Modulation Of Insulin Action Research Articles

The genetic and dietary landscape of the muscle insulin signalling network.

Metabolic disease is caused by a combination of genetic and environmental factors, yet few studies have examined how these factors influence signal transduction, a key mediator of metabolism. Using mass spectrometry-based phosphoproteomics, we quantified 23,126 phosphosites in skeletal muscle of five genetically distinct mouse strains in two dietary environments, with and without acute in vivo insulin stimulation. Almost half of the insulin-regulated phosphoproteome was modified by genetic background on an ordinary diet, and high-fat high-sugar feeding affected insulin signalling in a strain-dependent manner. Our data revealed coregulated subnetworks within the insulin signalling pathway, expanding our understanding of the pathway's organisation. Furthermore, associating diverse signalling responses with insulin-stimulated glucose uptake uncovered regulators of muscle insulin responsiveness, including the regulatory phosphosite S469 on Pfkfb2, a key activator of glycolysis. Finally, we confirmed the role of glycolysis in modulating insulin action in insulin resistance. Our results underscore the significance of genetics in shaping global signalling responses and their adaptability to environmental changes, emphasising the utility of studying biological diversity with phosphoproteomics to discover key regulatory mechanisms of complex traits.

The genetic and dietary landscape of the muscle insulin signalling network

Metabolic disease is caused by a combination of genetic and environmental factors, yet few studies have examined how these factors influence signal transduction, a key mediator of metabolism. Using mass spectrometry-based phosphoproteomics, we quantified 23,126 phosphosites in skeletal muscle of five genetically distinct mouse strains in two dietary environments, with and without acute in vivo insulin stimulation. Almost half of the insulin-regulated phosphoproteome was modified by genetic background on an ordinary diet, and high-fat high-sugar feeding affected insulin signalling in a strain-dependent manner. Our data revealed coregulated subnetworks within the insulin signalling pathway, expanding our understanding of the pathway’s organisation. Furthermore, associating diverse signalling responses with insulin-stimulated glucose uptake uncovered regulators of muscle insulin responsiveness, including the regulatory phosphosite S469 on Pfkfb2, a key activator of glycolysis. Finally, we confirmed the role of glycolysis in modulating insulin action in insulin resistance. Our results underscore the significance of genetics in shaping global signalling responses and their adaptability to environmental changes, emphasising the utility of studying biological diversity with phosphoproteomics to discover key regulatory mechanisms of complex traits.

Skeletal muscle integrin expression in non-obese men with varying degrees of insulin sensitivity.

The remodeling of skeletal muscle extracellular matrix (ECM) components is related to the degree of insulin resistance (IR). Membrane receptors such as integrins provide two-way signaling ("inside-out" and "outside-in" signaling) between ECM components of skeletal muscle (e.g., collagen, laminin, fibronectin) and intracellular signaling pathways. The aim of the study was to analyze the relationship between the expression of integrins in skeletal muscle and insulin sensitivity (IS) in young, healthy, non-obese volunteers. We studied 36 healthy non-obese male participants. Subjects were divided into three subgroups on the basis of the hyperinsulinemic-euglycemic clamp: upper IS tertile, medium IS tertile, and lower IS tertile. Vastus lateralis muscle biopsies were performed before each clamp. Next, analysis of integrin mRNA expression was performed. Waist circumference, percent body fat, fasting serum insulin, total cholesterol, triglycerides and LDL-cholesterol were higher in the lower IS tertile subgroup compared to the other two subgroups (p < 0.05). The lower IS tertile showed increased expression of ITGA5, ITGA6, ITGA7, SPARC (p < 0.05) in comparison with the upper IS tertile and ITGA6 (p < 0.05) compared to the medium IS tertile. ITGA2, ITGA3, ITGA5, ITGA6, ITGA7, SPARC correlated inversely with IS (p < 0.05). Skeletal muscle integrin are associated with low IS in healthy nonobese men. Our data suggest that factors associated with ECM in muscle may be involved in modulation of insulin action even at the early stages of the development of IR.

Skeletal muscle RUNX1 is related to insulin sensitivity through its effect on myogenic potential.

Skeletal muscle is the major site of insulin action. There are limited data on the relationship between insulin action and skeletal muscle myogenic/regenerative potential. RUNX1 is a transcription factor which plays a role in muscle development and regeneration. The aim of our study was to assess the role of skeletal muscle myogenic/regenerative potential in the development of insulin resistance through the studies on RUNX1 transcription factor. This study is a cross-sectional study. Experimental part with myoblast cell line culture. We examined 41 young healthy volunteers, 21 normal weight and 20 with overweight or obesity. Hyperinsulinemic-euglycemic clamp and vastus lateralis muscle biopsy were performed. In L6 myoblast and human skeletal muscle myoblasts (hSkMM) cell cultures, RUNX1 was silenced at two stages of development. Cell growth, the expression of markers of myogenesis, nuclei fusion index, Akt phosphorylation and glucose uptake were measured. Skeletal muscle RUNX1 expression was decreased in overweight/obese individuals in comparison with normal-weight individuals and was positively related to insulin sensitivity, independently of BMI. Runx1 loss-of-function at the stage of myoblast inhibited myoblast proliferation and differentiation and reduced insulin-stimulated Akt phosphorylation and insulin-stimulated glucose uptake. In contrast, Runx1 knockdown in myotubes did not affect Akt phosphorylation, glucose uptake and other parameters studied. Myogenic/regenerative potential of adult skeletal muscle may be an important determinant of insulin action. Our data suggest that muscle RUNX1 may play a role in the modulation of insulin action through its effect on myogenesis.

145-OR: Selenite Treatment Impacts Adipocyte Metabolism and Counteracts Detrimental Effects of Diet-Induced Insulin Resistance

The loss of insulin receptor (IR) in white adipose tissue (WAT) is a feature of type 2 diabetes. Previously, we have demonstrated that feeding mice a preventive selenium rich HFD (SRHFD) , while not influencing obesity development, counteracted diet-induced downregulation of IR and insulin resistance. This was caused by selenite-induced Glutathione peroxidase 3 (GPx3) , which enhanced IR expression and concomitant whole-body insulin sensitivity. The positive correlation between GPX3 and IR levels was also present in humans. In the current study, we investigate A) which selenite (Se) transporter is responsible for the beneficial Se-induced metabolism of WAT using of 3T3-L1 cells, and B) the potential therapeutic effect of selenite supplementation in diet-induced obese mice. We find that LDL Receptor Related Protein (LRP) 8 is necessary for Se-induced upregulation of GPx3 and IR expression to modulate insulin action, as siRNA mediated LRP8 knockdown in 3T3-L1 cells abrogates Se-induced insulin-sensitizing effects with e.g. reduced GPx3 and IR expression. To assess the metabolic effect of selenite supplementation in diet-induced obese mice, C57BL/6N mice received a HFD for 6 weeks, which was followed by a SRHFD for further 12 weeks. Unexpectedly, feeding obese mice a SRHFD resulted in a 10% increase in body weight gain compared to the HFD-fed control group. Nevertheless, these mice exhibited signs of improved metabolism with a shift towards smaller adipocytes, as indicator of improved adipocyte metabolism, and decreased plasma insulin levels. Yet, this was accompanied by unaltered inflammation, GPx3 and IR expression. In conclusion, our data suggest that LRP8 represents a novel Se-transporter in adipocytes controlling insulin sensitivity and that established obesity precludes the beneficial increase of Se-induced GPx3 and IR regulation in WAT, highlighting the potential importance of GPx3 as a mediator of adipose tissue insulin sensitivity. Disclosure R.Hauffe: None. M.Rath: None. A.Kleinridders: Other Relationship; Novozymes. Funding Deutsche Forschungsgemeinschaft (KL 2399/4-1) German Ministry of Education and Research BMBF (82DZD00302)

Assessment of Adiponectin and Resistin Indexes Compared to FBG and Useful as Diagnostic Biomarkers in Insulin Resistance and Type 2 Diabetes

Abstract:&#x0D; Background and aim: The world prevalence of diabetes among adults will be 6.4%, affecting 285 million adults, in year 2010, and will increase to 7.7% and 439 million adults by year 2030. Insulin resistance is a prerequisite root factor for development of type 2 diabetes (T2DM). 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),&#x0D; Methods: In this case control study, A total 204 Sudanese males and females were recruited to participate in this study (102 diabetic and 102 non-diabetic) and venous blood samples were collected. Serum levels of blood glucose were measured using the particle-enhanced immunoturbidimetric assay method Cobas C-311®.While Adiponectin and Resistine estimated by ELISA Kits.&#x0D; Results: In this results shows significant difference between the means fasting blood glucose (FBG), adiponectin, resistine of diabetic patient and non-diabetic patient. FBG (mean + SD) (164.5 ± 16.7) versus (95.7 ± 13.6), P = 0.041, adiponectin (mean + SD) (5.9 ± 1.6) versus (10.1 ± 1.3), P = 0.037, resistine (mean + SD) (18.2 ± 2.7) versus (12.2 ± 1.1), P = 0.023. In this study, observed from this results strong negative Correlation between the levels of serum Adiponectin and Fasting Blood Glucose, Adiponectin and Resistine. (P.value = 0.013, r = -7.9). (P.value = 0.019, r = -6.6). While showing in the other side moderate positive Correlation between the levels of serum Resistine and Fasting Blood Glucose. (P.value = 0.015, r = 6.0).&#x0D; Conclusion: Iccrease of Resistine and Fasting Blood Glucose and reduced of Adiponectin in diabetic patient compare to non-diabetic patient can be useful as diagnostic biomarkers.&#x0D; Keywords: Adiponectin and Resistin, insulin resistance, type 2 diabetes

The Role of Physical Activity in Nonalcoholic and Metabolic Dysfunction Associated Fatty Liver Disease.

Sedentary behavior constitutes a pandemic health threat contributing to the pathophysiology of obesity and type 2 diabetes (T2D). Sedentarism is further associated with liver disease and particularly with nonalcoholic/metabolic dysfunction associated fatty liver disease (NAFLD/MAFLD). Insulin resistance (IR) represents an early pathophysiologic key element of NAFLD/MAFLD, prediabetes and T2D. Current treatment guidelines recommend regular physical activity. There is evidence, that physical exercise has impact on a variety of molecular pathways, such as AMP-activated protein kinase and insulin signaling as well as glucose transporter 4 translocation, modulating insulin action, cellular substrate flow and in particular ectopic lipid and glycogen storage in a positive manner. Therefore, physical exercise can lead to substantial clinical benefit in persons with diabetes and/or NAFLD/MAFLD. However, experience from long term observational studies shows that the patients’ motivation to exercise regularly appears to be a major limitation. Strategies to integrate everyday physical activity (i.e., nonexercise activity thermogenesis) in lifestyle treatment schedules might be a promising approach. This review aggregates evidence on the impact of regular physical activity on selected molecular mechanisms as well as clinical outcomes of patients suffering from IR and NAFLD/MAFLD.

Dynamic interplay between AfadinS1795 phosphorylation and diet regulates glucose homeostasis in obese mice.

Afadin is a ubiquitously expressed scaffold protein with a recently discovered role in insulin signalling and glucose metabolism. Insulin-stimulated phosphorylation of Afadin at S1795 occurs in insulin-responsive tissues such as adipose tissue, muscle, liver, pancreas and heart. Afadin abundance and AfadinS1795 phosphorylation are dynamically regulated in metabolic tissues during diet-induced obesity progression. Genetic silencing of AfadinS1795 phosphorylation improves glucose homeostasis in the early stages of diet-induced metabolic dysregulation. AfadinS1795 phosphorylation contributes to the early development of obesity-related complications in mice. Obesity is associated with systemic insulin resistance and numerous metabolic disorders. Yet, the mechanisms underlying impaired insulin action during obesity remain to be fully elucidated. Afadin is a multifunctional scaffold protein with the ability to modulate insulin action through its phosphorylation at S1795 in adipocytes. In the present study, we report that insulin-stimulated AfadinS1795 phosphorylation is not restricted to adipose tissues, but is a common signalling event in insulin-responsive tissues including muscle, liver, pancreas and heart. Furthermore, a dynamic regulation of Afadin abundance occurred during diet-induced obesity progression, while its phosphorylation was progressively attenuated. To investigate the role of AfadinS1795 phosphorylation in the regulation of whole-body metabolic homeostasis, we generated a phospho-defective mouse model (Afadin SA) in which the Afadin phosphorylation site was silenced (S1795A) at the whole-body level using CRISPR-Cas9-mediated gene editing. Metabolic characterization of these mice under basal physiological conditions or during a high-fat diet (HFD) challenge revealed that preventing AfadinS1795 phosphorylation improved insulin sensitivity and glucose tolerance and increased liver glycogen storage in the early stage of diet-induced metabolic dysregulation, without affecting body weight. Together, our findings reveal that AfadinS1795 phosphorylation in metabolic tissues is critical during obesity progression and contributes to promote systemic insulin resistance and glucose intolerance in the early phase of diet-induced obesity.

Cell-autonomous defects contribute to insulin resistance in skeletal muscle.

Major pathogenesis and signaling underlying cell-autonomous muscle insulin resistance in type2 diabetes.

Defining the underlying defect in insulin action in type 2 diabetes.

Insulin resistance is one of the earliest defects in the pathogenesis of type 2 diabetes. Over the past 50years, elucidation of the insulin signalling network has provided important mechanistic insights into the abnormalities of glucose, lipid and protein metabolism that underlie insulin resistance. In classical target tissues (liver, muscle and adipose tissue), insulin binding to its receptor initiates a broad signalling cascade mediated by changes in phosphorylation, gene expression and vesicular trafficking that result in increased nutrient utilisation and storage, and suppression of catabolic processes. Insulin receptors are also expressed in non-classical targets, such as the brain and endothelial cells, where it helps regulate appetite, energy expenditure, reproductive hormones, mood/behaviour and vascular function. Recent progress in cell biology and unbiased molecular profiling by mass spectrometry and DNA/RNA-sequencing has provided a unique opportunity to dissect the determinants of insulin resistance in type 2 diabetes and the metabolic syndrome; best studied are extrinsic factors, such as circulating lipids, amino acids and other metabolites and exosomal microRNAs. More challenging has been defining the cell-intrinsic factors programmed by genetics and epigenetics that underlie insulin resistance. In this regard, studies using human induced pluripotent stem cells and tissues point to cell-autonomous alterations in signalling super-networks, involving changes in phosphorylation and gene expression both inside and outside the canonical insulin signalling pathway. Understanding how these multi-layered molecular networks modulate insulin action and metabolism in different tissues will open new avenues for therapy and prevention of type 2 diabetes and its associated pathologies.

Serum fetuin-A and Ser312 phosphorylated fetuin-A responses and markers of insulin sensitivity after a single bout of moderate intensity exercise.

Fetuin‐A (Fet‐A), secreted by the liver and adipose tissue, inhibits insulin receptor tyrosine kinase activity and modulates insulin action. Numerous studies have shown association of elevated serum Fet‐A concentrations with obesity, non‐alcoholic fatty liver disease, and type 2 diabetes. Both moderate body weight loss (5%–10%) and significant body weight loss have been shown to decrease serum Fet‐A and improve insulin sensitivity. Currently, there are no studies examining the effects of a single bout of exercise on serum Fet‐A or Ser312‐pFet‐A (pFet‐A) responses. We hypothesized that a single bout of moderate‐intensity exercise will lower serum Fet‐A and that these changes will be associated with an improvement in insulin sensitivity. Thirty‐one individuals with obesity and 11 individuals with normal body weight were recruited. Participants underwent a single bout of treadmill walking, expending 500 kcal at 60%–70% VO2max. Oral glucose tolerance tests (OGTT) were administered before the single bout of exercise (Pre Ex) and 24 h after exercise (24h Post Ex). In individuals with obesity, we observed a transient elevation of serum Fet‐A concentrations, but not pFet‐A, immediately after exercise (Post Ex). Further, a single bout of exercise decreased glucoseAUC, insulinAUC, and insulin resistance index in individuals with obesity. Consistent with this improvement in insulin sensitivity, we observed that Fet‐AAUC, pFet‐AAUC, 2 h pFet‐A, and 2 h pFet‐A/Fet‐A were significantly lower following a single bout of exercise. Further, reductions in serum Fet‐AAUC 24h Post Ex were correlated with a reduction in insulin resistance index. Together, this suggests that alterations in serum Fet‐A following a single bout of moderate‐intensity endurance exercise may play a role in the improvement of insulin sensitivity.Clinical Trial RegistrationNCT03478046; https://clinicaltrials.gov/ct2/show/NCT03478046.

1333-P: The Adipokine Fatty Acid Binding Protein 4 Promotes Glucose Production in Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is characterized by maternal hyperglycemia and insulin resistance that develops during pregnancy. Altered secretion of adipokines that modulate insulin action during pregnancy has been implicated in GDM pathogenesis. FABP4 is an adipokine with an important role in promoting insulin resistance in various animal models. In humans, FABP4 was suggested to regulate systemic metabolism. Although elevated levels of circulating FABP4 were demonstrated in GDM, its differential contribution to GDM pathophysiology is unclear. In this study, we aimed to determine the tissue source of elevated circulating FABP4 levels and to assess FABP4 differential contribution in promoting hepatic glucose production in GDM. We included 71 pregnant women defined as normal glucose tolerant (NGT) and 31 diagnosed with GDM. Maternal level of FABP4 before delivery was measured using ELISA. FABP4 circulating levels were increased in GDM compared to NGT (14.1 IQR: 11.5-21.4 ng/ml vs.10.3 IQR: 6.6-12.4 ng/ml, respectively, p=0.0014), with a rapid post-partum decline in FABP4 levels observed in both groups. Using biopsies of placenta, sub-cutaneous (sWAT) and visceral (vWAT) adipose tissues, we observed that FABP4 is secreted from these tissues during pregnancy. FABP4 secretion from vWAT of GDM women was ? 2 fold higher than that of NGT women. Depletion of FABP4 from vWAT conditioned media of NGT or GDM women using monoclonal antibodies, significantly suppressed glucose production in primary hepatocytes by ? 20% and ? 36%, respectively (p&amp;lt;0.05). Taken together, our data highlight the importance of FABP4 in the pathophysiology of enhanced hepatic glucose production in GDM. Disclosure R. Madah: None. I. Ron Ronen: None. M. Rathaus: None. R. Zemet: None. S. Amazaki Tovi: None. A. Tirosh: Advisory Panel; Self; Abbott, AstraZeneca, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Consultant; Self; DreaMed Diabetes. Research Support; Self; Medtronic. Funding Israeli Diabetes Association

Recurrent implantation failure is associated with increased levels of fetuin-A/alpha2-Heremans-Schmid-glycoprotein

ObjectiveRecurrent implantation failure is defined as the absence of implantation, after two or three consecutive cycles of in-vitro fertilization (IVF), intracytoplasmic sperm injection or frozen embryo replacement. Human fetuin-A/alpha2-Heremans-Schmid-glycoprotein is a plasma protein secreted by the liver that modulates insulin action in adipocytes. Increased fetuin-A promotes adipocyte dysfunction which results in decreased adiponectin and increased fatty acids and inflammatory cytokines. Fatty acids and inflammatory cytokines were previously reported in implantation failure. Also, fetuin-A inhibits receptor tyrosine kinase activity in trophoblast growth factors which decrease trophoblast viability and invasion. In this study, we aimed to find the association between fetuin-A and implantation failure. Study designA total of 78 women were included in this case-control study. Serum fetuin-A concentrations were measured in 42 women with recurrent IVF failure and 36 healthy women with regular cycles. ResultsThe mean serum fetuin-A levels of implantation failure and control women were 257.77 ± 32.18 and 219.59 ± 48.86 respectively with a p-value <0.001 (independent samples t-test). Our results showed a statistically significant difference between serum fetuin-A levels of implantation failure women and controls. ConclusionSo far reasons for implantation failure are only partially understood. The current study reveals the association between implantation failure and fetuin-A. Further studies with large population sizes are needed to investigate whether fetuin-A can be used as a marker before controlled ovarian stimulation began or regulation of fetuin-A levels with treatment or lifestyle interventions can improve implantation success.

A STUDY ON THE CORRELATION OF ADENOSINE DEAMINASE AND GLYCATED HAEMOGLOBIN IN THE PATIENTS OF TYPE 2 DIABETES MELLITUS.

Background &amp; Objectives: Adenosine modulates insulin action on various tissues and its concentration in tissues is affected by Adenosine Deaminase (ADA) levels. ADA is an enzyme involved in purine metabolism and is considered to be a marker of T cell activation. Immunological disturbances in type 2 diabetic individuals have an association with cell mediated responses and inappropriate T-lymphocyte function. Hence, the study was undertaken to determine the levels of Serum ADA activity in patients of type 2 DM and its correlation with parameters of glycemic profile such as Fasting blood sugar (FBS) and Glycated Haemoglobin.&#x0D; Material and Methods- A total of 100 patients diagnosed for type 2 DM visiting the Outpatient Department of General Medicine and Endocrinology at Mahatma Gandhi Medical College &amp; Hospital, Jaipur were enrolled for the study based on predefined inclusion and exclusion criteria. Blood samples were collected for all enrolled patients and analysed for the investigations like Serum BSF, HbA1c and Serum ADA.&#x0D; Results- In the study, BSF, mean HbA1c and serum ADA level was significantly higher in diabetic group in comparison to control group (p=0.000). The diabetic group was subdivided on the basis of HbA1c levels, HbA1c ≤ 8% as good glycemic control and HbA1c &gt; 8% as poor glycemic control. BSF, mean HbA1c and serum ADA levels were observed to be significantly higher in poor glycemic control group as compared to that of good glycemic control. A significant positive correlation between S. ADA and HbA1c activity was also seen (r= 0.388).&#x0D; Conclusion- Increased ADA level can be used to determine the glycemic status in the patients of type 2 DM and serve as a marker for insulin resistance. Hence, by analysing ADA levels in diabetes, glycemic control and insulin resistance can be assessed. Raised ADA levels can be an early indicator of progressive diabetic change and help to take preventive measures for the development of diabetic complication and thereby improving the outcome of the disease.&#x0D; Keywords- Diabetes Mellitus, Adenosine Deaminase, Glycated haemoglobin

Mice lacking angiotensin type 2 receptor exhibit a sex-specific attenuation of insulin sensitivity

The renin-angiotensin system modulates insulin action. Pharmacological stimulation of angiotensin type 2 receptor (AT2R) was shown to have beneficial metabolic effects in various animal models of insulin resistance and type 2 diabetes and also to increase insulin sensitivity in wild type mice. In this study we further explored the role of the AT2R on insulin action and glucose homeostasis by investigating the glycemic profile and in vivo insulin signaling status in insulin-target tissues from both male and female AT2R knockout (KO) mice. When compared to the respective wild-type (WT) group, glycemia and insulinemia was unaltered in AT2RKO mice regardless of sex. However, female AT2RKO mice displayed decreased insulin sensitivity compared to their WT littermates. This was accompanied by a compensatory increase in adiponectinemia and with a specific attenuation of the activity of main insulin signaling components (insulin receptor, Akt and ERK1/2) in adipose tissue with no apparent alterations in insulin signaling in either liver or skeletal muscle. These parameters remained unaltered in male AT2RKO mice as compared to male WT mice. Present data show that the AT2R has a physiological role in the conservation of insulin action in female but not in male mice. Our results suggest a sexual dimorphism in the control of insulin action and glucose homeostasis by the AT2R and reinforce the notion that pharmacological modulation of the balance between the AT1R and AT2R receptor could be important for treatment of metabolic syndrome and type 2 diabetes.

Chronic administration of the angiotensin type 2 receptor agonist C21 improves insulin sensitivity in C57BL/6 mice.

The renin–angiotensin system modulates insulin action. Angiotensin type 1 receptor exerts a deleterious effect, whereas the angiotensin type 2 receptor (AT2R) appears to have beneficial effects providing protection against insulin resistance and type 2 diabetes. To further explore the role of the AT2R on insulin action and glucose homeostasis, in this study we administered C57Bl/6 mice with the synthetic agonist of the AT2R C21 for 12 weeks (1 mg/kg per day; ip). Vehicle‐treated animals were used as control. Metabolic parameters, glucose, and insulin tolerance, in vivo insulin signaling in main insulin‐target tissues as well as adipose tissue levels of adiponectin, and TNF‐α were assessed. C21‐treated animals displayed decreased glycemia together with unaltered insulinemia, increased insulin sensitivity, and increased glucose tolerance compared to nontreated controls. This was accompanied by a significant decrease in adipocytes size in epididymal adipose tissue and significant increases in both adiponectin and UCP‐1 expression in this tissue. C21‐treated mice showed an increase in both basal Akt and ERK1/2 phosphorylation levels in the liver, and increased insulin‐stimulated Akt activation in adipose tissue. This positive modulation of insulin action induced by C21 appeared not to involve the insulin receptor. In C21‐treated mice, adipose tissue and skeletal muscle became unresponsive to insulin in terms of ERK1/2 phosphorylation levels. Present data show that chronic pharmacological activation of AT2R with C21 increases insulin sensitivity in mice and indicate that the AT2R has a physiological role in the conservation of insulin action.

Chronic blockade of the AT2 receptor with PD123319 impairs insulin signaling in C57BL/6 mice

The renin-angiotensin system modulates insulin action. Angiotensin type 1 receptor exerts a deleterious effects while the angiotensin type 2 receptor (AT2R) appears to have beneficial effects providing protection against insulin resistance and type 2 diabetes. Although recent reports indicate that agonism of AT2R ameliorates diabetes and insulin resistance, the phenotype of AT2R-knockout mice seems to be controversial relating this aspect. Thus, in this study we have explored the role of AT2R in the control of insulin action. To that end, C57Bl/6 mice were administered the synthetic AT2R antagonist PD123319 for 21days (10mg/kg/day ip); vehicle treated animals were used as control. Glucose tolerance, metabolic parameters, in vivo insulin signaling in main insulin-target tissues as well as levels of adiponectin, TNF-α, MCP-1 and IL-6 in adipose tissue were assessed. AT2R blockade with PD123319 induced a marginal effect on glucose homeostasis but an important reduction in the insulin-induced phosphorylation of the insulin receptor and Akt in both liver and adipose tissue. Insulin signaling in skeletal muscle remained unaltered after treatment with PD123319, which could explain the minimal effect on glucose homeostasis induced by PD123319. Our current results reinforce the notion that the AT2R has a physiological role in the conservation of insulin action.

Rapamycin negatively impacts insulin signaling, glucose uptake and uncoupling protein-1 in brown adipocytes

New onset diabetes after transplantation (NODAT) is a metabolic disorder that affects 40% of patients on immunosuppressive agent (IA) treatment, such as rapamycin (also known as sirolimus). IAs negatively modulate insulin action in peripheral tissues including skeletal muscle, liver and white fat. However, the effects of IAs on insulin sensitivity and thermogenesis in brown adipose tissue (BAT) have not been investigated. We have analyzed the impact of rapamycin on insulin signaling, thermogenic gene-expression and mitochondrial respiration in BAT. Treatment of brown adipocytes with rapamycin for 16h significantly decreased insulin receptor substrate 1 (IRS1) protein expression and insulin-mediated protein kinase B (Akt) phosphorylation. Consequently, both insulin-induced glucose transporter 4 (GLUT4) translocation to the plasma membrane and glucose uptake were decreased. Early activation of the N-terminal Janus activated kinase (JNK) was also observed, thereby increasing IRS1 Ser 307 phosphorylation. These effects of rapamycin on insulin signaling in brown adipocytes were partly prevented by a JNK inhibitor. In vivo treatment of rats with rapamycin for three weeks abolished insulin-mediated Akt phosphorylation in BAT. Rapamycin also inhibited norepinephrine (NE)-induced lipolysis, the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and uncoupling protein (UCP)-1 in brown adipocytes. Importantly, basal mitochondrial respiration, proton leak and maximal respiratory capacity were significantly decreased in brown adipocytes treated with rapamycin. In conclusion, we demonstrate, for the first time the important role of brown adipocytes as target cells of rapamycin, suggesting that insulin resistance in BAT might play a major role in NODAT development.

Adenosine deaminase activity and zinc levels in the serum of patients with diabetes mellitus

Abstract Objective Adenosine deaminase (ADA) specifically catalyzes the deamination of adenosine which has been proved to play an important role in modulation of insulin action on glucose metabolism. Zinc is an essential micronutrient that is directly involved in the physiology of insulin and may be an important agent to activate the ADA. We aimed to evaluate serum ADA activity, zinc levels and the relationship between these two parameters in diabetes mellitus. Methods We investigated serum ADA activity and zinc levels in type I (n = 100) and type II diabetes mellitus patients (n = 151). Results ADA activities of diabetic patients were significantly elevated, whereas zinc levels were significantly lower than those of healthy controls (p &lt; 0.001). Compared with the well-controlled diabetic patient groups (HbA1c &lt; 7%), the poorly controlled diabetic groups (HbA1c &gt; 8%) showed significantly increased ADA activity (p &lt; 0.001). In contrast, zinc concentrations in the poorly controlled diabetic groups were not significantly different from those in the well-controlled diabetic patients (p = 0.246). Significant positive correlation was observed between ADA activity and HbA1c (r = 0.794). There was no correlation between ADA activity and zinc levels (r = 0.043; p &gt; 0.05). Conclusion Elevated ADA activity in diabetic patients with poor glycemic control may be a useful marker for therapy modulation.

English

An increasing trend of type2 Diabetes mellitus is seen with age. Visceral or central obesity is a very common risk factor for developing type 2 diabetes Mellitus. Hence any index which reliably measures obesity can be used as a tool to predict the risk of Diabetes. We have attempted to correlate waist to hip ratio (WHR) as an anthropometric index to predict the risk of diabetes. When WHR of men is more than 0.9 and women is more than 0.8 the risk increases. MATERIALS & METHODS: 300 diabetic patients (150 males, 150 females) and 300 controls (150 males, 150 females) were selected and their WHR were measured. The study was done in Gandhi medical college over a period of 2 years. Individuals were grouped according to gender and HWR. Data analysis was done by excel sheet and SPSS software. RESULTS: There was significant association between WHR and DM in both males and females. DISCUSSION: Obesity especially visceral leads to insulin resistance and finally DM. This is because adipocytes produce biologic products which modulate insulin action. CONCLUSIONS: Our study proves that HWR screening is a simple and cost effective anthropometric predictor of risk for diabetes. This can be used for mass screening as it is quick and needs less expertise.