal, Naresh; Sharma, Barjesh Chander

    2005-10-01

    Non-alcoholic steatohepatitis (NASH) is one of the most common liver disorders. This is highly prevalent in obese and diabetic subjects. Persons with central obesity are at particular risk. Other clinical predictors are age more than 40-50 years and hyperlipidemias, but none of these factors is invariable for causation of NASH. Other reported associations are, celiac disease, Wilson's Disease and few other metabolic diseases. Drugs, particularly amiodarone, tamoxifen, nucleoside analogues and methotrxate have also been linked to NASH. The disease is evenly distributed in both sexes but advanced disease is more common in women. Ethnic variation exists and African Americans are less affected than Hispanic Americans. Specific clinical features of NASH are infrequent. Patients usually come to clinical attention by elevated liver enzymes found on routine evaluation but on history, about two third of patients will admit to have mild fatigue and about half will report right upper quadrant pain. Rarely, patient may present with a complication of cirrhosis. Physical examination may reveal hepatomegaly and splenomegaly. Research in last few years has stressed that development of steatosis, stetohepatitis, fibrosis with subsequent cirrhosis are most probably the result of insulin resistance. Therefore, clinical features may reflect existence of insulin resistance. Obesity, particularly central obesity is most important of these. Patients may have sleep apnea syndrome. Hypertension and manifestations of diabetes mellitus like polyuria, polydypsia, and neurological deficits may occur. Patients may have varying combination of obesity, diabetes, hyperlipidemia, hypertension and impaired fibrinolysis (syndrome X). Children with insulin resistance may show acanthosis nigricance. Patients with polycystic ovary syndrome, which consists of insulin resistance, diabetes, obesity, hirsutism, oligo or polymenorrha and hyperlipidemia may have NASH. Other rare manifestations of insulin

  13. The Effects of Insulin Resistance on Individual Tissues: An Application of a Mathematical Model of Metabolism in Humans.

    PubMed

    Pearson, Taliesin; Wattis, Jonathan A D; King, John R; MacDonald, Ian A; Mazzatti, Dawn J

    2016-06-01

    Whilst the human body expends energy constantly, the human diet consists of a mix of carbohydrates and fats delivered in a discontinuous manner. To deal with this sporadic supply of energy, there are transport, storage and utilisation mechanisms, for both carbohydrates and fats, around all tissues of the body. Insulin-resistant states such as type 2 diabetes and obesity are characterised by reduced efficiency of these mechanisms. Exactly how these insulin-resistant states develop, for example whether there is an order in which tissues become insulin resistant, is an active area of research with the hope of gaining a better overall understanding of insulin resistance. In this paper, we use a previously derived system of 12 first-order coupled differential equations that describe the transport between, and storage in, different tissues of the human body. We briefly revisit the derivation of the model before parametrising the model to account for insulin resistance. We then solve the model numerically, separately simulating each individual tissue as insulin resistant, and discuss and compare these results, drawing three main conclusions. The implications of these results are in accordance with biological intuition. First, insulin resistance in a tissue creates a knock-on effect on the other tissues in the body, whereby they attempt to compensate for the reduced efficiency of the insulin-resistant tissue. Second, insulin resistance causes a fatty liver, and the insulin resistance of tissues other than the liver can cause fat to accumulate in the liver. Finally, although insulin resistance in individual tissues can cause slightly reduced skeletal muscle metabolic flexibility, it is when the whole body is insulin resistant that the biggest effect on skeletal muscle flexibility is seen. PMID:27306890

  14. Impact of Adiposity on Incident Hypertension Is Modified by Insulin Resistance in Adults: Longitudinal Observation From the Bogalusa Heart Study.

    PubMed

    Zhang, Tao; Zhang, Huijie; Li, Shengxu; Li, Ying; Liu, Yaozhong; Fernandez, Camilo; Harville, Emily; Bazzano, Lydia; He, Jiang; Chen, Wei

    2016-01-01

    Adiposity and insulin resistance are closely associated with hypertension. This study aims to investigate whether the association between adiposity and hypertension is modified by insulin resistance. The cohort consisted of 1624 middle-aged normotensive black and white adults aged 18 to 43 years at baseline who followed for 16 years on average. Overweight/obesity at baseline was defined as body mass index (BMI) ≥25, and insulin resistance was measured using homeostasis model assessment of insulin resistance. Prevalence of incident hypertension was compared between the insulin-sensitive adiposity and insulin-resistant adiposity groups. The prevalence of incident hypertension was higher in the insulin-resistant adiposity than in the insulin-sensitive adiposity group (32.1% versus 22.1%, P<0.001). In multivariable logistic analyses, adjusted for baseline age, race, sex, follow-up years, and smoking, baseline insulin-resistant obesity was associated with incident hypertension (odds ratio, 1.9; P=0.008). Odds ratios did not differ between blacks and whites (P=0.238). Of note, the odds ratios of BMI associated with hypertension significantly increased with increasing quartiles of baseline homeostasis model assessment (odds ratio, 1.3, 1.1, 1.5, and 2.5 in quartiles I, II, III, and IV, respectively; P=0.006 for trend). Slopes of increasing follow-up blood pressure with baseline BMI, measured as regression coefficients (β), were significantly greater in insulin-resistant than in insulin-sensitive individuals (β=0.74 versus β=0.35 for systolic blood pressure, P=0.004 for difference; β=0.51 versus β=0.23 for diastolic blood pressure, P=0.001 for difference). These findings suggest that insulin resistance has a synergistic effect on the obesity-hypertension association in young adults, indicating that the role of adiposity in the development of hypertension is modified by insulin resistance. PMID:26573703

  15. Resistance exercise increase lean body mass and improves basal and hepatic insulin sensitivity in obese adolescents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Little is known about the metabolic effects of resistance exercise, for instance, weight lifting. We studied whether a resistance exercise program improves insulin sensitivity and glucose metabolism in sedentary obese adolescents. Elevn obese subjects (15.7 +/- 0.4 year; 35.4 +/- 0.8 kg/m2; 41.3 +/-...

  16. Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance

    PubMed Central

    Nishimoto, Sachiko; Fukuda, Daiju; Higashikuni, Yasutomi; Tanaka, Kimie; Hirata, Yoichiro; Murata, Chie; Kim-Kaneyama, Joo-ri; Sato, Fukiko; Bando, Masahiro; Yagi, Shusuke; Soeki, Takeshi; Hayashi, Tetsuya; Imoto, Issei; Sakaue, Hiroshi; Shimabukuro, Michio; Sata, Masataka

    2016-01-01

    Obesity stimulates chronic inflammation in adipose tissue, which is associated with insulin resistance, although the underlying mechanism remains largely unknown. Here we showed that obesity-related adipocyte degeneration causes release of cell-free DNA (cfDNA), which promotes macrophage accumulation in adipose tissue via Toll-like receptor 9 (TLR9), originally known as a sensor of exogenous DNA fragments. Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9−/−) macrophages. Fat-fed Tlr9−/− mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9−/− mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plasma ssDNA level was significantly higher in patients with computed tomography–determined visceral obesity and was associated with homeostasis model assessment of insulin resistance (HOMA-IR), which is the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance. PMID:27051864

  17. Effects of Combination of Thiazolidinediones with Melatonin in Dexamethasone-induced Insulin Resistance in Mice

    PubMed Central

    Ghaisas, M. M.; Ahire, Y. S.; Dandawate, P. R.; Gandhi, S. P.; Mule, M.

    2011-01-01

    In type 2 Diabetes, oxidative stress plays an important role in development and aggregation of insulin resistance. In the present study, long term administration of the dexamethasone led to the development of insulin resistance in mice. The effect of thiazolidinediones pioglitazone and rosiglitazone, with melatonin on dexamethasone-induced insulin resistance was evaluated in mice. Insulin resistant mice were treated with combination of pioglitazone (10 mg/kg/day, p.o.) or rosiglitazone (5 mg/kg/day, p.o.) with melatonin 10 mg/kg/day p.o. from day 7 to day 22. In the biochemical parameters, the serum glucose, triglyceride levels were significantly lowered (P<0.05) in the combination groups as compared to dexamethasone treated group as well as with individual groups of pioglitazone, rosiglitazone, and melatonin. There was also, significant increased (P<0.05) in the body weight gain in combination treated groups as compared to dexamethasone as well as individual groups. The combination groups proved to be effective in normalizing the levels of superoxide dismutase, catalase, glutathione reductase and lipid peroxidation in liver homogenates may be due to antioxidant effects of melatonin and decreased hyperglycemia induced insulin resistance by thiazolidinediones. The glucose uptake in the isolated hemidiaphragm of mice was significantly increased in combination treated groups (PM and RM) than dexamethasone alone treated mice as well as individual (pioglitazone, rosiglitazone, melatonin) treated groups probably via increased in expression of GLUT-4 by melatonin and thiazolidinediones as well as increased in insulin sensitivity by thiazolidinediones. Hence, it can be concluded that combination of pioglitazone and rosiglitazone, thiazolidinediones, with melatonin may reduces the insulin resistance via decreased in oxidative stress and control on hyperglycemia. PMID:23112392

  18. PP2A inhibition results in hepatic insulin resistance despite Akt2 activation.

    PubMed

    Galbo, Thomas; Perry, Rachel J; Nishimura, Erica; Samuel, Varman T; Quistorff, Bjørn; Shulman, Gerald I

    2013-10-01

    In the liver, insulin suppresses hepatic gluconeogenesis by activating Akt, which inactivates the key gluconeogenic transcription factor FoxO1 (Forkhead Box O1). Recent studies have implicated hyperactivity of the Akt phosphatase Protein Phosphatase 2A (PP2A) and impaired Akt signaling as a molecular defect underlying insulin resistance. We therefore hypothesized that PP2A inhibition would enhance insulin-stimulated Akt activity and decrease glucose production. PP2A inhibitors increased hepatic Akt phosphorylation and inhibited FoxO1in vitro and in vivo, and suppressed gluconeogenesis in hepatocytes. Paradoxically, PP2A inhibition exacerbated insulin resistance in vivo. This was explained by phosphorylation of both hepatic glycogen synthase (GS) (inactivation) and phosphorylase (activation) resulting in impairment of glycogen storage. Our findings underline the significance of GS and Phosphorylase as hepatic PP2A substrates and importance of glycogen metabolism in acute plasma glucose regulation. PMID:24150286

  19. Liver-derived systemic factors drive β-cell hyperplasia in insulin resistant states

    SciTech Connect

    El Ouaamari, Abdelfattah; Kawamori, Dan; Dirice, Ercument; Liew, Chong Wee; Shadrach, Jennifer L.; Hu, Jiang; Katsuta, Hitoshi; Hollister-Lock, Jennifer; Qian, Weijun; Wagers, Amy J.; Kulkarni, Rohit N.

    2013-02-21

    Integrative organ cross-talk regulates key aspects of energy homeostasis and its dysregulation may underlie metabolic disorders such as obesity and diabetes. To test the hypothesis that cross-talk between the liver and pancreatic islets modulates β-cell growth in response to insulin resistance, we used the Liver-specific Insulin Receptor Knockout (LIRKO) mouse, a unique model that exhibits dramatic islet hyperplasia. Using complementary in vivo parabiosis and transplantation assays, and in vitro islet culture approaches, we demonstrate that humoral, non-neural, non-cell autonomous factor(s) induce β-cell proliferation in LIRKO mice. Furthermore, we report that a hepatocyte-derived factor(s) stimulates mouse and human β-cell proliferation in ex vivo assays, independent of ambient glucose and insulin levels. These data implicate the liver as a critical source of β-cell growth factors in insulin resistant states.

  20. β-Adrenergic Responsive Induction of Insulin Resistance in Liver of Aging Rats.

    PubMed

    Muscogiuri, Giovanna; Kamat, Amrita; Balas, Bogdan; Giaccari, Andrea; Defronzo, Ralph A; Musi, Nicolas; Katz, Michael S

    2011-01-01

    INTRODUCTION. We previously demonstrated increases in β-adrenergic receptor (β-AR) density in rat liver, in association with increased β-AR-mediated stimulation of glucose output in rat hepatocytes, during senescent aging. We therefore hypothesized that pharmacologic β-adrenergic stimulation might induce insulin resistance and glucose output in liver of aging rats in vivo. METHODS. In this study, pancreatic clamps were performed on young adult (4-month-old) and senescent (24-month-old) Fischer 344 male rats by infusing somatostatin (3 μg/kg/min) at time 0 to inhibit insulin secretion, and then infusing insulin (1 mU/kg/min) to replace basal insulin concentrations. At time 0 rats also received either the β-AR agonist isoproterenol (100 ng/kg/min) or saline (control). After 120 min the insulin infusion rate was increased to 4 mU/kg/min for an additional 120 min. Tritiated glucose was infused throughout the study to measure glucose turnover rates. RESULTS AND CONCLUSION. The results of the pancreatic clamp studies demonstrated that under saline control conditions hepatic glucose production (HGP) was suppressed during hyperinsulinemia in both young and old rats, with a trend toward reduced insulin sensitivity in the older animals. Isoproterenol infusion impaired insulin-induced suppression of HGP in both age groups. The results suggest that β-AR stimulation by isoproterenol increases HGP and acutely induces hepatic insulin resistance in both young and old rats. A similar role for β-adrenergic-mediated hepatic insulin resistance in aging humans would suggest a novel therapeutic target for the treatment or prevention of glucose dysregulation and diabetes developing with advancing age. PMID:21438725

  1. SIRT1 attenuates high glucose-induced insulin resistance via reducing mitochondrial dysfunction in skeletal muscle cells.

    PubMed

    Zhang, Hao-Hao; Ma, Xiao-Jun; Wu, Li-Na; Zhao, Yan-Yan; Zhang, Peng-Yu; Zhang, Ying-Hui; Shao, Ming-Wei; Liu, Fei; Li, Fei; Qin, Gui-Jun

    2015-05-01

    Insulin resistance is often characterized as the most critical factor contributing to the development of type 2 diabetes mellitus (T2DM). Sustained high glucose is an important extracellular environment that induces insulin resistance. Acquired insulin resistance is associated with reduced insulin-stimulated mitochondrial activity as a result of increased mitochondrial dysfunction. Silent information regulator 1 (SIRT1) is one member of the SIRT2 (Sir2)-like family of proteins involved in glucose homeostasis and insulin secretion in mammals. Although SIRT1 has a therapeutic effect on metabolic deterioration in insulin resistance, it is still not clear how SIRT1 is involved in the development of insulin resistance. Here, we demonstrate that pcDNA3.1 vector-mediated overexpression of SIRT1 attenuates insulin resistance in the high glucose-induced insulin-resistant skeleton muscle cells. These beneficial effects were associated with ameliorated mitochondrial dysfunction. Further studies have demonstrated that SIRT1 restores mitochondrial complex I activity leading to decreased oxidative stress and mitochondrial dysfunction. Furthermore, SIRT1 significantly elevated the level of another SIRT which is named SIRT3, and SIRT3 siRNA-suppressed SIRT1-induced mitochondria complex activity increments. Taken together, these results showed that SIRT1 improves insulin sensitivity via the amelioration of mitochondrial dysfunction, and this is achieved through the SIRT1-SIRT3-mitochondrial complex I pathway. PMID:25710929

  2. Hypertension and abnormal fat distribution but not insulin resistance in mice with P465L PPARγ

    PubMed Central

    Tsai, Yau-Sheng; Kim, Hyo-Jeong; Takahashi, Nobuyuki; Kim, Hyung-Suk; Hagaman, John R.; Kim, Jason K.; Maeda, Nobuyo

    2004-01-01

    Peroxisome proliferator–activated receptor γ (PPARγ), the molecular target of a class of insulin sensitizers, regulates adipocyte differentiation and lipid metabolism. A dominant negative P467L mutation in the ligand-binding domain of PPARγ in humans is associated with severe insulin resistance and hypertension. Homozygous mice with the equivalent P465L mutation die in utero. Heterozygous mice grow normally and have normal total adipose tissue weight. However, they have reduced interscapular brown adipose tissue and intra-abdominal fat mass, and increased extra-abdominal subcutaneous fat, compared with wild-type mice. They have normal plasma glucose levels and insulin sensitivity, and increased glucose tolerance. However, during high-fat feeding, their plasma insulin levels are mildly elevated in association with a significant increase in pancreatic islet mass. They are hypertensive, and expression of the angiotensinogen gene is increased in their subcutaneous adipose tissues. The effects of P465L on blood pressure, fat distribution, and insulin sensitivity are the same in both male and female mice regardless of diet and age. Thus the P465L mutation alone is sufficient to cause abnormal fat distribution and hypertension but not insulin resistance in mice. These results provide genetic evidence for a critical role for PPARγ in blood pressure regulation that is not dependent on altered insulin sensitivity. PMID:15254591

  3. Crif1 Deficiency Reduces Adipose OXPHOS Capacity and Triggers Inflammation and Insulin Resistance in Mice

    PubMed Central

    Ryu, Min Jeong; Kim, Soung Jung; Kim, Yong Kyung; Choi, Min Jeong; Tadi, Surendar; Lee, Min Hee; Lee, Seong Eun; Chung, Hyo Kyun; Jung, Saet Byel; Kim, Hyun-Jin; Jo, Young Suk; Kim, Koon Soon; Lee, Sang-Hee; Kim, Jin Man; Kweon, Gi Ryang; Park, Ki Cheol; Lee, Jung Uee; Kong, Young Yun; Lee, Chul-Ho; Chung, Jongkyeong; Shong, Minho

    2013-01-01

    Impaired mitochondrial oxidative phosphorylation (OXPHOS) has been proposed as an etiological mechanism underlying insulin resistance. However, the initiating organ of OXPHOS dysfunction during the development of systemic insulin resistance has yet to be identified. To determine whether adipose OXPHOS deficiency plays an etiological role in systemic insulin resistance, the metabolic phenotype of mice with OXPHOS–deficient adipose tissue was examined. Crif1 is a protein required for the intramitochondrial production of mtDNA–encoded OXPHOS subunits; therefore, Crif1 haploinsufficient deficiency in mice results in a mild, but specific, failure of OXPHOS capacity in vivo. Although adipose-specific Crif1-haploinsufficient mice showed normal growth and development, they became insulin-resistant. Crif1-silenced adipocytes showed higher expression of chemokines, the expression of which is dependent upon stress kinases and antioxidant. Accordingly, examination of adipose tissue from Crif1-haploinsufficient mice revealed increased secretion of MCP1 and TNFα, as well as marked infiltration by macrophages. These findings indicate that the OXPHOS status of adipose tissue determines its metabolic and inflammatory responses, and may cause systemic inflammation and insulin resistance. PMID:23516375

  4. [Gestational and non-gestational factors for perinatal programming of insulin resistance].

    PubMed

    Varadinova, M; Metodieva, R; Boyadjieva, N

    2014-01-01

    Insulin resistance is well known problem in type 2 diabetes mellitus (T2DM). Various factors play roles in the mechanisms of prenatal programming of insulin resistance. Gestational or non-gestational factors are illustrated in the present paper. Adipocytes (fat cells) produce at least 50 proteins (adipokines; peptides, cytokines, etc.), and a large part of them are involved in prenatal development of insulin resistance. The role of pro-inflammatory cytokines as the tumor necrosis factor 1 (TNF alpha), interleukin-6 (IL-6) and interleukin-1 beta (IL-1 beta) is documented. Leptin from adipocytes as well as from the placenta is involved in pathology of metabolism and plays a role as a gestational factor for the prenatal insulin resistance and the risk for T2DM. Epigenetic mechanisms as the methylation of DNA and histones, the acetylation of histones are documented for prenatal development of insulin resistance. Epigenetic modulations may explain the risk of T2DM for generations. New data indicated that the placenta does not produce adiponectin and it is also one of the important factors for the development of gestational diabetes and risk for the fetus. Taken together all factors documented in the present paper may predict the risk for prenatal T2DM. PMID:25558670

  5. Hypoglycemic effect of aqueous shallot and garlic extracts in rats with fructose-induced insulin resistance.

    PubMed

    Jalal, Razieh; Bagheri, Sayyed Majid; Moghimi, Ali; Rasuli, Morteza Behnam

    2007-11-01

    The present study has been carried out to investigate the effect of aqueous extract of shallot (Allium ascalonicum) and garlic (Allium satium) on the fasting insulin resistance index (FIRI) and intraperitoneal glucose tolerance test (IPGTT) of fructose-induced insulin resistance rats. Male albino Wistar rats were fed either normal or high-fructose diet for a period of eight weeks. Fasting blood glucose level, fasting blood triglyceride level, FIRI, and the area under the glucose tolerance curve were significantly elevated in fructose-fed animals. Fructose-induced insulin resistance rats treated by aqueous shallot or garlic extract (500 mg/kg body weight/day, i.p.) for duration of eight weeks. Control animals only received normal saline (0.9%). The results showed that neither shallot nor garlic extracts significantly altered the FIRI and the IPGTT at the fourth week after treatment. The fasting blood glucose in fructose-induced insulin resistance animals has been significantly decreased in 8-week treated animals by both shallot and garlic extracts. Shallot extract administration, but not garlic extract, for a period of eight weeks can significantly improve the intraperitoneal glucose tolerance and diminish the FIRI. These results indicate that shallot and garlic extracts have a hypoglycemic influence on the fructose-induced insulin resistance animals and aqueous shallot extract is a stronger hypoglycemic agent than the garlic extract. PMID:18299719

  6. Metabolic signatures of insulin resistance in 7,098 young adults.

    PubMed

    Würtz, Peter; Mäkinen, Ville-Petteri; Soininen, Pasi; Kangas, Antti J; Tukiainen, Taru; Kettunen, Johannes; Savolainen, Markku J; Tammelin, Tuija; Viikari, Jorma S; Rönnemaa, Tapani; Kähönen, Mika; Lehtimäki, Terho; Ripatti, Samuli; Raitakari, Olli T; Järvelin, Marjo-Riitta; Ala-Korpela, Mika

    2012-06-01

    Metabolite associations with insulin resistance were studied in 7,098 young Finns (age 31 ± 3 years; 52% women) to elucidate underlying metabolic pathways. Insulin resistance was assessed by the homeostasis model (HOMA-IR) and circulating metabolites quantified by high-throughput nuclear magnetic resonance spectroscopy in two population-based cohorts. Associations were analyzed using regression models adjusted for age, waist, and standard lipids. Branched-chain and aromatic amino acids, gluconeogenesis intermediates, ketone bodies, and fatty acid composition and saturation were associated with HOMA-IR (P < 0.0005 for 20 metabolite measures). Leu, Ile, Val, and Tyr displayed sex- and obesity-dependent interactions, with associations being significant for women only if they were abdominally obese. Origins of fasting metabolite levels were studied with dietary and physical activity data. Here, protein energy intake was associated with Val, Phe, Tyr, and Gln but not insulin resistance index. We further tested if 12 genetic variants regulating the metabolites also contributed to insulin resistance. The genetic determinants of metabolite levels were not associated with HOMA-IR, with the exception of a variant in GCKR associated with 12 metabolites, including amino acids (P < 0.0005). Nonetheless, metabolic signatures extending beyond obesity and lipid abnormalities reflected the degree of insulin resistance evidenced in young, normoglycemic adults with sex-specific fingerprints. PMID:22511205

  7. Identification of cutoff points for Homeostatic Model Assessment for Insulin Resistance index in adolescents: systematic review

    PubMed Central

    de Andrade, Maria Izabel Siqueira; Oliveira, Juliana Souza; Leal, Vanessa Sá; da Lima, Niedja Maria Silva; Costa, Emília Chagas; de Aquino, Nathalia Barbosa; de Lira, Pedro Israel Cabral

    2016-01-01

    Abstract Objective: To identify cutoff points of the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index established for adolescents and discuss their applicability for the diagnosis of insulin resistance in Brazilian adolescents. Data source: A systematic review was performed in the PubMed, Lilacs and SciELO databases, using the following descriptors: "adolescents", "insulin resistance" and "Receiver Operating Characteristics Curve". Original articles carried out with adolescents published between 2005 and 2015 in Portuguese, English or Spanish languages, which included the statistical analysis using Receiver Operating Characteristics Curve to determine the index cutoff (HOMA-IR) were included. Data synthesis: A total of 184 articles were identified and after the study phases were applied, seven articles were selected for the review. All selected studies established their cutoffs using a Receiver Operating Characteristics Curve, with the lowest observed cutoff of 1.65 for girls and 1.95 for boys and the highest of 3.82 for girls and 5.22 for boys. Of the studies analyzed, one proposed external validity, recommending the use of the HOMA-IR cutoff>2.5 for both genders. Conclusions: The HOMA-IR index constitutes a reliable method for the detection of insulin resistance in adolescents, as long as it uses cutoffs that are more adequate for the reality of the study population, allowing early diagnosis of insulin resistance and enabling multidisciplinary interventions aiming at health promotion of this population. PMID:26559605

  8. Adipokines and Insulin Resistance in Young Adult Survivors of Childhood Cancer

    PubMed Central

    Latoch, Eryk; Muszynska-Roslan, Katarzyna; Panas, Agata; Panasiuk, Anna; Sawicka-Zukowska, Malgorzata; Zelazowska-Rutkowska, Beata; Zabrocka, Ewa; Krawczuk-Rybak, Maryna

    2016-01-01

    We examined the association between adipokines (leptin, adiponectin, and resistin), radiotherapy, measurement of body fat, and insulin resistance among young adult survivors of childhood cancer (CCS). Materials and Methods. Seventy-six survivors were included (mean age 24.1 ± 3.5 years). Insulin resistance (IR) was calculated using the homeostasis model assessment (HOMA-IR). The serum levels of adipokines were assayed by immunoassays. Fat mass was evaluated by DXA. Results. Mean adiponectin level and mean body FAT were higher in the examined females than in males (10009 ± 6367 ng/mL versus 6433 ± 4136 ng/mL, p < 0.01; 35.98 ± 9.61% versus 22.7 ± 7.46%, p < 0.001). Among CCS, one of 75 patients met the criteria of insulin resistance, and in 14 patients there was impaired fasting glucose. The multiple regression model for females showed that leptin/adiponectin ratio (LA ratio) significantly affected HOMA-IR (increase of 0.024 per each unit of LA ratio; p < 0.05). Radiotherapy had no effect on serum adipokines and IR. Conclusion. The observed results support the hypothesis that adiponectin might be associated with insulin resistance and it can not be ruled out that changes in the mean level of adiponectin per FAT mass or leptin/adiponectin ratio may precede the occurrence of insulin resistance in the future. PMID:27212946

  9. Novel Grb14-Mediated Cross Talk between Insulin and p62/Nrf2 Pathways Regulates Liver Lipogenesis and Selective Insulin Resistance.

    PubMed

    Popineau, Lucie; Morzyglod, Lucille; Carré, Nadège; Caüzac, Michèle; Bossard, Pascale; Prip-Buus, Carina; Lenoir, Véronique; Ragazzon, Bruno; Fauveau, Véronique; Robert, Lorenne; Guilmeau, Sandra; Postic, Catherine; Komatsu, Masaaki; Canonne-Hergaux, François; Guillou, Hervé; Burnol, Anne-Françoise

    2016-08-15

    A long-standing paradox in the pathophysiology of metabolic diseases is the selective insulin resistance of the liver. It is characterized by a blunted action of insulin to reduce glucose production, contributing to hyperglycemia, while de novo lipogenesis remains insulin sensitive, participating in turn to hepatic steatosis onset. The underlying molecular bases of this conundrum are not yet fully understood. Here, we established a model of selective insulin resistance in mice by silencing an inhibitor of insulin receptor catalytic activity, the growth factor receptor binding protein 14 (Grb14) in liver. Indeed, Grb14 knockdown enhanced hepatic insulin signaling but also dramatically inhibited de novo fatty acid synthesis. In the liver of obese and insulin-resistant mice, downregulation of Grb14 markedly decreased blood glucose and improved liver steatosis. Mechanistic analyses showed that upon Grb14 knockdown, the release of p62/sqstm1, a partner of Grb14, activated the transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), which in turn repressed the lipogenic nuclear liver X receptor (LXR). Our study reveals that Grb14 acts as a new signaling node that regulates lipogenesis and modulates insulin sensitivity in the liver by acting at a crossroad between the insulin receptor and the p62-Nrf2-LXR signaling pathways. PMID:27215388

  10. Inhibition of Src homology 2 domain-containing phosphatase 1 increases insulin sensitivity in high-fat diet-induced insulin-resistant mice.

    PubMed

    Krüger, Janine; Wellnhofer, Ernst; Meyborg, Heike; Stawowy, Philipp; Östman, Arne; Kintscher, Ulrich; Kappert, Kai

    2016-03-01

    Insulin resistance plays a crucial role in the development of type 2 diabetes. Insulin receptor signalling is antagonized and tightly controlled by protein tyrosine phosphatases (PTPs). However, the precise role of the PTP src homology 2 domain-containing phosphatase 1 (SHP-1) in insulin resistance has not been explored. Male C57BL/6J mice were fed a high-fat diet (HFD, 60% kcal from fat), to induce insulin resistance, or a low-fat diet (LFD, 10% kcal from fat) for 10 weeks. Afterwards, HFD-fed mice were pharmacologically treated with the SHP-1 (Ptpn6) inhibitor sodium stibogluconate and the broad spectrum pan-PTP inhibitor bis(maltolato)oxovanadium(IV) (BMOV). Both inhibitors ameliorated the metabolic phenotype, as evidenced by reduced body weight, improved insulin sensitivity and glucose tolerance, which was not due to altered PTP gene expression. In parallel, phosphorylation of the insulin receptor and of the insulin signalling key intermediate Akt was enhanced, and both PTP inhibitors and siRNA-mediated SHP-1 downregulation resulted in an increased glucose uptake in vitro. Finally, recombinant SHP-1 was capable of dephosphorylating the ligand-induced tyrosine-phosphorylated insulin receptor. These results indicate a central role of SHP-1 in insulin signalling during obesity, and SHP-1 inhibition as a potential therapeutic approach in metabolic diseases. PMID:27047746

  11. Long-term fatty liver-induced insulin resistance in orotic acid-induced nonalcoholic fatty liver rats.

    PubMed

    Han, Xiuqing; Liu, Chunhua; Xue, Yong; Wang, Jingfeng; Xue, Changhu; Yanagita, Teruyoshi; Gao, Xiang; Wang, Yuming

    2016-04-01

    We investigated whether fatty liver preceded insulin resistance or vice versa using a long-term orotic acid (OA)-induced nonalcoholic fatty liver disease (NAFLD) model without the confounding effects of obesity and hyperlipidemia and explored the role of the liver in insulin resistance. Male Wistar rats were fed with or without OA supplementation for 30, 60, and 90 days. The NAFLD group showed increased liver lipid at 30, 60, and 90 days; glucose intolerance was noted at 60 and 90 days. Furthermore, partial liver proteins and gene expressions related to upstream signaling of insulin were decreased. However, the liver glycogen content was elevated, and gluconeogenesis genes expressions were obviously decreased at 90 days. The occurrence of fatty liver preceded insulin resistance in OA-induced NAFLD without the interference of obesity and hyperlipidemia, and hepatic insulin resistance may not play a conclusive role in insulin resistance in this model. PMID:26775542

  12. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux.

    PubMed

    Samuel, Varman T; Shulman, Gerald I

    2016-01-01

    Insulin resistance arises when the nutrient storage pathways evolved to maximize efficient energy utilization are exposed to chronic energy surplus. Ectopic lipid accumulation in liver and skeletal muscle triggers pathways that impair insulin signaling, leading to reduced muscle glucose uptake and decreased hepatic glycogen synthesis. Muscle insulin resistance, due to ectopic lipid, precedes liver insulin resistance and diverts ingested glucose to the liver, resulting in increased hepatic de novo lipogenesis and hyperlipidemia. Subsequent macrophage infiltration into white adipose tissue (WAT) leads to increased lipolysis, which further increases hepatic triglyceride synthesis and hyperlipidemia due to increased fatty acid esterification. Macrophage-induced WAT lipolysis also stimulates hepatic gluconeogenesis, promoting fasting and postprandial hyperglycemia through increased fatty acid delivery to the liver, which results in increased hepatic acetyl-CoA content, a potent activator of pyruvate carboxylase, and increased glycerol conversion to glucose. These substrate-regulated processes are mostly independent of insulin signaling in the liver but are dependent on insulin signaling in WAT, which becomes defective with inflammation. Therapies that decrease ectopic lipid storage and diminish macrophage-induced WAT lipolysis will reverse the root causes of type 2 diabetes. PMID:26727229

  13. Celastrol Protects against Antimycin A-Induced Insulin Resistance in Human Skeletal Muscle Cells.

    PubMed

    Abu Bakar, Mohamad Hafizi; Cheng, Kian-Kai; Sarmidi, Mohamad Roji; Yaakob, Harisun; Huri, Hasniza Zaman

    2015-01-01

    Mitochondrial dysfunction and inflammation are widely accepted as key hallmarks of obesity-induced skeletal muscle insulin resistance. The aim of the present study was to evaluate the functional roles of an anti-inflammatory compound, celastrol, in mitochondrial dysfunction and insulin resistance induced by antimycin A (AMA) in human skeletal muscle cells. We found that celastrol treatment improved insulin-stimulated glucose uptake activity of AMA-treated cells, apparently via PI3K/Akt pathways, with significant enhancement of mitochondrial activities. Furthermore, celastrol prevented increased levels of cellular oxidative damage where the production of several pro-inflammatory cytokines in cultures cells was greatly reduced. Celastrol significantly increased protein phosphorylation of insulin signaling cascades with amplified expression of AMPK protein and attenuated NF-κB and PKC θ activation in human skeletal muscle treated with AMA. The improvement of insulin signaling pathways by celastrol was also accompanied by augmented GLUT4 protein expression. Taken together, these results suggest that celastrol may be advocated for use as a potential therapeutic molecule to protect against mitochondrial dysfunction-induced insulin resistance in human skeletal muscle cells. PMID:25961164

  14. Visceral Fat Accumulation, Insulin Resistance, and Elevated Depressive Symptoms in Middle-Aged Japanese Men

    PubMed Central

    Yamamoto, Shuichiro; Matsushita, Yumi; Nakagawa, Toru; Honda, Toru; Hayashi, Takeshi; Noda, Mitsuhiko; Mizoue, Tetsuya

    2016-01-01

    Objective To investigate visceral fat accumulation and markers of insulin resistance in relation to elevated depressive symptoms (EDS). Methods Participants were 4,333 male employees (mean age, 49.3 years) who underwent abdominal computed tomography scanning, measured fasting insulin, and did not self-report diabetes and mental disorders under treatment and history of cancer, myocardial infarction, and stroke. Multivariable logistic regression was used to assess the association of EDS with abdominal fat deposition and markers of insulin resistance. Results Visceral fat area (VFA) and fasting insulin were significantly, positively associated with EDS. Multivariable-adjusted odds ratios (95% confidence interval) of high VFA for the lowest through highest quartile of depression score were 1 (reference), 1.18 (0.97–1.42), 1.25 (1.02–1.54), 1.23 (1.01–1.51), respectively, and corresponding figures for high fasting insulin were 1 (reference), 0.98 (0.80–1.19), 1.12 (0.91–1.38), and 1.29 (1.06–1.57), respectively. Subcutaneous fat area was not associated with EDS. Conclusions Results suggest that EDS is related to visceral, but not subcutaneous, fat accumulation and insulin resistance in middle-aged Japanese men. PMID:26891344

  15. Ozone exposure triggers insulin resistance through muscle c-Jun N-terminal kinase activation.

    PubMed

    Vella, Roxane E; Pillon, Nicolas J; Zarrouki, Bader; Croze, Marine L; Koppe, Laetitia; Guichardant, Michel; Pesenti, Sandra; Chauvin, Marie-Agnès; Rieusset, Jennifer; Géloën, Alain; Soulage, Christophe O

    2015-03-01

    A growing body of evidence suggests that exposure to traffic-related air pollution is a risk factor for type 2 diabetes. Ozone, a major photochemical pollutant in urban areas, is negatively associated with fasting glucose and insulin levels, but most aspects of this association remain to be elucidated. Using an environmentally realistic concentration (0.8 parts per million), we demonstrated that exposure of rats to ozone induced whole-body insulin resistance and oxidative stress, with associated endoplasmic reticulum (ER) stress, c-Jun N-terminal kinase (JNK) activation, and disruption of insulin signaling in skeletal muscle. Bronchoalveolar lavage fluids from ozone-treated rats reproduced this effect in C2C12 myotubes, suggesting that toxic lung mediators were responsible for the phenotype. Pretreatment with the chemical chaperone 4-phenylbutyric acid, the JNK inhibitor SP600125, or the antioxidant N-acetylcysteine alleviated insulin resistance, demonstrating that ozone sequentially triggered oxidative stress, ER stress, and JNK activation to impair insulin signaling in muscle. This study is the first to report that ozone plays a causative role in the development of insulin resistance, suggesting that it could boost the development of diabetes. We therefore provide a potential mechanism linking pollutant exposure and the increased incidence of metabolic diseases. PMID:25277399

  16. Inflammation and Oxidative Stress: The Molecular Connectivity between Insulin Resistance, Obesity, and Alzheimer's Disease

    PubMed Central

    Verdile, Giuseppe; Keane, Kevin N.; Cruzat, Vinicius F.; Medic, Sandra; Sabale, Miheer; Rowles, Joanne; Wijesekara, Nadeeja; Martins, Ralph N.; Fraser, Paul E.; Newsholme, Philip

    2015-01-01

    Type 2 diabetes (T2DM), Alzheimer's disease (AD), and insulin resistance are age-related conditions and increased prevalence is of public concern. Recent research has provided evidence that insulin resistance and impaired insulin signalling may be a contributory factor to the progression of diabetes, dementia, and other neurological disorders. Alzheimer's disease (AD) is the most common subtype of dementia. Reduced release (for T2DM) and decreased action of insulin are central to the development and progression of both T2DM and AD. A literature search was conducted to identify molecular commonalities between obesity, diabetes, and AD. Insulin resistance affects many tissues and organs, either through impaired insulin signalling or through aberrant changes in both glucose and lipid (cholesterol and triacylglycerol) metabolism and concentrations in the blood. Although epidemiological and biological evidence has highlighted an increased incidence of cognitive decline and AD in patients with T2DM, the common molecular basis of cell and tissue dysfunction is rapidly gaining recognition. As a cause or consequence, the chronic inflammatory response and oxidative stress associated with T2DM, amyloid-β (Aβ) protein accumulation, and mitochondrial dysfunction link T2DM and AD. PMID:26693205

  17. The Emerging Role of Branched-Chain Amino Acids in Insulin Resistance and Metabolism

    PubMed Central

    Yoon, Mee-Sup

    2016-01-01

    Insulin is required for maintenance of glucose homeostasis. Despite the importance of insulin sensitivity to metabolic health, the mechanisms that induce insulin resistance remain unclear. Branched-chain amino acids (BCAAs) belong to the essential amino acids, which are both direct and indirect nutrient signals. Even though BCAAs have been reported to improve metabolic health, an increased BCAA plasma level is associated with a high risk of metabolic disorder and future insulin resistance, or type 2 diabetes mellitus (T2DM). The activation of mammalian target of rapamycin complex 1 (mTORC1) by BCAAs has been suggested to cause insulin resistance. In addition, defective BCAA oxidative metabolism might occur in obesity, leading to a further accumulation of BCAAs and toxic intermediates. This review provides the current understanding of the mechanism of BCAA-induced mTORC1 activation, as well as the effect of mTOR activation on metabolic health in terms of insulin sensitivity. Furthermore, the effects of impaired BCAA metabolism will be discussed in detail. PMID:27376324

  18. Sodium Salicylate Reduced Insulin Resistance in the Retina of a Type 2 Diabetic Rat Model

    PubMed Central

    Jiang, Youde; Thakran, Shalini; Bheemreddy, Rajini; Coppess, William; Walker, Robert J.; Steinle, Jena J.

    2015-01-01

    Sodium salicylate has been reported to reduce markers of diabetic retinopathy in a type 1 rat model. Because rates of type 2 diabetes are on the rise, we wanted to determine whether salicylate could improve insulin resistance in a type 2 rat model, as well as improve retinal function. We treated lean and obese BBZDR/Wor type 2 diabetic rats with salicylate in their chow for 2 months. Prior to salicylate treatment, rats underwent an electroretinogram to measure retinal function. After 2 months of treatment, rats underwent an additional electroretinogram prior to sacrifice. In addition to the animal model, we also treated retinal endothelial cells (REC) and rat Müller cells with salicylate and performed the same analyses as done for the rat retinal lysates. To investigate the role of salicylate in insulin signaling, we measured TNFα and caspase 3 levels by ELISA, as well as performed Western blotting for insulin receptor substrate 1, insulin receptor, SOCS3, and pro- and anti-apoptotic markers. Data demonstrated that salicylate significantly improved retinal function, as well as reduced TNFα and SOCS3-induced insulin resistance in all samples. Overall, results suggest that salicylate is effective in reducing insulin resistance in the retina of type 2 diabetic rat models. PMID:25874611

  19. Inflammation and Oxidative Stress: The Molecular Connectivity between Insulin Resistance, Obesity, and Alzheimer's Disease.

    PubMed

    Verdile, Giuseppe; Keane, Kevin N; Cruzat, Vinicius F; Medic, Sandra; Sabale, Miheer; Rowles, Joanne; Wijesekara, Nadeeja; Martins, Ralph N; Fraser, Paul E; Newsholme, Philip

    2015-01-01

    Type 2 diabetes (T2DM), Alzheimer's disease (AD), and insulin resistance are age-related conditions and increased prevalence is of public concern. Recent research has provided evidence that insulin resistance and impaired insulin signalling may be a contributory factor to the progression of diabetes, dementia, and other neurological disorders. Alzheimer's disease (AD) is the most common subtype of dementia. Reduced release (for T2DM) and decreased action of insulin are central to the development and progression of both T2DM and AD. A literature search was conducted to identify molecular commonalities between obesity, diabetes, and AD. Insulin resistance affects many tissues and organs, either through impaired insulin signalling or through aberrant changes in both glucose and lipid (cholesterol and triacylglycerol) metabolism and concentrations in the blood. Although epidemiological and biological evidence has highlighted an increased incidence of cognitive decline and AD in patients with T2DM, the common molecular basis of cell and tissue dysfunction is rapidly gaining recognition. As a cause or consequence, the chronic inflammatory response and oxidative stress associated with T2DM, amyloid-β (Aβ) protein accumulation, and mitochondrial dysfunction link T2DM and AD. PMID:26693205

  20. The Emerging Role of Branched-Chain Amino Acids in Insulin Resistance and Metabolism.

    PubMed

    Yoon, Mee-Sup

    2016-01-01

    Insulin is required for maintenance of glucose homeostasis. Despite the importance of insulin sensitivity to metabolic health, the mechanisms that induce insulin resistance remain unclear. Branched-chain amino acids (BCAAs) belong to the essential amino acids, which are both direct and indirect nutrient signals. Even though BCAAs have been reported to improve metabolic health, an increased BCAA plasma level is associated with a high risk of metabolic disorder and future insulin resistance, or type 2 diabetes mellitus (T2DM). The activation of mammalian target of rapamycin complex 1 (mTORC1) by BCAAs has been suggested to cause insulin resistance. In addition, defective BCAA oxidative metabolism might occur in obesity, leading to a further accumulation of BCAAs and toxic intermediates. This review provides the current understanding of the mechanism of BCAA-induced mTORC1 activation, as well as the effect of mTOR activation on metabolic health in terms of insulin sensitivity. Furthermore, the effects of impaired BCAA metabolism will be discussed in detail. PMID:27376324

  1. Green tea extract decreases oxidative stress and improves insulin sensitivity in an animal model of insulin resistance, the fructose- fed rat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Metabolic syndrome is characterized by insulin resistance, dyslipidemia, and increased oxidative stress. Tea polyphenols, as both insulin potentiating factors and antioxidants, might act in preventing the metabolic syndrome. We aimed to determine the effects of green tea extract consumption on oxida...

  2. Elevated total and central adiposity and low physical activity are associated with insulin resistance in children.

    PubMed

    Krekoukia, Maria; Nassis, George P; Psarra, Glykeria; Skenderi, Katerina; Chrousos, George P; Sidossis, Labros S

    2007-02-01

    The aim of this study was 2-fold: (1) to examine insulin resistance, blood lipid levels, and inflammatory markers in 9- to 11.5-year-old obese and lean children and (2) to identify factors that influence insulin resistance in this cohort of youths. Body mass index, skinfold thickness, waist circumference, physical activity (4-day triaxial accelerometer), cardiorespiratory fitness (submaximal bicycle ergometer test), and dietary intake (3-day food records) were evaluated in 27 obese and 27 lean boys and girls. Fasting blood samples were analyzed for insulin, glucose, lipids and lipoproteins, C-reactive protein (CRP), interleukin 6, soluble intercellular adhesion molecule, and soluble vascular cell adhesion molecule. Homeostasis model assessment (HOMA) was used to evaluate insulin resistance (HOMA-IR). Obese children presented higher HOMA-IR, CRP, and blood lipid levels (all P < .01) compared with lean children. Total body fat and waist circumference were positively associated with fasting insulin (r > or = 0.51), HOMA-IR (r > or = 0.56), CRP (r > or = 0.51), and blood triacylglycerol (r > or = 0.38), and were inversely correlated with high-density lipoprotein cholesterol (r > or = -0.39; all P < .01). Cardiorespiratory fitness was inversely associated with HOMA-IR (r = -0.24; P < .05), but this association disappeared when adjusted for age, sex, and fat mass. Waist circumference and total daily physical activity explained 49% of the variance in HOMA-IR in these children. In conclusion, these findings suggest that total and central adiposity are positively associated and physical activity is negatively associated with insulin resistance in children. Interventions to improve glucose metabolism in youth should target at reducing total body and abdominal fat and increasing physical activity. The lack of association between inflammatory markers and HOMA-IR suggests that obesity may precede the elevation of these markers in the evolution of insulin resistance in youth

  3. Sirtuin3 Dysfunction Is the Key Determinant of Skeletal Muscle Insulin Resistance by Angiotensin II

    PubMed Central

    Macconi, Daniela; Perico, Luca; Longaretti, Lorena; Morigi, Marina; Cassis, Paola; Buelli, Simona; Perico, Norberto; Remuzzi, Giuseppe; Benigni, Ariela

    2015-01-01

    Background Angiotensin II promotes insulin resistance. The mechanism underlying this abnormality, however, is still poorly defined. In a different setting, skeletal muscle metabolism and insulin signaling are regulated by Sirtuin3. Objective Here, we investigate whether angiotensin II-induced insulin resistance in skeletal muscle is associated with Sirtuin3 dysregulation and whether pharmacological manipulation of Sirtuin3 confers protection. Study Design Parental and GLUT4-myc L6 rat skeletal muscle cells exposed to angiotensin II are used as in vitro models of insulin resistance. GLUT4 translocation, glucose uptake, intracellular molecular signals such as mitochondrial reactive oxygen species, Sirtuin3 protein expression and activity, along with its downstream targets and upstream regulators, are analyzed both in the absence and presence of acetyl-L-carnitine. The role of Sirtuin3 in GLUT4 translocation and intracellular molecular signaling is also studied in Sirtuin3-silenced as well as over-expressing cells. Results Angiotensin II promotes insulin resistance in skeletal muscle cells via mitochondrial oxidative stress, resulting in a two-fold increase in superoxide generation. In this context, reactive oxygen species open the mitochondrial permeability transition pore and significantly lower Sirtuin3 levels and activity impairing the cell antioxidant defense. Angiotensin II-induced Sirtuin3 dysfunction leads to the impairment of AMP-activated protein kinase/nicotinamide phosphoribosyltransferase signaling. Acetyl-L-carnitine, by lowering angiotensin II-induced mitochondrial superoxide formation, prevents Sirtuin3 dysfunction. This phenomenon implies the restoration of manganese superoxide dismutase antioxidant activity and AMP-activated protein kinase activation. Acetyl-L-carnitine protection is abrogated by specific Sirtuin3 siRNA. Conclusions Our data demonstrate that angiotensin II-induced insulin resistance fosters mitochondrial superoxide generation, in

  4. Predictors of insulin resistance in pediatric burn injury survivors 24 to 36 months post-burn

    PubMed Central

    Chondronikola, Maria; Meyer, Walter J.; Sidossis, Labros S.; Ojeda, Sylvia; Huddleston, Joanna; Stevens, Pamela; Børsheim, Elisabet; Suman, Oscar E.; Finnerty, Celeste C.; Herndon, David N.

    2014-01-01

    Background Burn injury is a dramatic event with acute and chronic consequences including insulin resistance. However, factors associated with insulin resistance have not been previously investigated. Purpose To identify factors associated with long-term insulin resistance in pediatric burn injury survivors. Methods The study sample consisted of 61 pediatric burn injury survivors 24 to 36 months after the burn injury, who underwent an oral glucose tolerance test. To assess insulin resistance, we calculated the area under the curve for glucose and insulin. The diagnostic criteria of the American Diabetes Association were used to define individuals with impaired glucose metabolism. Additional data collected include body composition, anthropometric measurements, burn characteristics and demographic information. The data were analyzed using multivariate linear regression analysis. Results Approximately 12% of the patients met the criteria for impaired glucose metabolism. After adjusting for possible confounders, burn size, age and percent body fat were associated with the area under the curve for glucose (p<0.05 for all). Time post-burn and lean mass were inversely associated with the area under the curve for glucose (p<0.05 for both). Similarly, older age predicted higher insulin area under the curve. Conclusion A significant proportion of pediatric injury survivors suffer from glucose abnormalities 24–36 months post-burn. Burn size, time post-burn, age, lean mass and adiposity are significant predictors of insulin resistance in pediatric burn injury survivors. Clinical evaluation and screening for abnormal glucose metabolism should be emphasized in patients with large burns, older age and survivors with high body fat. PMID:24918945

  5. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes.

    PubMed

    Perry, Rachel J; Samuel, Varman T; Petersen, Kitt F; Shulman, Gerald I

    2014-06-01

    Non-alcoholic fatty liver disease and its downstream sequelae, hepatic insulin resistance and type 2 diabetes, are rapidly growing epidemics, which lead to increased morbidity and mortality rates, and soaring health-care costs. Developing interventions requires a comprehensive understanding of the mechanisms by which excess hepatic lipid develops and causes hepatic insulin resistance and type 2 diabetes. Proposed mechanisms implicate various lipid species, inflammatory signalling and other cellular modifications. Studies in mice and humans have elucidated a key role for hepatic diacylglycerol activation of protein kinase Cε in triggering hepatic insulin resistance. Therapeutic approaches based on this mechanism could alleviate the related epidemics of non-alcoholic fatty liver disease and type 2 diabetes. PMID:24899308

  6. Interleukin-6 signaling promotes alternative macrophage activation to limit obesity-associated insulin resistance and endotoxemia

    PubMed Central

    Mauer, Jan; Chaurasia, Bhagirath; Goldau, Julia; Vogt, Merly C.; Ruud, Johan; Nguyen, Khoa D.; Theurich, Sebastian; Hausen, A. Christine; Schmitz, Joel; Brönneke, Hella S.; Estevez, Emma; Allen, Tamara L.; Mesaros, Andrea; Partridge, Linda; Febbraio, Mark A.; Chawla, Ajay; Wunderlich, F. Thomas; Brüning, Jens C.

    2014-01-01

    Obesity and insulin resistance are closely associated with the development of low-grade inflammation. Interleukin 6 (IL-6) is linked to obesity-associated inflammation, however its role in this context remains controversial. Here, we show that mice with inactivated Il6ra gene in myeloid cells (Il6raΔmyel) displayed exaggerated deterioration of glucose homeostasis upon diet-induced obesity due to enhanced insulin resistance. Insulin target tissues showed increased inflammation and a shift in macrophage polarization. IL-6 induced IL-4-receptor expression and augmented the response to IL-4 in macrophages in a cell-autonomous manner. Il6raΔmyel mice were resistant to IL-4-mediated alternative macrophage polarization and exhibited increased susceptibility to LPS-induced endotoxemia. These results reveal IL-6 signaling as an important determinant for alternative macrophage-activation and assign IL-6 an unexpected homeostatic role to limit inflammation. PMID:24681566

  7. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes

    PubMed Central

    Perry, Rachel J.; Samuel, Varman T.; Petersen, Kitt F.; Shulman, Gerald I.

    2015-01-01

    Non-alcoholic fatty liver disease and its downstream sequelae, hepatic insulin resistance and type 2 diabetes, are rapidly growing epidemics, which lead to increased morbidity and mortality rates, and soaring health-care costs. Developing interventions requires a comprehensive understanding of the mechanisms by which excess hepatic lipid develops and causes hepatic insulin resistance and type 2 diabetes. Proposed mechanisms implicate various lipid species, inflammatory signalling and other cellular modifications. Studies in mice and humans have elucidated a key role for hepatic diacylglycerol activation of protein kinase Cε in triggering hepatic insulin resistance. Therapeutic approaches based on this mechanism could alleviate the related epidemics of non-alcoholic fatty liver disease and type 2 diabetes. PMID:24899308

  8. Estrogen deprivation in primate pregnancy leads to insulin resistance in offspring.

    PubMed

    Maniu, Adina; Aberdeen, Graham W; Lynch, Terrie J; Nadler, Jerry L; Kim, Soon O K; Quon, Michael J; Pepe, Gerald J; Albrecht, Eugene D

    2016-08-01

    This study tested the hypothesis that estrogen programs mechanisms within the primate fetus that promote insulin sensitivity and glucose homeostasis in offspring. Glucose tolerance tests were performed longitudinally in prepubertal offspring of baboons untreated or treated on days 100 to 165/175 of gestation (term is 184 days) with the aromatase inhibitor letrozole, which decreased fetal estradiol levels by 95%. Basal plasma insulin levels were over two-fold greater in offspring delivered to letrozole-treated than untreated animals. Moreover, the peak 1min, average of the 1, 3, and 5min, and area under the curve blood glucose and plasma insulin levels after an i.v. bolus of glucose were greater (P<0.05 and P<0.01, respectively) in offspring deprived of estrogen in utero than in untreated animals and partially or completely restored in letrozole plus estradiol-treated baboons. The value for the homeostasis model assessment of insulin resistance was 2.5-fold greater (P<0.02) and quantitative insulin sensitivity check index lower (P<0.01) in offspring of letrozole-treated versus untreated animals and returned to almost normal in letrozole plus estradiol-treated animals. The exaggerated rise in glucose and insulin levels after glucose challenge in baboon offspring deprived of estrogen in utero indicates that pancreatic beta cells had the capacity to secrete insulin, but that peripheral glucose uptake and/or metabolism were impaired, indicative of insulin resistance and glucose intolerance. We propose that estrogen normally programs mechanisms in utero within the developing primate fetus that lead to insulin sensitivity, normal glucose tolerance, and the capacity to metabolize glucose after birth. PMID:27207093

  9. Insulin resistance and β cell function in patients with β-thalassemia major.

    PubMed

    Ghergherehchi, Robabeh; Habibzadeh, Afshin

    2015-01-01

    Iron overload is a common finding in chronically transfused β-thalassemia major (β-TM) patients with possible effect on β cell function and insulin resistance. In this study we aimed to evaluate glucose metabolism, insulin resistance and β cell function in β-TM patients. A total of 78 transfusion-dependent β-TM patients and 40 age and sex matched normal children were included. Oral glucose tolerance tests (OGTT) were performed in all subjects. Fasting plasma insulin level, insulin resistance index (IRI) and β cell function index (BFI) were also estimated. β-Thalassemia major patients had significantly more abnormal OGTT than the control group. β-Thalassemia major patients had significantly higher levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) fasting blood sugar and IRI than the control group. Findings between β-thalassemia (β-thal) patients, with and without abnormal OGTT results, were also compared; β-thal patients with abnormal OGTT had significantly higher duration of chelation therapy, serum ferritin levels, AST, ALT and increased IRI and decreased BFI in comparison to patients with normal OGTT. Abnormal glucose metabolism is common in β-TM patients with chelation therapy and multiple transfusions which are attributable to impaired β cells' function and increased insulin resistance. PMID:25572183

  10. Persistent Organic Pollutants and Concern Over the Link with Insulin Resistance Related Metabolic Diseases.

    PubMed

    Mostafalou, Sara

    2016-01-01

    Persistent organic pollutants (POPs) are mostly halogenated compounds tending to persist in the environment, enter into the food chain, and accumulate in fat mass of mammals due to their high lipophilicity. They include some organochlorine pesticides, polychlorinated biphenyls, brominated flame retardants and polycyclic aromatic hydrocarbons. Some of these chemicals were widely used in the past so that their residues can be detected in the human body, though their usage has been banned for years. POPs have been shown to perturb the health of biological systems in different ways evidenced by carcinogenicity and disrupting effects on endocrine, immune, and reproductive systems. There are many epidemiologic and experimental studies on the association of exposure to POPs with insulin resistance and related metabolic disorders like obesity, diabetes, and metabolic syndrome. Inflammation as a known mechanism accompanying insulin resistance has also been shown to arise in insulin target tissues exposed to POPs. This review addresses the breast milk concentration of POPs in different regions of the world, synthesizes the current information on the association of POPs with insulin resistance related metabolic disorders, and discusses the inflammation as an involved mechanism. Considering high prevalence of insulin resistance related metabolic diseases and their relation with POPs, much need is felt regarding international and regional programs to not only limit their production and usage but eliminate these persistent pollutants from the environment. PMID:26670033

  11. Vagus Nerve Stimulation Improves Cardiac Function by Preventing Mitochondrial Dysfunction in Obese-Insulin Resistant Rats

    PubMed Central

    Samniang, Bencharunan; Shinlapawittayatorn, Krekwit; Chunchai, Titikorn; Pongkan, Wanpitak; Kumfu, Sirinart; Chattipakorn, Siriporn C.; KenKnight, Bruce H.; Chattipakorn, Nipon

    2016-01-01

    Long-term high-fat diet (HFD) consumption leads to not only obese-insulin resistance, but also impaired left ventricular (LV) function. Vagus nerve stimulation (VNS) has been shown to exert cardioprotection. However, its effects on the heart and metabolic parameters under obese-insulin resistant condition is not known. We determined the effects of VNS on metabolic parameters, heart rate variability (HRV) and LV function in obese-insulin resistant rats. Male Wistar rats were fed with HFD for 12 weeks, and were randomly divided into sham and VNS groups. VNS was applied for the next 12 weeks. Echocardiography, blood pressure and HRV were examined. Blood samples were collected for metabolic parameters. At the end, the heart was removed for determination of apoptosis, inflammation, oxidative stress, and cardiac mitochondrial function. VNS for 12 weeks significantly decreased plasma insulin, HOMA index, total cholesterol, triglyceride, LDL and visceral fat. Serum adiponectin was significantly increased in the VNS group. VNS also significantly decreased blood pressure, improved HRV and LV function, decreased cardiac MDA, TNF-α and Bax levels, and improved cardiac mitochondrial function. VNS improves metabolic and hemodynamic parameters, and the LV function via its ability against apoptosis, inflammation and oxidative stress, and preserved cardiac mitochondrial function in obese-insulin resistant rats. PMID:26830020

  12. PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance

    PubMed Central

    Kulkarni, Rohit N.; Jhala, Ulupi S.; Winnay, Jonathon N.; Krajewski, Stan; Montminy, Marc; Kahn, C. Ronald

    2004-01-01

    Inadequate compensatory β cell hyperplasia in insulin-resistant states triggers the development of overt diabetes. The mechanisms that underlie this crucial adaptive response are not fully defined. Here we show that the compensatory islet-growth response to insulin resistance in 2 models — insulin receptor (IR)/IR substrate–1 (IRS-1) double heterozygous mice and liver-specific IR KO (LIRKO) mice — is severely restricted by PDX-1 heterozygosity. Six-month-old IR/IRS-1 and LIRKO mice both showed up to a 10-fold increase in β cell mass, which involved epithelial-to-mesenchymal transition. In both models, superimposition of PDX-1 haploinsufficiency upon the background of insulin resistance completely abrogated the adaptive islet hyperplastic response, and instead the β cells showed apoptosis resulting in premature death of the mice. This study shows that, in postdevelopmental states of β cell growth, PDX-1 is a critical regulator of β cell replication and is required for the compensatory response to insulin resistance. PMID:15372107

  13. Galanin antagonist increases insulin resistance by reducing glucose transporter 4 effect in adipocytes of rats.

    PubMed

    Guo, Lili; Shi, Mingyi; Zhang, Ling; Li, Guangzhi; Zhang, Lingxiang; Shao, Hu; Fang, Penghua; Ma, Yingping; Li, Jian; Shi, Qiaojia; Sui, Yumei

    2011-08-01

    Seeing that galanin increases animal body weight on the conditions of inhibiting insulin secretion and animals with metabolic disorder of galanin easily suffer from diabetes, we postulate that endogenous galanin is necessary to reduce insulin resistance in adipocytes. To test this hypothesis, we compared four groups of rats to examine whether an increase in galanin secretion stimulated by swimming may reduce insulin resistance. The rats from sedentary and trained drug groups were injected by M35, a galanin antagonist. The rats from trained control and trained drug groups swam after each injection for four weeks. We found that exercise significantly elevated plasma galanin contents and glucose transporter 4 (GLUT4) mRNA levels in adipocytes. Meanwhile, M35 treatment reduced GLUT4 and GLUT4 mRNA levels, and glucose infusing rates in euglycemic-hyperinsulinemic clamp tests. The ratios of GLUT4 concentrations at plasma membranes to total cell membranes in both drug groups were lower compared with each control group, respectively. These observations suggest that endogenous galanin reduces insulin resistance by increasing GLUT4 contents and promoting GLUT4 transportation from intracellular membranes to plasma membranes in adipocytes. Galanin is an important hormone to reduce insulin resistance in rats. PMID:21664358

  14. [Extreme subcutaneous and intramuscular insulin resistance at type 1 diabetes mellitus].

    PubMed

    Pinheiro, Anielli; Tácito, Lúcia H B; Pires, Antônio C

    2011-04-01

    Insulin resistance signs reduced cellular response to this hormone and dysfunction of glucose transport to intracellular compartment. This phenomenon is associated to genetic factors and principally behavior factors correlating to obesity and its comorbidities, as type 2 diabetes mellitus, hypertension and dyslipidemia. However clinical factors of insulin resistance are still present at not obese type 1 diabetes in a known syndrome called type 1 diabetes mellitus with resistance to insulin administered subcutaneously and intramuscularly (DRIASM). This is a rare condition that consists into insulin resistance at subcutaneously and intramuscularly use and normal or near to normal sensitivity at intravenously way. Treatments until now proposed are ineffective and are related to frequent fails and complications. We report here two cases of DRIASM in 45 and 46 female patients that are different from others yet related because they have late diabetes type 1, sustained hyperglycemia associated to catabolic, microangiopathy and neuropathic complications without any ketoacidosis episode. The treatment vary from alternative ways for insulin infusion to inscription to a possible performance of pancreas transplantation like a experiment of definitive treatment. This report was approved by Research Ethic Committee from São José do Rio Preto medical school. PMID:21655874

  15. Peroxisome Proliferator-Activated Receptor Agonist Treatment of Alcohol-Induced Hepatic Insulin Resistance

    PubMed Central

    de la Monte, Suzanne M.; Pang, Maoyin; Chaudhry, Rajeeve; Duan, Kevin; Longato, Lisa; Carter, Jade; Ouh, Jiyun; Wands, Jack R.

    2011-01-01

    Chronic ethanol exposure impairs insulin signaling in the liver. Peroxisome-proliferator activated receptor (PPAR) agonists function as insulin sensitizers and are used to treat type 2 diabetes mellitus. We examined the therapeutic effectiveness of PPAR agonists in reducing alcoholic hepatitis and hepatic insulin resistance in a model of chronic ethanol feeding. Adult male Long Evans rats were pair fed with isocaloric liquid diets containing 0% (control) or 37% ethanol (caloric content; 9.2% v/v) for 8 weeks. After 3 weeks on the diets, the rats were treated with vehicle, or a PPAR-α, PPAR-δ, or PPAR-γ agonist twice weekly by i.p. injection. Livers were harvested for histopathological, gene expression (RT-PCR), protein (Western and ELISA), and receptor binding studies. Ethanol-fed rats developed steatohepatitis with disordered hepatic chord architecture, increased hepatocellular apoptosis, reduced binding to the insulin, IGF-1, and IGF-2 receptors, and decreased expression of glyceraldehyde-3-phosphate dehydrogenase and aspartyl-(asparaginyl)-β-hydroxylase (mediates remodeling), which are regulated by insulin/IGF signaling. PPAR-α, PPAR-δ, or PPAR-γ agonist treatments reduced the severity of ethanol-mediated liver injury, including hepatic architectural disarray and steatosis. In addition, PPAR-δ and PPAR-γ agonists reduced insulin/IGF resistance and increased insulin/IGF-responsive gene expression. In conclusion, PPAR agonists may help reduce the severity of chronic ethanol-induced liver injury and insulin/IGF resistance, even in the context of continued high-level ethanol consumption. PMID:21426453

  16. Hepatocyte TRAF3 promotes insulin resistance and type 2 diabetes in mice with obesity

    PubMed Central

    Chen, Zheng; Canet, Mark J.; Sheng, Liang; Jiang, Lin; Xiong, Yi; Yin, Lei; Rui, Liangyou

    2015-01-01

    Objective Metabolic inflammation is believed to promote insulin resistance and type 2 diabetes progression in obesity. TRAF3, a cytoplasmic signaling protein, has been known to mediate/modulate cytokine signaling in immune cells. The goal is to define the metabolic function of hepatic TRAF3 in the setting of obesity. Methods Hepatocyte-specific TRAF3 knockout mice were generated using the loxp/albumin-cre system. Liver TRAF3 was deleted in adult obese mice via Cre adenoviral infection. Both high fat diet-induced and genetic obesity were examined. TRAF3 levels and insulin signaling were measured by immunoblotting. Insulin sensitivity, hepatic glucose production, and glucose metabolism were examined by glucose, insulin, and pyruvate tolerance tests. Hepatic steatosis was examined by Oil red O staining of liver sections and measuring liver triacylglycerol levels. Results Liver TRAF3 levels were lower in the fasted states in normal mice, and were aberrantly higher in obese mice and in mice with streptozotocin-induced hyperglycemia. Glucose directly increased TRAF3 levels in primary hepatocytes. Hepatocyte-specific deletion of TRAF3 decreased hyperinsulinemia, insulin resistance, glucose intolerance, and hepatic steatosis in mice with either high fat diet-induced obesity or genetic obesity (ob/ob); conversely, in lean mice, adenovirus-mediated overexpression of TRAF3 in the liver induced hyperinsulinemia, insulin resistance, and glucose intolerance. Deletion of TRAF3 enhanced the ability of insulin to stimulate phosphorylation of Akt in hepatocytes, whereas overexpression of TRAF3 suppressed insulin signaling. Conclusions Glucose increases the levels of hepatic TRAF3. TRAF3 in turn promotes hyperglycemia through increasing hepatic glucose production, thus forming a glucose-TRAF3 reinforcement loop in the liver. This positive feedback loop may drive the progression of type 2 diabetes and nonalcoholic fatty liver disease in obesity. PMID:26909311

  17. Lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe?

    PubMed Central

    Nunn, Alistair VW; Bell, Jimmy D; Guy, Geoffrey W

    2009-01-01

    The metabolic syndrome may have its origins in thriftiness, insulin resistance and one of the most ancient of all signalling systems, redox. Thriftiness results from an evolutionarily-driven propensity to minimise energy expenditure. This has to be balanced with the need to resist the oxidative stress from cellular signalling and pathogen resistance, giving rise to something we call 'redox-thriftiness'. This is based on the notion that mitochondria may be able to both amplify membrane-derived redox growth signals as well as negatively regulate them, resulting in an increased ATP/ROS ratio. We suggest that 'redox-thriftiness' leads to insulin resistance, which has the effect of both protecting the individual cell from excessive growth/inflammatory stress, while ensuring energy is channelled to the brain, the immune system, and for storage. We also suggest that fine tuning of redox-thriftiness is achieved by hormetic (mild stress) signals that stimulate mitochondrial biogenesis and resistance to oxidative stress, which improves metabolic flexibility. However, in a non-hormetic environment with excessive calories, the protective nature of this system may lead to escalating insulin resistance and rising oxidative stress due to metabolic inflexibility and mitochondrial overload. Thus, the mitochondrially-associated resistance to oxidative stress (and metabolic flexibility) may determine insulin resistance. Genetically and environmentally determined mitochondrial function may define a 'tipping point' where protective insulin resistance tips over to inflammatory insulin resistance. Many hormetic factors may induce mild mitochondrial stress and biogenesis, including exercise, fasting, temperature extremes, unsaturated fats, polyphenols, alcohol, and even metformin and statins. Without hormesis, a proposed redox-thriftiness tipping point might lead to a feed forward insulin resistance cycle in the presence of excess calories. We therefore suggest that as oxidative stress

  18. Trigonella foenum-graecum water extract improves insulin sensitivity and stimulates PPAR and γ gene expression in high fructose-fed insulin-resistant rats

    PubMed Central

    Mohammadi, Abbas; Gholamhosseinian, Ahmad; Fallah, Hossein

    2016-01-01

    Background: Insulin resistance is the main defect associated with the metabolic syndrome. In obesity, the decreased adiponectin levels and elevation of plasma-free fatty acids are the main factors associated with insulin resistance. In this study, we evaluated the effect of trigonella foenum-graecum (TFG) extract on insulin sensitivity in high fructose-fed insulin-resistant rats. Materials and Methods: Experimental rats were fed with a high fructose diet for eight weeks. After the first six weeks, the animals were treated with trigonella foenum-graecum extract or pioglitazone for two weeks. Serum glucose, triglycerides, cholesterol, and HDL-c were measured. The insulin and adiponectin levels were assayed by the enzyme-linked immunosorbent assay (ELISA), and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was calculated. The plasma-free fatty acid profile was obtained by gas chromatography. PPARγ and GLUT4 gene expression were assessed by real-time polymerase chain reaction (PCR) and western blotting. Results: In the trigonella foenum-graecum- extract treated group the following results were obtained: Insulin (49.02 ± 6.93 pmol/L), adiponectin (7.1 ± 0.64 μg/ml), and triglycerides (110.3 ± 16.7 mg/dl), which were significantly different and improved compared to the control group (insulin (137 ± 34 pmol/l), adiponectin (3.9 ± 0.15 μg/ml), glucose (187 ± 15 mg/dl), and triglycerides (217 ± 18 mg/dl). Also the PPARγ gene expression was significantly increased compared to the control group. Conclusion: This study demonstrates the beneficial effects of trigonella foenum-graecum extract on insulin resistance in rats fed on a high-fructose diet. At least three mechanisms are involved, including direct insulin-like effect, increase in adiponectin levels, and PPARγ protein expression. PMID:27110551

  19. Neuropoietin Attenuates Adipogenesis and Induces Insulin Resistance in Adipocytes*

    PubMed Central

    White, Ursula A.; Stewart, William C.; Mynatt, Randall L.; Stephens, Jacqueline M.

    2008-01-01

    Recent findings have implicated gp130 receptor ligands, particularly ciliary neurotrophic factor (CNTF), as potential anti-obesity therapeutics. Neuropoietin (NP) is a recently discovered cytokine in the gp130 family that shares functional and structural features with CNTF and signals via the CNTF receptor tripartite complex comprised of CNTFRα, LIF receptor, and gp130. NP plays a role in the development of the nervous system, but the effects of NP on adipocytes have not been previously examined. Because CNTF exerts anti-obesogenic effects in adipocytes and NP shares the same receptor complex, we investigated the effects of NP on adipocyte development and insulin action. Using cultured 3T3-L1 adipocytes, we observed that NP has the ability to block adipogenesis in a dose- and time-dependent manner. We also observed that cultured adipocytes, as well as murine adipose tissue, are highly responsive to acute NP treatment. Rodents injected with NP had a substantial increase in STAT3 tyrosine phosphorylation and ERK 1 and 2 activation. We also observed the induction of SOCS-3 mRNA in 3T3-L1 adipocytes following NP treatment. Unlike CNTF, our studies have revealed that NP also substantially attenuates insulin-stimulated glucose uptake in 3T3-L1 adipocytes. In addition, NP blocks insulin action in adipose tissue in vivo. These observations are supported by data demonstrating that NP impairs insulin signaling via decreased activation of both IRS-1 and Akt. In summary, we have observed that both adipocytes in vitro and in vivo are highly responsive to NP, and this cytokine has the ability to affect insulin signaling in fat cells. These novel observations suggest that NP, unlike CNTF, may not be a viable obesity therapeutic. PMID:18562323

  20. Identification of new biomarker candidates for glucocorticoid induced insulin resistance using literature mining

    PubMed Central

    2013-01-01

    Background Glucocorticoids are potent anti-inflammatory agents used for the treatment of diseases such as rheumatoid arthritis, asthma, inflammatory bowel disease and psoriasis. Unfortunately, usage is limited because of metabolic side-effects, e.g. insulin resistance, glucose intolerance and diabetes. To gain more insight into the mechanisms behind glucocorticoid induced insulin resistance, it is important to understand which genes play a role in the development of insulin resistance and which genes are affected by glucocorticoids. Medline abstracts contain many studies about insulin resistance and the molecular effects of glucocorticoids and thus are a good resource to study these effects. Results We developed CoPubGene a method to automatically identify gene-disease associations in Medline abstracts. We used this method to create a literature network of genes related to insulin resistance and to evaluate the importance of the genes in this network for glucocorticoid induced metabolic side effects and anti-inflammatory processes. With this approach we found several genes that already are considered markers of GC induced IR, such as phosphoenolpyruvate carboxykinase (PCK) and glucose-6-phosphatase, catalytic subunit (G6PC). In addition, we found genes involved in steroid synthesis that have not yet been recognized as mediators of GC induced IR. Conclusions With this approach we are able to construct a robust informative literature network of insulin resistance related genes that gave new insights to better understand the mechanisms behind GC induced IR. The method has been set up in a generic way so it can be applied to a wide variety of disease networks. PMID:23379763

  1. Aβ-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Aβ Secretion in Neural Cells.

    PubMed

    Najem, Dema; Bamji-Mirza, Michelle; Yang, Ze; Zhang, Wandong

    2016-06-01

    Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) toxicity, tau pathology, insulin resistance, neuroinflammation, and dysregulation of cholesterol homeostasis, all of which play roles in neurodegeneration. Insulin has polytrophic effects on neurons and may be at the center of these pathophysiological changes. In this study, we investigated possible relationships among insulin signaling and cholesterol biosynthesis, along with the effects of Aβ42 on these pathways in vitro. We found that neuroblastoma 2a (N2a) cells transfected with the human gene encoding amyloid-β protein precursor (AβPP) (N2a-AβPP) produced Aβ and exhibited insulin resistance by reduced p-Akt and a suppressed cholesterol-synthesis pathway following insulin treatment, and by increased phosphorylation of insulin receptor subunit-1 at serine 612 (p-IRS-S612) as compared to parental N2a cells. Treatment of human neuroblastoma SH-SY5Y cells with Aβ42 also increased p-IRS-S612, suggesting that Aβ42 is responsible for insulin resistance. The insulin resistance was alleviated when N2a-AβPP cells were treated with higher insulin concentrations. Insulin increased Aβ release from N2a-AβPP cells, by which it may promote Aβ clearance. Insulin increased cholesterol-synthesis gene expression in SH-SY5Y and N2a cells, including 24-dehydrocholesterol reductase (DHCR24) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) through sterol-regulatory element-binding protein-2 (SREBP2). While Aβ42-treated SH-SY5Y cells exhibited increased HMGCR expression and c-Jun phosphorylation as pro-inflammatory responses, they also showed down-regulation of neuro-protective/anti-inflammatory DHCR24. These results suggest that Aβ42 may cause insulin resistance, activate JNK for c-Jun phosphorylation, and lead to dysregulation of cholesterol homeostasis, and that enhancing insulin signaling may relieve the insulin-resistant phenotype and the dysregulated cholesterol-synthesis pathway to promote A

  2. Resveratrol activates duodenal Sirt1 to reverse insulin resistance in rats through a neuronal network.

    PubMed

    Côté, Clémence D; Rasmussen, Brittany A; Duca, Frank A; Zadeh-Tahmasebi, Melika; Baur, Joseph A; Daljeet, Mira; Breen, Danna M; Filippi, Beatrice M; Lam, Tony K T

    2015-05-01

    Resveratrol improves insulin sensitivity and lowers hepatic glucose production (HGP) in rat models of obesity and diabetes, but the underlying mechanisms for these antidiabetic effects remain elusive. One process that is considered a key feature of resveratrol action is the activation of the nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase sirtuin 1 (SIRT1) in various tissues. However, the low bioavailability of resveratrol raises questions about whether the antidiabetic effects of oral resveratrol can act directly on these tissues. We show here that acute intraduodenal infusion of resveratrol reversed a 3 d high fat diet (HFD)-induced reduction in duodenal-mucosal Sirt1 protein levels while also enhancing insulin sensitivity and lowering HGP. Further, we found that duodenum-specific knockdown of Sirt1 expression for 14 d was sufficient to induce hepatic insulin resistance in rats fed normal chow. We also found that the glucoregulatory role of duodenally acting resveratrol required activation of Sirt1 and AMP-activated protein kinase (Ampk) in this tissue to initiate a gut-brain-liver neuronal axis that improved hypothalamic insulin sensitivity and in turn, reduced HGP. In addition to the effects of duodenally acting resveratrol in an acute 3 d HFD-fed model of insulin resistance, we also found that short-term infusion of resveratrol into the duodenum lowered HGP in two other rat models of insulin resistance--a 28 d HFD-induced model of obesity and a nicotinamide (NA)-streptozotocin (STZ)-HFD-induced model of mild type 2 diabetes. Together, these studies highlight the therapeutic relevance of targeting duodenal SIRT1 to reverse insulin resistance and improve glucose homeostasis in obesity and diabetes. PMID:25849131

  3. Intermedin Restores Hyperhomocysteinemia-induced Macrophage Polarization and Improves Insulin Resistance in Mice.

    PubMed

    Pang, Yanli; Li, Yang; Lv, Ying; Sun, Lulu; Zhang, Songyang; Li, Yin; Wang, Yuhui; Liu, George; Xu, Ming-Jiang; Wang, Xian; Jiang, Changtao

    2016-06-01

    Hyperhomocysteinemia (HHcy) is a condition characterized by an abnormally high level of homocysteine, an inflammatory factor. This condition has been suggested to promote insulin resistance. To date, the underlying molecular mechanism remains largely unknown, and identifying novel therapeutic targets for HHcy-induced insulin resistance is of high priority. It is well known that intermedin (IMD), a calcitonin family peptide, exerts potent anti-inflammatory effects. In this study, the effects of IMD on HHcy-induced insulin resistance were investigated. Glucose tolerance and insulin tolerance tests were performed on mice treated with IMD by minipump implantation (318 ng/kg/h for 4 weeks) or adipocyte-specific IMD overexpression mice (Adipo-IMD transgenic mice). The expression of genes and proteins related to M1/M2 macrophages and endoplasmic reticulum stress (ERS) was evaluated in adipose tissues or cells. The expression of IMD was identified to be lower in the plasma and adipose tissues of HHcy mice. In both IMD treatment by minipump implantation and Adipo-IMD transgenic mice, IMD reversed HHcy-induced insulin resistance, as revealed by glucose tolerance and insulin tolerance tests. Further mechanistic study revealed that IMD reversed the Hcy-elevated ratio of M1/M2 macrophages by inhibiting AMP-activated protein kinase activity. Adipo-IMD transgenic mice displayed reduced ERS and lower inflammation in adipose tissues with HHcy. Soluble factors from Hcy-treated macrophages induced adipocyte ERS, which was reversed by IMD treatment. These findings revealed that IMD treatment restores the M1/M2 balance, inhibits chronic inflammation in adipose tissues, and improves systemic insulin sensitivity of HHcy mice. PMID:27080257

  4. Blood-Based Indicators of Insulin Resistance and Metabolic Syndrome in Bottlenose Dolphins (Tursiops truncatus)

    PubMed Central

    Venn-Watson, Stephanie; Smith, Cynthia Rowe; Stevenson, Sacha; Parry, Celeste; Daniels, Risa; Jensen, Eric; Cendejas, Veronica; Balmer, Brian; Janech, Michael; Neely, Benjamin A.; Wells, Randall

    2013-01-01

    Similar to people with metabolic syndrome, bottlenose dolphins (Tursiops truncatus) can have a sustained postprandial hyperglycemia and hyperinsulinemia, dyslipidemia, and fatty liver disease. A panel of potential postprandial blood-based indicators of insulin resistance and metabolic syndrome were compared among 34 managed collection dolphins in San Diego Bay, CA, USA (Group A) and 16 wild, free-ranging dolphins in Sarasota Bay, FL, USA (Group B). Compared to Group B, Group A had higher insulin (2.1 ± 2.5 and 13 ± 13 μIU/ml), glucose (87 ± 19 and 108 ± 12 mg/dl), and triglycerides (75 ± 28 and 128 ± 45 mg/dl) as well as higher cholesterol (total, high-density lipoprotein cholesterol, and very low density lipoprotein cholesterol), iron, transferrin saturation, gamma-glutamyl transpeptidase (GGT), alanine transaminase, and uric acid. Group A had higher percent unmodified adiponectin. While Group A dolphins were older, the same blood-based differences remained when controlling for age. There were no differences in body mass index (BMI) between the groups, and comparisons between Group B and Group A dolphins have consistently demonstrated lower stress hormones levels in Group A. Group A dolphins with high insulin (greater than 14 μIU/ml) had higher glucose, iron, GGT, and BMI compared to Group A dolphins with lower insulin. These findings support that some dolphin groups may be more susceptible to insulin resistance compared to others, and primary risk factors are not likely age, BMI, or stress. Lower high-molecular weight adiponectin has been identified as an independent risk factor for type 2 diabetes in humans and may be a target for preventing insulin resistance in dolphins. Future investigations with these two dolphin populations, including dietary and feeding differences, may provide valuable insight for preventing and treating insulin resistance in humans. PMID:24130551

  5. Steatosis and insulin resistance in hepatitis C: a way out for the virus?

    PubMed

    Del Campo, José A; Romero-Gómez, Manuel

    2009-10-28

    The hepatitis C virus (HCV) induces lipid accumulation in vitro and in vivo. The pathogenesis of steatosis is due to both viral and host factors. Viral steatosis is mostly reported in patients with genotype 3a, whereas metabolic steatosis is often associated with genotype 1 and metabolic syndrome. Several molecular mechanisms responsible for steatosis have been associated with the HCV core protein, which is able to induce gene expression and activity of sterol regulatory element binding protein 1 (SREBP1) and peroxisome proliferator-activated receptor gamma (PPARgamma), increasing the transcription of genes involved in hepatic fatty acid synthesis. Steatosis has been also implicated in viral replication. In infected cells, HCV core protein is targeted to lipid droplets which serve as intracellular storage organelles. These studies have shown that lipid droplets are essential for virus assembly. Thus, HCV promotes steatosis as an efficient mechanism for stable viral replication. Chronic HCV infection can also induce insulin resistance. In patients with HCV, insulin resistance is more strongly associated with viral load than visceral obesity. HCV seems to lead to insulin resistance through interference of intracellular insulin signalling by HCV proteins, mainly, the serine phosphorylation of insulin receptor-1 (IRS-1) and impairment of the downstream Akt signalling pathway. The HCV core protein interferes with in vitro insulin signalling by genotype-specific mechanisms, where the role of suppressor of cytokine signal 7 (SOCS-7) in genotype 3a and mammalian target of rapamycin (mTOR) in genotype 1 in IRS-1 downregulation play key roles. Steatosis and insulin resistance have been associated with fibrosis progression and a reduced rate of sustained response to peginterferon plus ribavirin. PMID:19859993

  6. Mechanisms of insulin resistance in the amygdala: influences on food intake.

    PubMed

    Areias, Maria Fernanda Condes; Prada, Patricia Oliveira

    2015-04-01

    Obesity is increasing worldwide and is triggered, at least in part, by enhanced caloric intake. Food intake is regulated by a complex mechanism involving the hypothalamus and hindbrain circuitries. However, evidences have showing that reward systems are also important in regulating feeding behavior. In this context, amygdala is considered a key extra-hypothalamic area regulating feeding behavior in human beings and rodents. This review focuses on the regulation of food intake by amygdala and the mechanisms of insulin resistance in this brain area. Similar to the hypothalamus the anorexigenic effect of insulin is mediated via PI3K (phosphoinositide 3-kinase)/Akt (protein kinase B) pathway in the amygdala. Insulin decreases NPY (neuropeptide Y) and increases oxytocin mRNA levels in the amygdala. High fat diet and saturated fatty acids induce inflammation, ER (endoplasmic reticulum) stress and the activation of serine kinases such as PKCθ (protein kinase C theta), JNK (c-Jun N-terminal kinase) and IKKβ (inhibitor of nuclear factor kappa-B kinase beta) in the amygdala, which have an important role in insulin resistance in this brain region. Overexpressed PKCθ in the CeA (central nucleus of amygdala) of rats increases weight gain, food intake, insulin resistance and hepatic triglycerides content. The inhibition of ER stress ameliorates insulin action/signaling, increases oxytocin and decreases NPY gene expression in the amygdala of high fat feeding rodents. Those data suggest that PKCθ and ER stress are main mechanisms of insulin resistance in the amygdala of obese rats and play an important role regulating feeding behavior. PMID:25601576

  7. Insulin Secretory Defect and Insulin Resistance in Isolated Impaired Fasting Glucose and Isolated Impaired Glucose Tolerance

    PubMed Central

    Aoyama-Sasabe, Sae; Fukushima, Mitsuo; Xin, Xin; Taniguchi, Ataru; Nakai, Yoshikatsu; Mitsui, Rie; Takahashi, Yoshitaka; Tsuji, Hideaki; Yabe, Daisuke; Yasuda, Koichiro; Kurose, Takeshi; Inagaki, Nobuya; Seino, Yutaka

    2016-01-01

    Objective. To investigate the characteristics of isolated impaired glucose tolerance (IGT) and isolated impaired fasting glucose (IFG), we analyzed the factors responsible for elevation of 2-hour postchallenge plasma glucose (2 h PG) and fasting plasma glucose (FPG) levels. Methods. We investigated the relationship between 2 h PG and FPG levels who underwent 75 g OGTT in 5620 Japanese subjects at initial examination for medical check-up. We compared clinical characteristics between isolated IGT and isolated IFG and analyzed the relationships of 2 h PG and FPG with clinical characteristics, the indices of insulin secretory capacity, and insulin sensitivity. Results. In a comparison between isolated IGT and isolated IFG, insulinogenic index was lower in isolated IGT than that of isolated IFG (0.43 ± 0.34 versus 0.50 ± 0.47, resp.; p < 0.01). ISI composite was lower in isolated IFG than that of isolated IGT (6.87 ± 3.38 versus 7.98 ± 4.03, resp.; p < 0.0001). In isolated IGT group, insulinogenic index showed a significant correlation with 2 h PG (r = −0.245, p < 0.0001) and had the strongest correlation with 2 h PG (β = −0.290). In isolated IFG group, ISI composite showed a significant correlation with FPG (r = −0.162, p < 0.0001) and had the strongest correlation with FPG (β = −0.214). Conclusions. We have elucidated that decreased early-phase insulin secretion is the most important factor responsible for elevation of 2 h PG levels in isolated IGT subjects, and decreased insulin sensitivity is the most important factor responsible for elevation of FPG levels in isolated IFG subjects. PMID:26788515

  8. Deepure Tea Improves High Fat Diet-Induced Insulin Resistance and Nonalcoholic Fatty Liver Disease

    PubMed Central

    Deng, Jing-Na; Li, Juan; Mu, Hong-Na; Liu, Yu-Ying; Wang, Ming-Xia; Pan, Chun-Shui; Fan, Jing-Yu; Ye, Fei; Han, Jing-Yan

    2015-01-01

    This study was to explore the protective effects of Deepure tea against insulin resistance and hepatic steatosis and elucidate the potential underlying molecular mechanisms. C57BL/6 mice were fed with a high fat diet (HFD) for 8 weeks to induce the metabolic syndrome. In the Deepure tea group, HFD mice were administrated with Deepure tea at 160 mg/kg/day by gavage for 14 days. The mice in HFD group received water in the same way over the same period. The age-matched C57BL/6 mice fed with standard chow were used as normal control. Compared to the mice in HFD group, mice that received Deepure tea showed significantly reduced plasma insulin and improved insulin sensitivity. Deepure tea increased the expression of insulin receptor substrate 2 (IRS-2), which plays an important role in hepatic insulin signaling pathway. Deepure tea also led to a decrease in hepatic fatty acid synthesis and lipid accumulation, which were mediated by the downregulation of sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthesis (FAS), and acetyl-CoA carboxylase (ACC) proteins that are involved in liver lipogenesis. These results suggest that Deepure tea may be effective for protecting against insulin resistance and hepatic steatosis via modulating IRS-2 and downstream signaling SREBP-1c, FAS, and ACC. PMID:26504484

  9. Insulin Resistance and Skeletal Muscle Vasculature: Significance, Assessment and Therapeutic Modulators

    PubMed Central

    Manrique, Camila; Sowers, James R.

    2014-01-01

    Overnutrition and sedentarism are closely related to the alarming incidence of obesity and type 2 diabetes mellitus (DM2) in the Western world. Resistance to the actions of insulin is a common occurrence in conditions such as obesity, hypertension and DM2. In the skeletal muscle vasculature, insulin promotes vasodilation and its own transport across the vascular wall to reach its target tissue. Furthermore, insulin resistance (IR) in the skeletal muscle vasculature results in impaired skeletal muscle glucose uptake and altered whole-body glucose homeostasis. The development of different invasive and noninvasive techniques has allowed the characterization of the actions of insulin and other vasoactive hormones in the skeletal muscle vasculature in both health and disease. Current treatment strategies for DM2 do not necessarily address the impaired effect of insulin in the vasculature. Understanding the effects of insulin and other metabolically active hormones in the vasculature should facilitate the development of new therapeutic strategies targeted at the modulation of IR and improvement of whole-body glucose tolerance. PMID:25737689

  10. Insulin

    NASA Technical Reports Server (NTRS)

    2004-01-01

    The manipulation of organic materials--cells, tissues, and even living organisms--offers many exciting possibilities for the future from organic computers to improved aquaculture. Commercial researchers are using the microgravity environment to produce large near perfect protein crystals Research on insulin has yielded crystals that far surpass the quality of insulin crystals grown on the ground. Using these crystals industry partners are working to develop new and improved treatments for diabetes. Other researchers are exploring the possibility of producing antibiotics using plant cell cultures which could lead to both orbital production and the improvement of ground-based antibiotic production.

  11. Effect of Salsalate on Insulin Action, Secretion, and Clearance in Nondiabetic, Insulin-Resistant Individuals: A Randomized, Placebo-Controlled Study

    PubMed Central

    Liu, Alice; Ariel, Danit; Abbasi, Fahim; Lamendola, Cindy; Grove, Kaylene; Tomasso, Vanessa; Ochoa, Hector; Reaven, Gerald

    2014-01-01

    OBJECTIVE Salsalate treatment has been shown to improve glucose homeostasis, but the mechanism remains unclear. The aim of this study was to evaluate the effect of salsalate treatment on insulin action, secretion, and clearance rate in nondiabetic individuals with insulin resistance. RESEARCH DESIGN AND METHODS This was a randomized (2:1), single-blind, placebo-controlled study of salsalate (3.5 g daily for 4 weeks) in nondiabetic individuals with insulin resistance. All individuals had measurement of glucose tolerance (75-g oral glucose tolerance test), steady-state plasma glucose (SSPG; insulin suppression test), and insulin secretion and clearance rate (graded-glucose infusion test) before and after treatment. RESULTS Forty-one individuals were randomized to salsalate (n = 27) and placebo (n = 14). One individual from each group discontinued the study. Salsalate improved fasting (% mean change −7% [95% CI −10 to −14] vs. 1% [−3 to 5], P = 0.005) but not postprandial glucose concentration compared with placebo. Salsalate also lowered fasting triglyceride concentration (−25% [−34 to −15] vs. −6% [−26 to 14], P = 0.04). Salsalate had no effect on SSPG concentration or insulin secretion rate but significantly decreased insulin clearance rate compared with placebo (−23% [−30 to −16] vs. 3% [−10 to 15], P < 0.001). Salsalate was well tolerated, but four individuals needed a dose reduction due to symptoms. CONCLUSIONS Salsalate treatment in nondiabetic, insulin-resistant individuals improved fasting, but not postprandial, glucose and triglyceride concentration. These improvements were associated with a decrease in insulin clearance rate without change in insulin action or insulin secretion. PMID:24963111

  12. Interference with Akt signaling pathway contributes curcumin-induced adipocyte insulin resistance.

    PubMed

    Zhang, Deling; Zhang, Yemin; Ye, Mao; Ding, Youming; Tang, Zhao; Li, Mingxin; Zhou, Yu; Wang, Changhua

    2016-07-01

    Previous study has shown that curcumin directly or indirectly suppresses insulin signaling in 3T3-L1 adipocytes. However, the underlying mechanism remains unclear. Here we experimentally demonstrate that curcumin inhibited the ubiquitin-proteasome system (UPS) function, activated autophagy, and reduced protein levels of protein kinase B (Akt) in a dose- and time-dependent manner in 3T3-L1 adipocytes, accompanied with attenuation of insulin-stimulated Akt phosphorylation, plasma membrane translocation of glucose transporter type 4 (GLUT4), and glucose uptake. These in vitro inhibitory effects of curcumin on Akt protein expression and insulin action were reversed by pharmacological and genetic inhibition of autophagy but not by inhibition of the UPS and caspases. In addition, Akt reduction in adipose tissues of mice treated with curcumin could be recovered by administration of autophagy inhibitor bafilomycin A1 (BFA). This new finding provides a novel mechanism by which curcumin induces insulin resistance in adipocytes. PMID:27113027

  13. Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease.

    PubMed

    Salameh, Therese S; Rhea, Elizabeth M; Banks, William A; Hanson, Angela J

    2016-09-01

    An increased risk for Alzheimer's disease is associated with dyslipidemia and insulin resistance. A separate literature shows the genetic risk for developing Alzheimer's disease is strongly correlated to the presence of the E4 isoform of the apolipoprotein E carrier protein. Understanding how apolipoprotein E carrier protein, lipids, amyloid β peptides, glucose, central nervous system insulin, and peripheral insulin interact with one another in Alzheimer's disease is an area of increasing interest. Here, we will review the evidence relating apolipoprotein E carrier protein, lipids, and insulin action to Alzheimer's disease and Aβ peptides and then propose mechanisms as to how these factors might interact with one another to impair cognition and promote Alzheimer's disease. PMID:27470930

  14. Limited theraputic effect of n-acetylcysteine on hepatic insulin resistance in an experimental model of alcohol-induced steatohepatitis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Alcohol-related steatohepatitis is associated with increased oxidative stress, DNA damage, lipotoxicity, and insulin resistance in liver. Hypothesis: Since inflammation and oxidative stress can promote insulin resistance, effective treatment with anti-oxidants, e.g. N-acetylcysteine (NAC), may rest...

  15. Leptin receptor polymorphisms interact with polyunsaturated fatty acids to augment risk of insulin resistance and metabolic syndrome in adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The leptin receptor (LEPR) is associated with insulin resistance, a key feature of metabolic syndrome (MetS). Gene-fatty acid interactions may affect MetS risk. The objective was to investigate the relationship among LEPR polymorphisms, insulin resistance, andMetSrisk and whether plasma fatty acids,...

  16. Greater physical activity levels during pregnancy are associated with lower inflammation and insulin resistance in obese women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Compared to lean pregnant women, obese women develop greater insulin resistance and systemic inflammation during pregnancy. Identifying lifestyle factors that can reduce the metabolic effect of obesity during pregnancy is critical to protect both the mother and the fetus from insulin resistance and ...

  17. Vitamin D Status Is Negatively Correlated with Insulin Resistance in Chinese Type 2 Diabetes.

    PubMed

    Zhang, Jie; Ye, Jianhong; Guo, Gang; Lan, Zhenhao; Li, Xing; Pan, Zhiming; Rao, Xianming; Zheng, Zongji; Luo, Fangtao; Lin, Luping; Lin, Zhihua; Xue, Yaoming

    2016-01-01

    Objectives. Vitamin D deficiency plays a role in insulin resistance and the pathogenesis of type 2 diabetes mellitus. Little information is available about the association between vitamin D status and insulin resistance in the Chinese population. Currently, vitamin D status is evaluated by the concentrations of serum 25-hydroxyvitamin D [25(OH)D]. This study explores the relationship between insulin resistance and serum 25-hydroxyvitamin D concentrations in Chinese patients with type 2 diabetes mellitus. Subjects and Methods. This study included 117 patients with type 2 diabetes. The following variables were measured: 25-hydroxyvitamin D [25(OH)D], glycosylated hemoglobin A1c (HbA1c), fasting blood glucose (FBS), fasting blood insulin (FINS), fasting blood C-peptide, serum creatinine (SCr), glomerular filtration rate (eGFR), body mass index (BMI), and homeostatic model estimates of insulin resistance (HOMA-IR). Results. The cases were divided into three groups: Group 1 (G1) with 25(OH)D ≤ 20 ng/mL [≤50 nmol/L], Group 2 (G2) with 25(OH)D values from 20 ng/mL [50 nmol/L] to 30 ng/mL [75 nmol/L], and Group 3 (G3) with 25(OH)D ≥ 30 ng/mL [≥75 nmol/L], with 52.6%, 26.3%, and 21.1% of subjects in Groups 1-3, respectively. There was a negative correlation between 25(OH)D and HOMA-IR (β = -0.314, p = 0.001) adjusted by age, BMI, and eGFR. Conclusion. Better vitamin D status may be protective of glucose homeostasis since 25(OH)D was negatively associated with insulin resistance in Chinese patients with type 2 diabetes. PMID:27413370

  18. Levocetirizine ameliorates high fructose diet-induced insulin resistance, vascular dysfunction and hepatic steatosis in rats.

    PubMed

    Shawky, Noha M; Shehatou, George S G; Abdel Rahim, Mona; Suddek, Ghada M; Gameil, Nariman M

    2014-10-01

    This study investigates the possible protective effects of levocetirizine against fructose-induced insulin resistance, hepatic steatosis and vascular dysfunction, in comparison to pioglitazone, a standard insulin sensitizer. Male Sprague Dawley rats (150-200 g) were divided into 4 groups. Three groups were fed on high fructose diets (HFD) containing 60% w/w fructose, while the fourth control group was fed on standard laboratory food for 8 weeks. AUCOGTT, AUCITT, fasting glucose, HOMA-IR, hepatic glutathione (GSH) and malondialdehyde (MDA) levels, serum total cholesterol, LDL-C, C-reactive protein (CRP) level and lactate dehydrogenase (LDH) activit