Hepatic Insulin Resistance in Obese Non-Diabetic Subjects and in Type 2 Diabetic Patients

Objective: Obese non-diabetic patients are characterized by an extra-hepatic insulin resistance. Whether obese patients also have decreased hepatic insulin sensitivity remains controversial. Research Methods and Procedures: To estimate their hepatic insulin sensitivity, we measured the rate of exogenous insulin infusion required to maintain mildly elevated glycemia in obese patients with type 2 diabetes, obese non-diabetic patients, and lean control subjects during constant infusions of somatostatin and physiological low-glucagon replacement infusions. To account for differences in insulin concentrations among the three groups of subjects, an additional protocol was also performed in healthy lean subjects with higher insulin infusion rates and exogenous dextrose infusion. Results: The insulin infusion rate required to maintain glycemia at 8.5 mM was increased 4-fold in obese patients with type 2 diabetes and 1.5-fold in obese non-diabetic patients. The net endogenous glucose production (measured with 6,6-²H₂-glucose) and total glucose output (measured with 2-²H₁-glucose) were ∼30% lower in the patients than in the lean subjects. Net endogenous glucose production and total glucose output were both markedly increased in both groups of obese patients compared with lean control subjects during hyperinsulinemia. Discussion: Our data indicate that both obese non-diabetic and obese type 2 diabetic patients have a blunted suppressive action of insulin on glucose production, indicating hepatic and renal insulin resistance.     

Regulation of glucose transporter messenger RNA levels in rat adipose tissue by insulin

Analysis of glucose transporter mRNA levels in adipose tissue from streptozotocin (STZ)-induced diabetic rats demonstrated a specific decrease (10-fold) in adipose tissue GLUT-4 mRNA with no significant effect on GLUT-1 mRNA levels. Treatment of STZ-diabetic rats with twice daily injections of insulin for 1-3 days resulted in a 16-fold increase in the relative amount of GLUT-4 mRNA to levels approximately 2-fold greater than those in control animals. However, after 7 days of insulin therapy the amount of GLUT-4 mRNA decreased approximately 2-fold back to the levels in the control animals. Normalization of the STZ-induced serum hyperglycemia by phlorizin treatment, which inhibits renal tubular reabsorption of glucose, had no effect on GLUT-4 mRNA in the absence of insulin. Similar to STZ-diabetes, fasting for 48 h also reduced adipose GLUT-4 mRNA levels. Parenteral administration of insulin with glucose over 7.5 h, but not glucose alone, increased the levels of the GLUT-4 mRNA 3- to 4-fold. These studies demonstrate that the relative glycemic state does not influence GLUT-4 glucose transporter mRNA expression in vivo and strongly suggests that insulin is a major factor regulating the levels of GLUT-4 mRNA in adipose tissue.     

Retinol‐binding Protein 4 (RBP4) Protein Expression Is Increased in Omental Adipose Tissue of Severely Obese Patients

Visceral fat has been linked to insulin resistance and type 2 diabetes mellitus (T2DM); and emerging data links RBP4 gene expression in adipose tissue with insulin resistance. In this study, we examined RBP4 protein expression in omental adipose tissue obtained from 24 severely obese patients undergoing bariatric surgery, and 10 lean controls (4 males/6 females, BMI = 23.2 ± 1.5 kg/m²) undergoing elective abdominal surgeries. Twelve of the obese patients had T2DM (2 males/10 females, BMI: 44.7 ± 1.5 kg/m²) and 12 had normal glucose tolerance (NGT: 4 males/8 females, BMI: 47.6 ± 1.9 kg/m²). Adipose RBP4, glucose transport protein‐4 (GLUT4), and p85 protein expression were determined by western blot. Blood samples from the bariatric patients were analyzed for serum RBP4, total cholesterol, triglycerides, and glucose. Adipose RBP4 protein expression (NGT: 11.0 ± 0.6; T2DM: 11.8 ± 0.7; lean: 8.7 ± 0.8 arbitrary units) was significantly increased in both NGT (P = 0.03) and T2DM (P = 0.005), compared to lean controls. GLUT4 protein was decreased in both NGT (P = 0.02) and T2DM (P = 0.03), and p85 expression was increased in T2DM subjects, compared to NGT (P = 0.03) and lean controls (P = 0.003). Regression analysis showed a strong correlation between adipose RBP4 protein and BMI for all subjects, as well as between adipose RBP4 and fasting glucose levels in T2DM subjects (r = 0.76, P = 0.004). Further, in T2DM, serum RBP4 was correlated with p85 expression (r = 0.68, P = 0.01), and adipose RBP4 protein trended toward an association with p85 protein (r = 0.55, P = 0.06). These data suggest that RBP4 may regulate adiposity, and p85 expression in obese‐T2DM, thus providing a link to impaired insulin signaling and diabetes in severely obese patients.     

Increased Levels of Plasma Acylcarnitines in Obesity and Type 2 Diabetes and Identification of a Marker of Glucolipotoxicity

Dysregulation of fatty acid oxidation (FAO) is recognized as important in the pathophysiology of obesity and insulin resistance (IR). However, demonstrating FAO defects in vivo in humans has entailed complex and invasive methodologies. Recently, the identification of genetic blocks in FAO has been vastly simplified by using tandem mass spectrometry (MS/MS) of dried bloodspots to specify acylcarnitine (AcylCN) alterations characteristic for each disorder. This technology has recently been applied to examine FAO alterations in human and animal models of obesity and type 2 diabetes mellitus (T2DM). This study focused on characterizing AcylCN profiles in human plasma from individuals with obesity and T2DM during fasting and insulin‐stimulated conditions. Following an overnight fast, plasma was obtained from lean (n = 12), obese nondiabetic (n = 14), and T2DM (n = 10) participants and analyzed for AcylCN using MS/MS. Plasma samples were also obtained at the end of a 4‐h insulin‐stimulated euglycemic clamp. In obesity and T2DM, long‐chain AcylCNs were similarly significantly increased in the fasted state; free‐CN levels were also elevated. Additionally, T2DM subjects of comparable BMI had increased short‐ and medium‐chain AcylCNs, both saturated and hydroxy, as well as increased C₄‐dicarboxylcarnitine (C₄DC–CN) that correlated with an index of poor glycemic control (HbA_1c; r = 0.74; P < 0.0001). Insulin infusion reduced all species of plasma AcylCN but this reduction was blunted in T2DM. Plasma long‐chain AcylCN species are increased in obesity and T2DM, suggesting that more fatty acids can enter mitochondria. In T2DM, many shorter species accumulate, suggesting that they have a generalized complex oxidation defect.     

Restoration of acute insulin response in T2DM subjects 1 month after biliopancreatic diversion

Objective: Biliopancreatic diversion (BPD) restores normal glucose tolerance in a few weeks in morbid obese subjects with type 2 diabetes, improving insulin sensitivity. However, there is less known about the effects of BPD on insulin secretion. We tested the early effects of BPD on insulin secretion in obese subjects with and without type 2 diabetes. Methods and Procedures: Twenty‐one consecutive morbid obese subjects, 9 with type 2 diabetes (T2DM) and 12 with normal fasting glucose (NFG) were evaluated, just before and 1 month after BPD, by measuring body weight (BW), glucose, adipocitokines, homeostasis model assessment of insulin resistance (HOMA‐IR), acute insulin response (AIR) to e.v. glucose and the insulinogenic index adjusted for insulin resistance ([ΔI5/ΔG5]/HOMA‐IR). Results: Preoperatively, those with T2DM differed from those with NFG in showing higher levels of fasting glucose, reduced AIR (57.9 ± 29.5 vs. 644.9 ± 143.1 pmol/l, P < 0.01) and reduced adjusted insulinogenic index (1.0 ± 0.5 vs. 17.6 ± 3.9 1/mmol², P < 0.001). One month following BPD, in both groups BW was reduced (by ～11%), but all subjects were still severely obese; HOMA‐IR and leptin decreased significanlty, while high‐molecular weight (HMW) adiponectin and adjusted insulinogenic index increased. In the T2DM group, fasting glucose returned to non‐diabetic values. AIR did not change in the NFG group, while in the T2DM group it showed a significant increase (from 58.0 ± 29.5 to 273.8 ± 47.2 pmol/l, P < 0.01). In the T2DM group, the AIR percentage variation from baseline was significantly related to changes in fasting glucose (r = 0.70, P = 0.02), suggesting an important relationship exists between impaired AIR and hyperglycaemia. Discussion: BPD is able to restore AIR in T2DM even just 1 month after surgery. AIR restoration is associated with normalization of fasting glucose concentrations.     

Pathophysiological correlation of arginase-1 in development of type 2 diabetes from obesity in adolescents

BackgroundThere is great interest to understand causal pathophysiological correlation between obesity and diabetes mellitus (DM). Vascular endothelial dysfunction is crucially involved in pathogenesis of vascular complications in DM. Recently, increased arginase expression and activity have been described as underlying mechanisms of endothelial dysfunction in DM and vascular inflammation in obesity. By limiting L-arginine bioavailability to endothelial nitric oxide synthase (NOS III), nitric oxide production is potentially impaired.MethodsWe investigated the impact of plasma from diabetic and obese adolescents on arginase and NOS III expression in cultured human endothelial cells (ECs). A total of 148 male adolescents participated in this study including 18 obese, 28 type 1-, 28 type 2-DM patients, and 74 age-matched healthy volunteers.ResultsA concurrent increase in arginase-1 (1.97-fold) and decrease in NOS III expression (1.45-fold) was observed in ECs exposed to type 2 diabetic plasma compared to control subjects. ECs incubated with type 1 DM plasma had a diminished NOS III level without impact on arginase-1 expression. Urea-assay featured an increased arginase activity in treated ECs with type 1- or 2-DM plasma. Despite increased pro-inflammatory cytokines and chemokines in obese plasma, arginase-1 expression/activity did not change in treated ECs. However, NOS III expression was significantly reduced. Pearson analysis revealed positive correlation between arginase-1, but not NOS III, expression with FBS in ECs treated with type 2-DM plasma.ConclusionsOur data demonstrate that increased arginase-1 expression/activity in ECs, as critical pathogenic factor is correlated with development of obesity-related type 2-DM and linked vascular disease.     

Fasting-based estimates of insulin sensitivity in overweight and obesity: a critical appraisal

Objective: To identify simple methods to estimate the degree of insulin resistance. Research Methods and Procedures: The performance of a wide range of fasting‐based index estimates of insulin sensitivity was compared by receiver operating characteristic analysis (area under curves and their 95% confidence intervals) against the M value from euglycemic insulin clamp studies collected in the San Antonio (non‐Hispanic whites and Hispanic residents of San Antonio, TX) and European Group for the Study of Insulin Resistance (non‐diabetic white Europeans) databases (n = 638). Results: Insulin resistance differed substantially between lean (BMI < 25 kg/m²), overweight or obese (BMI ≥ 25 kg/m²), and type 2 diabetic individuals. Estimates of insulin resistance were, therefore, assessed in each group separately. In the overweight and obese subgroup (n = 302), the receiver operating characteristic performance of fasting‐based indices varied from 0.72 (0.62 to 0.82), in the case of the insulin/glucose ratio, to 0.80 (0.72 to 0.88) in the case of Belfiore free fatty acids. One superior method could not be identified; the confidence intervals overlapped, and no statistically significant differences emerged. All indices performed better when using the whole study population, with fasting plasma insulin, homeostatic model assessment, insulin/glucose ratio, quantitative insulin sensitivity check index, glucose/insulin ratio, Belfiore glycemia, revised quantitative insulin sensitivity check index, McAuley index, and Belfiore free fatty acids showing area under curves of 0.83, 0.90, 0.66, 0.90, 0.66, 0.90, 0.85, 0.83, and 0.86, respectively, because of the inclusion of very insulin sensitive (lean) and very insulin resistant cases (diabetic subjects). Discussion: In conclusion, a superior fasting‐based index estimate to distinguish between the presence and absence of insulin resistance in overweight and obesity could not be identified despite the use of the large datasets.     

Elevated circulating vaspin levels were decreased by rosiglitazone therapy in T2DM patients with poor glycemic control on metformin alone

Vaspin has been regarded as a novel adipokine with potential insulin sensitizing properties. The aim of the present study is to investigate the effects of rosiglitazone therapy on plasma vaspin in type 2 diabetes patients (T2DM) inadequately controlled on metformin alone. A total of 105 subjects, including 37 subjects with normal glucose tolerance (NGT), 37 subjects with impaired glucose regulating (IGR), and 31 T2DM patients with poor glycemic control on metformin alone were enrolled in this study. Fasting plasma vaspin levels were higher in T2DM patients with poor glycemic control than that in IGR and NGT groups (1.19 ± 0.74 vs. 0.46 ± 0.26 and 0.54 ± 0.28 μg/L, P < 0.05). There was no difference between IGR and NGT groups. In T2DM patients, fasting plasma vaspin concentrations were significantly decreased after rosiglizatone therapy for 12 weeks (1.19 ± 0.74 vs. 0.91 ± 0.54 μg/L, P < 0.05), accompanied with significant amelioration of insulin sensitivity and glucose control. Plasma vaspin levels were positively associated with the fasting insulin and the homeostasis model assessment of IR (HOMA-IR). In conclusion, plasma vaspin level is higher in T2DM patients with poor glycemic control. And rosiglitazone therapy decreased plasma vaspin levels through glucose and insulin sensitivity regulation.     

Carnitine acetyltransferase: A new player in skeletal muscle insulin resistance?

Carnitine acetyltransferase (CRAT) deficiency has previously been shown to result in muscle insulin resistance due to accumulation of long-chain acylcarnitines. However, differences in the acylcarnitine profile and/or changes in gene expression and protein abundance of CRAT in myotubes obtained from obese patients with type 2 diabetes mellitus (T2DM) and glucose-tolerant obese and lean controls remain unclear. The objective of the study was to examine whether myotubes from obese patients with T2DM express differences in gene expression and protein abundance of CRAT and in acylcarnitine species pre-cultured under glucose and insulin concentrations similar to those observed in healthy individuals in the over-night fasted, resting state. Primary myotubes obtained from obese persons with or without T2DM and lean controls (n=9 in each group) were cultivated and harvested for LC-MS-based profiling of acylcarnitines. The mRNA expression and protein abundance of CRAT were determined by qPCR and Western Blotting, respectively. Our results suggest that the mRNA levels and protein abundance of CRAT were similar between groups. Of the 14 different acylcarnitine species measured by LC-MS, the levels of palmitoylcarnitine (C16) and octadecanoylcarnitine (C18) were slightly reduced in myotubes derived from T2DM patients (p<0.05) compared to glucose-tolerant obese and lean controls. This suggests that the CRAT function is not the major contributor to primary insulin resistance in cultured myotubes obtained from obese T2DM patients.     

Impact of curcumin treatment on diabetic albino rats

The current study was aimed to study the effect of curcumin on the expression levels of brain glucose transporter 1 protein (GLUT1) and femoral muscle glucose transporter 4 protein (GLUT4), in addition to study its possible therapeutic role in ameliorating insulin resistance and the metabolic disturbance in the obese and type 2 diabetic male albino Wistar rat model. Diabetes was induced by a high-fat (HF) diet with low dose streptozotocin (STZ). Curcumin was administered intragastrically for 8 weeks (80 mg/kg BW/day). The HF-diet group developed obesity, hyperglycemia, hyperinsulinemia, reduced liver glycogen content with significant dyslipidemia. In the diabetic control group, hyperglycemia and insulin resistance high calculated homeostasis model assessment (HOMA-IR-index score) were pronounced, with reductions in liver and muscle glycogen contents, concomitant with dyslipidemia and significantly elevated malondialdehyde levels in liver and pancreas. GLUT1 and GLUT4 were down-regulated in the obese and the diabetic control groups, respectively. Curcumin, showed glucose-lowering effect and decreased insulin resistance, dyslipidemia and malondialdehyde levels in both tissues, it increased liver & muscle glycogen contents, compared to the diabetic control. Curcumin significantly up-regulated GLUT4 gene expression, compared to the diabetic control group. In conclusions, these results indicate a therapeutic role of curcumin in improving the diabetic status, obesity and enhancing the expression of GLUT4 gene.     

Amylin effect in extrapancreatic tissues participating in glucose homeostasis, in normal, insulin-resistant and type 2 diabetic state

Amylin is co-secreted with insulin, responds to the same stimuli, is anorectic, lowers body weight by reducing fat mass, and is proposed for diabetes treatment. We examined the effect of a 3-day constant infusion of close to physiological doses of amylin in Wistar rats, on glucotransporter expression, glycogen content (G), glycogen synthase a activity (GSa) and glucose transport (GT), in liver, muscle and fat from insulin resistant (IR) and type 2 diabetic (T2D) models, compared to normal (N) animals; plasma glucose and insulin were measured. Plasma insulin in IR was higher than in N or T2D, and amylin normalized the value. In both, IR and T2D, liver G was lower than normal, accompanied by GLUT-2, mRNA and protein, higher and lower, respectively, than in N; amylin normalized G in both groups, without changes in GLUT-2, except for an mRNA increase in T2D. In IR and T2D, muscle GSa was reduced, together with respective over- and under-GLUT-4 expression; amylin induced only a trend toward GSa normalization in both groups. In isolated adipocytes, GT and GLUT-4 in IR and T2D were lower and higher, respectively, than in N; after amylin, not only GT was normalized in both groups but also the response to insulin was much more pronounced, including that in N, without major changes in GLUT-4. This suggests that the beneficial effect of amylin in states running with altered glucose homeostasis could occur by partially acting on the hexose metabolism of the liver and mainly on that of the adipose tissue.     

Improvement of myocardial glycolipid metabolic disorder in diabetic hamster with Astragalus polysaccharides treatment

The objective of the present study is to observe the effect of Astragalus polysaccharide (APS) on myocardial glucose and lipid metabolism in diabetes (DM) hamster and to explore its mechanism in intervention of DM cardiomyopathy. Low-dose- streptozotocin-induced hamsters (STZ, 40 mg/kg × 3 days, i.p.) with blood glucose >13.9 mmo/L were considered as type 2 diabetic models. We measure blood glucose, serum lipid, insulin, C-peptide, myocardial enzyme levels, myocardial glycogen staining, myocardial ultrastructure, fluorescence quantitative RT-PCR detection of myocardial PPAR-α and the target genes (FATP, ACS) and GLUT4 mRNA expression in normal control group, DM group and APS treatment group hamsters. There was significant glycolipid metabolic disorders in DM group compared with normal group. Glucose, glycosylated serum protein, myocardial enzymes and lipid levels in APS treatment group decreased significantly than DM group, but insulin and C-peptide levels was no difference. Myocardial glycogen staining and abnormal myocardial ultrastructure in APS treatment group were significantly improved than in DM group. Gene expression of myocardial PPAR-α and its target genes (FATP, ACS) in APS group were significantly lower than in DM group, while gene expression of GLUT4 in APS group was higher than DM group. APS can partially improve myocardial glucose and lipid metabolism disorders in diabetic hamsters and protect myocardium in some extent.     

Dendrobium candidum protects against diabetic kidney lesions through regulating vascular endothelial growth factor,Glucose Transporter 1, and connective tissue growth factor expression in rats

Diabetes mellitus (DM) remains a great health problem with approximate 30% of patients with DM eventually suffering from diabetic nephropathy. The search for exogenous protective factors has recently received wide attention. The current study aimed to investigate the protective effects of Dendrobium candidum (DC) on kidneys in diabetic rats. Initially, streptozotocin-induced diabetic rats were established and randomly divided into the model group, DC group (0.2, 0.4, and 0.8 g/kg) and irbesartan group (17.5 mg/kg). The biochemical indexes, pathological changes, and the expressions of vascular endothelial growth factor (VEGF), GLUT-1, and CTGF were examined. It was found that as compared with the model group, the kidney index, serum creatine, blood urea nitrogen, 24-hour urine protein, and VEGF of DC treatment groups were significantly decreased, and pathological changes in kidney were improved in the DC groups and irbesartan group ( P < 0.05 for each parameter). The protein and messenger RNA levels of GLUT-1 and CTGF in treatment groups were significantly lower than those in rats' renal cortex without treatment. Our data suggest that DC may protect the kidneys of diabetic rats via regulating expression of VEGF, GLUT-1, and CTGF.     

Exercise training increases glucose transporter protein GLUT-4 in skeletal muscle of obese Zucker (fa/fa) rats

The present study examined the level of GLUT-4 glucose transporter protein in gastrocnemius muscles of 36 week old genetically obese Zucker (fa/fa) rats and their lean (Fa/-) littermates, and in obese Zucker rats following 18 or 30 weeks of treadmill exercise training. Despite skeletal muscle insulin resistance, the level of GLUT-4 glucose transporter protein was similar in lean and obese Zucker rats. In contrast, exercise training increased GLUT-4 protein levels by 1.7 and 2.3 fold above sedentary obese rats. These findings suggest endurance training stimulates expression of skeletal muscle GLUT-4 protein which may be responsible for the previously observed increase in insulin sensitivity with training.     

The Insulin Tolerance Test in Morbidly Obese Patients Undergoing Bariatric Surgery

Objective: To assess the effect of massive weight loss in relation to insulin resistance and its correlation to changes in glycemic homeostasis and lipid profile in severely obese patients. Research Methods and Procedures: A prospective clinical intervention study was carried out with 31 morbidly obese women (body mass index: 54.2 ± 8.8 kg/m²) divided into three groups according to their glucose tolerance test: 14 normal, 8 impaired glucose tolerance, and 9 type 2 diabetes. All subjects underwent an insulin tolerance test with intravenous bolus of 0.1 U insulin/kg body weight before silastic ring vertical gastroplasty Roux‐en‐Y gastric bypass surgery, and again at 2, 4, 6, and 12 months postoperatively. Fasting plasma glucose, hemoglobin A1c, and lipid profile were also evaluated. Results: A reduction of 68 ± 15% in initial excess body weight was evident within 1 year. Along with weight loss, the following statistically significant changes were found: an increase in the insulin‐sensitivity index (Kitt) and a decrease in fasting plasma glucose and hemoglobin A1c, most notably in the type 2 diabetes group. An overall improvement in lipid profile was observed in all three groups. Discussion: Bariatric surgery was an effective therapeutic approach for these obese patients because it reduced both weight and insulin resistance, along with improving metabolic parameters. Significant correlations were found between insulin resistance and metabolic improvements. Weight loss after bariatric surgery induced an improvement in metabolic fitness, related to the reduction in insulin resistance over a range of glucose tolerance statuses from normal to diabetic.     

Acute impairment of insulin signalling by dexamethasone in primary cultured rat skeletal myocytes

In this study, we examined the cellular content of the insulin receptor substrate (IRS)-1, the levels of phosphorylated tyrosine (pY) and serine (pS) residues in IRS-1, and the glucose transporters GLUT-1 and GLUT-4 in primary cultured rat skeletal myocytes treated with the glucocorticoid, dexamethasone. Dexamethasone markedly increased basal and insulin-stimulated IRS-1 content 4 to 5-fold (p < 0.01). A similar level of increase was observed for IRS-1 pY content. However, dexamethasone treatment had no effect on IRS-1 pS content. Further, dexamethasone reduced the cellular content of GLUT-1 when insulin and glucose were absent (p < 0.05), but did not significantly affect the expression of GLUT-4 in the presence of insulin (p > 0.05). We conclude that dexamethasone treatment impairs insulin signalling by a mechanism independent of serine-phosphorylation-mediated IRS-1 depletion, or of impairment of GLUT-1 expression. Instead, dexamethasone-induced insulin resistance may be mediated via reduced cellular content of IRS-1 accompanied by parallel reduction in tyrosine phosphorylation in IRS-1.     

Glucose dysregulation in obese children: predictive, risk, and potential protective factors

Objective: The aim of our study was to determine the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes (DM2) in obese children and adolescents of Greek origin and compare our data with pertinent literature findings in an attempt to uncover predictive, risk, and preventive factors. Research Methods and Procedures: A total of 117 obese children and adolescents 12.1 ± 2.7 years old underwent a 2‐hour oral glucose tolerance test (OGTT). Insulin resistance (IR) and β‐cell function were estimated using the homeostasis model assessment (HOMA)‐IR and the insulinogenic index, respectively. Results: A total of 17 patients (14.5%) had IGT, and none had DM2. The overall prevalence rates of both IGT and DM2 in our subjects were lower than those reported in a recent multiethnic U.S. study. Nevertheless, the difference between our IGT data and those of the U.S. study was due mostly to the prepubertal subjects (9% vs. 25.4%), whereas no difference was observed in the pubertal population (18% vs. 21%). Fasting glucose, insulin, and HOMA‐IR values were not predictive of IGT. The absolute value of insulin at 2 hours of the OGTT combined with the time‐integrated glycemia (AUCG) can strongly predict IGT, whereas higher area under the curve for insulin (AUCI) values were found to be protective. Discussion: In ethnic groups less prone to diabetes development, IGT or DM2 in obese subjects is more likely to develop at puberty than at the prepubertal stage. It is advisable that physicians caring for obese adolescents perform an OGTT for early detection of IGT because HOMA‐IR values, although higher in IGT subjects and indicative of IR, cannot predict IGT.     

Impairment of the insulinotropic effect of gastric inhibitory polypeptide (GIP) in obese and diabetic rats is related to the down-regulation of its pancreatic receptors

The association of obesity with type 2 diabetes mellitus has been recognized for years. In type 2 diabetes, there is a possibility that an important part of the impaired insulin secretion is due to the gastric inhibitory polypeptide (GIP) hormone. This study investigated changes that occur in the pancreatic GIP receptors' (GIP-Rs) expression and in GIP secretion in obese and type 2 diabetic rats and its relation to plasma glucose and insulin levels during oral glucose tolerance test (OGTT) compared to control rats. During the first 20 min of the OGTT, both the obese and the diabetic rats had a significant increase in the glucose excursion and a significant decrease in early-insulin secretion compared to the control group, with more prominent changes in the diabetic group. The obese rats had a significant increase in fasting GIP level and in the incremental change of GIP from 0 to 20 min (GIP Delta 0-20: 60.1 + or - 6.66 pmol/l) compared to that of the control (33.96 + or - 4.69 pmol/l) and the diabetic (29.34 + or - 2.62 pmol/l) group, which were not significantly different from each other. However, there was a significant decrease in GIP-Rs expression in both the obese (88.07 + or - 10.36 microg/ml) and diabetic (87.51 + or - 4.72 microg/ml) groups compared to the control group (120.35 + or - 8.06 microg/ml). During the second hour of the OGTT, plasma GIP was decreasing in all groups, however, the obese group had a significant hyperinsulinemia compared to the other two groups. Moreover, the diabetic group had a significantly lower plasma insulin level until the 90 min interval and thereafter it showed a non-significant difference compared to the control group. In conclusion, both obese and diabetic rats had an impaired early-phase insulinotropic effect of GIP due to impaired gene expression of GIP-Rs which could be a potential target to prevent transition of obesity to diabetes and to improve insulin secretion in the latter.     

Diabetes Alters the Expression and Translocation of the Insulin-Sensitive Glucose Transporters 4 and 8 in the Atria

Although diabetes has been identified as a major risk factor for atrial fibrillation, little is known about glucose metabolism in the healthy and diabetic atria. Glucose transport into the cell, the rate-limiting step of glucose utilization, is regulated by the Glucose Transporters (GLUTs). Although GLUT4 is the major isoform in the heart, GLUT8 has recently emerged as a novel cardiac isoform. We hypothesized that GLUT-4 and -8 translocation to the atrial cell surface will be regulated by insulin and impaired during insulin-dependent diabetes. GLUT protein content was measured by Western blotting in healthy cardiac myocytes and type 1 (streptozotocin-induced, T1Dx) diabetic rodents. Active cell surface GLUT content was measured using a biotinylated photolabeled assay in the perfused heart. In the healthy atria, insulin stimulation increased both GLUT-4 and -8 translocation to the cell surface (by 100% and 240%, respectively, P<0.05). Upon insulin stimulation, we reported an increase in Akt (Th308 and s473 sites) and AS160 phosphorylation, which was positively (P<0.05) correlated with GLUT4 protein content in the healthy atria. During diabetes, active cell surface GLUT-4 and -8 content was downregulated in the atria (by 70% and 90%, respectively, P<0.05). Akt and AS160 phosphorylation was not impaired in the diabetic atria, suggesting the presence of an intact insulin signaling pathway. This was confirmed by the rescued translocation of GLUT-4 and -8 to the atrial cell surface upon insulin stimulation in the atria of type 1 diabetic subjects. In conclusion, our data suggest that: 1) both GLUT-4 and -8 are insulin-sensitive in the healthy atria through an Akt/AS160 dependent pathway; 2) GLUT-4 and -8 trafficking is impaired in the diabetic atria and rescued by insulin treatment. Alterations in atrial glucose transport may induce perturbations in energy production, which may provide a metabolic substrate for atrial fibrillation during diabetes.