Whole-body Insulin-mediated Glucose Uptake Research Articles

Adipocyte Insulin Resistance in PCOS: Relationship With GLUT-4 Expression and Whole-Body Glucose Disposal and β-Cell Function.

Impaired sensitivity to the antilipolytic action of insulin in adipose tissue (AT) may play a role in determining metabolic dysfunction in polycystic ovary syndrome (PCOS). To test the hypothesis that insulin resistance (IR) in AT is associated with whole-body insulin sensitivity and β-cell function in PCOS. Prospective cross-sectional study. Eighteen participants with PCOS and 18-matched control participants underwent a modified frequently sampled intravenous glucose tolerance test (mFSIVGTT); subgroups underwent single-slice computed tomography scans determining AT distribution and adipocyte glucose transporter type 4 (GLUT-4) expression. IR in AT in basal (by the adipose insulin resistance index [Adipo-IR]) and dynamic (mFSIVGTT-derived indices of insulin-mediated nonesterified fatty acids [NEFA] suppression [NEFAnadir, TIMEnadir, and %NEFAsupp]) states; whole-body insulin-mediated glucose uptake and insulin secretion in basal (by homeostatic model assessment [HOMA]-IR and HOMA-β%) and dynamic (mFSIVGTT-derived insulin sensitivity index [Si], acute insulin response to glucose [AIRg], and disposition index [Di]) states. Participants with PCOS had higher HOMA-IR and HOMA-β%, lower Si and Di, higher longer TIMEnadir, higher Adipo-IR and NEFAnadir, and a trend toward lower GLUT-4, than the control group participants. Adipo-IR was associated with dynamic state IR in AT (NEFAnadir TIMEnadir, and %NEFAsupp), but only in PCOS, and with HOMA-IR and HOMA-β% in both groups. NEFAnadir and TIMEnadir were negatively and %NEFAsupp positively associated with Si only in PCOS, but not with AIRg and Di, or GLUT-4 expression. Women with PCOS demonstrated increased IR in AT, which is closely associated with whole-body IR but not with dynamic state β-cell function or adipocyte GLUT-4 gene expression.

Double diabetes: the cardiovascular implications of combining type 1 with type 2 diabetes

Double diabetes: the cardiovascular implications of combining type 1 with type 2 diabetes

Strain‐Dependent Differences for Suppression of Insulin‐Stimulated Glucose Uptake in Skeletal and Cardiac Muscle by Ethanol

Chronic ethanol (EtOH) consumption impairs the ability of insulin to suppress hepatic glucose production in a strain-dependent manner, with hepatic insulin resistance being greater in Long-Evans (LE) than Sprague-Dawley (SD) rats. We assessed whether strain differences exist for whole-body and tissue glucose uptake under basal and insulin-stimulated conditions and whether they were associated with coordinate strain-dependent elevations in muscle cytokines. Male rats (160 g) were provided the Lieber-DeCarli EtOH-containing (36% total energy) diet or pair-fed a control diet for 8 weeks. Rats were studied in the basal state or during a euglycemic hyperinsulinemic clamp, and whole-body glucose flux assessed using (3) H-glucose and in vivo tissue glucose uptake by (14) C-2-deoxyglucose. EtOH impaired whole-body insulin-mediated glucose uptake (IMGU) more in SD than LE rats. This difference was due to impaired IMGU by gastrocnemius and heart in EtOH-fed SD versus LE rats. However, decreased IMGU in adipose tissue (epididymal and perirenal) produced by EtOH was comparable between strains. EtOH-induced insulin resistance in muscle from SD rats was associated with reduced AKT and AS160 phosphorylation and plasma membrane-localized GLUT4 protein as well as enhanced phosphorylation of c-Jun N-terminal kinase (JNK) and IRS-1 (S307), changes which were absent in muscle from LE rats. EtOH increased tumor necrosis factor alpha (TNFα) mRNA in gastrocnemius and fat under basal conditions in both SD and LE rats; however, hyperinsulinemia decreased TNFα in skeletal muscle from LE, but not SD rats. Interleukin (IL)-6 mRNA in gastrocnemius was increased under basal conditions and increased further in response to insulin in SD rats, but no EtOH- or insulin-induced change was detected in muscle IL-6 of LE rats. These data indicate strain-dependent differences in EtOH-induced IMGU in skeletal and cardiac muscle, but not fat, associated with sustained increases in TNFα and IL-6 mRNA and JNK activation and decreased plasma membrane GLUT4 in response to insulin.

Obesity and Insulin Resistance: An Ongoing Saga

Although the adverse effects of excess adiposity on insulin-mediated glucose uptake (IMGU) are well-recognized (1,2), the mechanism and/or mechanisms that explain this relationship continue to be debated. The article by Kursawe et al. (3) in this issue of Diabetes provides another, and potentially important, mechanism linking excess adiposity and IMGU. However, to put their findings into perspective, it might be helpful to provide a brief history of other approaches to this issue. The experimental methods utilized in earlier mechanistic studies are reminiscent of the study by Kursawe et al. (3) and led to the view that metabolic abnormalities associated with obesity were related to changes in fat cell size rather than number (4–7). For example, ex vivo studies on adipose tissue isolated from obese humans demonstrated that the larger the fat cell, the more diminished the response to insulin (4). Furthermore, insulin sensitivity of isolated fat improved following weight loss-associated decreases in fat cell size. Although these data indicated that differences in fat cell size affected insulin action, the fat cell is not a major consumer of glucose (8). Thus, these data do not necessarily explain why large fat cells would have an adverse effect on whole-body IMGU. Furthermore, why some individuals had large fat cells and …

Classical PKC is not associated with defective insulin signaling in patients with impaired glucose tolerance

Background and aim To investigate the role of insulin signaling defects in impaired glucose tolerance (IGT), we assessed the functionality of the insulin signaling cascade before and after insulin stimulation in both IGT group and control group. Methods Ten IGT subjects and 15 control subjects were recruited for this study. Whole-body insulin-mediated glucose uptake was determined using a euglycemic hyperinsulinemic clamp test. Muscle biopsies were obtained from the vastus lateralis muscle before and after insulin stimulation, to assess the insulin signaling cascade. Results The insulin-stimulated incremental changes in phosphorylated IR-beta, IRS, Akt, and GSK-3 beta and in the membrane-associated PKC-zeta protein level were reduced in the IGT group compared with those in the control group ( p < 0.05). The membrane-associated PKC-lambda protein level was also reduced in the IGT group, but not significantly so ( p = 0.08). The incremental changes in the protein levels of PKC-alpha, -beta, and -theta were not significantly different between the two groups. Conclusion The subjects with IGT showed decreased membrane-associated PKC-zeta/lambda activity in response to insulin stimulation, as well as defects in early insulin signaling. Our results suggest that membrane-associated PKC-alpha and -beta may not be associated with insulin resistance in IGT.

No impairment of endothelial function or insulin sensitivity with 4 weeks of the HIV protease inhibitors atazanavir or lopinavir-ritonavir in healthy subjects without HIV infection: a placebo-controlled trial.

Dyslipidemia alone does not fully explain the increase in cardiovascular events among patients receiving protease inhibitor (PI)-based treatment for human immunodeficiency virus infection. Some PIs, such as indinavir, directly induce endothelial dysfunction, an effect that may mediate that portion of the increase in cardiovascular events that is not attributable to dyslipidemia. Endothelium-dependent vasodilation, insulin-mediated vasodilation, and whole-body and leg glucose uptake during use of a 1-h euglycemic hyperinsulinemic clamp (insulin infusion, 40 mU/m(2)/min) were measured in healthy men before and after 4 weeks of treatment with placebo (12 men), with 400 mg atazanavir per day (9 men), or with 400 mg lopinavir and 100 mg ritonavir twice per day (9 men). Median age (36 years) and mean body mass index SD (23.4+/-2.6; calculated as weight in kilograms divided by the square of height in meters) did not differ between groups. Endothelium-dependent vasodilation, expressed as the percentage change in the leg blood flow response to intrafemoral artery infusion of 15 microg/min of the endothelium-dependent vasodilator methacholine, did not change after 4 weeks of treatment in any group:mean percentage change +/- SD, 154+/-102 from baseline and 242+/-254 at week 4 with atazanavir (P=.36), 76+/-62 and 86+/-79, respectively, with lopinavir-ritonavir (P=.68), and 111+/-86 and 127+/-153, respectively,with placebo (P=.63; for between-group differences, P=.55). The response to the endothelium-independent vasodilator nitroprusside was not different at week 4 for any group, nor was insulin-mediated vasodilation or leg or whole-body insulin-mediated glucose uptake (all within-group P values were 1.1). Unlike the dramatic impairment seen with indinavir, the newer PIs atazanavir and lopinavir-ritonavir do not induce endothelial dysfunction in healthy subjects. Thus, endothelial dysfunction does not appear to be a PI drug class effect. The cause of the non-lipid-mediated increase in cardiovascular events that are reported with PIs remains unclear.

Insulin resistance affects the regulation of lipoprotein lipase in the postprandial period and in an adipose tissue-specific manner.

Insulin is a potent stimulator of adipose tissue lipoprotein lipase (LPL). Logically, the postprandial period is therefore a privileged time of the day for the regulation of LPL by insulin in this tissue. It is not clear to what extent a defect such as insulin resistance could affect this regulation and contribute to postprandial, as well as fasting, hypertriglyceridaemia. The aim of the present protocol was to study the relationship between insulin resistance and LPL in adipose tissue and in plasma, in the particular context of the postprandial period. For this study, 26 adult nondiabetic individuals (12 women and 14 men) with a wide range of whole-body insulin-mediated glucose uptake (as assessed with an insulin suppression test) were studied. An abdominal subcutaneous fat biopsy on one occasion, and post-heparin plasma on another occasion, were obtained 4 h into a standardized meal profile administered in the fasting state. Postprandial triglyceride excursions (evaluated by the incremental area under the curve during the metabolic meal profile) were inversely correlated to adipose tissue LPL mRNA levels (rho = -0.43, P < 0.03) as well as to adipose tissue LPL heparin-releasable activity (rho = -0.58, P < 0.01). Steady-state plasma glucose (SSPG) concentrations during the insulin suppression test, a reflection of the degree of insulin resistance, were also negatively correlated to adipose tissue LPL mRNA (rho = -0.50, P < 0.02) and activity (rho = -0.56, P < 0.01). There was no correlation between plasma post-heparin LPL activity/mass and postprandial triglycerides nor with insulin resistance. Regulation of adipose tissue LPL is significantly affected in insulin-resistant individuals in the postprandial period. This presumed impaired effect of insulin on LPL postprandially could be an important contributor to the atherogenic dyslipidaemia described in insulin resistance syndrome.

Insulin-mediated vasodilatation, but not glucose uptake or endothelium-mediated vasodilatation, is enhanced in young females compared with males

In order to evaluate possible differences between men and women with regard to the ability of insulin to induce vasodilatation, promote glucose uptake and enhance endothelium-dependent vasodilatation, 12 young (22-28 years), non-obese women and 15 corresponding males were subjected to 2 h of euglycaemic hyperinsulinaemia (insulin infusion rate of 56 m-units x min(-1) x m(-2)). Forearm blood flow was measured by venous occlusion plethysmography. Endothelium-dependent vasodilatation was evaluated by the local intra-arterial infusion of methacholine into the brachial artery (2-4 microg/min). The cardiac index was measured by thoracic bioimpedance. A 2 h period of hyperinsulinaemia increased the plasma insulin concentration to a similar degree in both sexes (females, 84 +/- 8.8 m-units/l; males, 87 +/- 7.5 m-units/l), but induced a more marked increase in forearm blood flow in females than in males (+104 +/- 67% and +52 +/- 30% respectively; P<0.01; 95% confidence interval for difference 11-94%). Furthermore, a significant decrease in total peripheral resistance (-20 +/- 6.9%; P<0.01) and an increase in cardiac index (+23 +/- 13%; P<0.01) were seen in women only (P<0.05 compared with men). Blood pressure and heart rate were not altered in either sex. Whole-body insulin-mediated glucose uptake and forearm glucose uptake did not differ between the sexes, and the ability of insulin to enhance endothelium-dependent vasodilatation (+19%; P<0.01) was similar in men and women. In conclusion, the present study shows that the ability of insulin to cause vasodilatation was greater in non-obese young women compared with men. However, no differences between the sexes were seen with regard to insulin-mediated glucose uptake and the ability of insulin to enhance endothelium-dependent vasodilatation.

Protection from obesity and insulin resistance in mice overexpressing human apolipoprotein C1.

Apolipoprotein (APO) C1 is a 6.6-kDa protein present in plasma and associated with lipoproteins. Using hyperinsulinemic-euglycemic clamp tests, we previously found that in APOC1 transgenic mice, the whole-body insulin-mediated glucose uptake is increased concomitant with a decreased fatty acid uptake. These latter results are confirmed in the present study, showing that APOC1 transgenic mice exhibit a 50% reduction in the uptake of the fatty acid analog 15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid in white adipose tissue stores. We next investigated whether APOC1 overexpression can modulate the initiation and/or development of obesity and insulin resistance. When crossbred on the genetically obese ob/ob background, APOC1 transgenic mice were fully protected from the development of obesity compared with ob/ob only mice, as reflected by a strong reduction in body weight (21 +/- 4 vs. 44 +/- 7 g), total adipose tissue stores (15 +/- 3 vs. 25 +/- 3% body wt), and average adipocyte size (7,689 +/- 624 vs. 15,295 +/- 1,289 microm(2)). Although less pronounced, APOC1 overexpression also reduced body weight on a wild-type background, solely due to a reduction in adipose tissue. Furthermore, despite elevated plasma free fatty acid and triglyceride levels, APOC1 overexpression significantly improved insulin sensitivity in ob/ob mice, as demonstrated by a strong reduction in plasma glucose and insulin levels, as well as a better performance in the glucose tolerance test. In conclusion, a marked reduction in the uptake of fatty acids into adipocytes may underlie the protection from obesity and insulin resistance in transgenic mice overexpressing human APOC1.

Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR).

Insulin resistance and insulin hypersecretion are established features of obesity. Their prevalence, however, has only been inferred from plasma insulin concentrations. We measured insulin sensitivity (as the whole-body insulin-mediated glucose uptake) and fasting posthepatic insulin delivery rate (IDR) with the use of the euglycemic insulin clamp technique in a large group of obese subjects in the database of the European Group for the Study of Insulin Resistance (1,146 nondiabetic, normotensive Caucasian men and women aged 18-85 yr, with a body mass index (BMI) ranging from 15 to 55 kg.m-2). Insulin resistance, defined as the lowest decile of insulin sensitivity in the lean subgroup (608 subjects with a mean BMI of 29 kg.m-2). Insulin sensitivity declined linearly with BMI at an age- and sex-adjusted rate of 1.2 micromol.min-1.kg FFM-1 per BMI unit (95% confidence intervals = 1.0-1.4). Insulin hypersecretion, defined as the upper decile of IDR, was significantly (P<0.0001) more prevalent (38%) than insulin resistance in the obese group. In the whole dataset, IDR rose as a function of both BMI and insulin resistance in a nonlinear fashion. Neither the waist circumference nor the waist-to-hip ratio, indices of body fat distribution, was related to insulin sensitivity after adjustment for age, gender, and BMI; both, however, were positively associated (P<0.001) with insulin hypersecretion, particularly in women. In nondiabetic, normotensive obese subjects, the prevalence of insulin resistance is relatively low, and is exceeded by the prevalence of insulin hypersecretion, particularly in women with central obesity. In the obese with preserved insulin sensitivity, risk for diabetes, cardiovascular risk, and response to treatment may be different than in insulin resistant obesity.

Impaired nonoxidative glucose metabolism in patients with liver cirrhosis: Effects of two insulin doses

Glucose intolerance is encountered in the majority of cirrhotic patients. This alteration has been attributed to a defective insulin-mediated glucose uptake in peripheral tissue, where nonoxidative glucose disposal seems to be chiefly impaired. To further investigate insulin action under euglycemic conditions, we studied how physilogical (100 μU/mL) and pharmacological (100, μU/mL) plasma insulin concentrations affect whole-body insulin-mediated glucose uptake, as well as oxidative and nonoxidative glucose disposal, in cirrhotic patients and controls. To this aim, a sequential two-step insulin euglycemic clamp combined with indirect calorimetry was performed in eight cirrhotic patients and six control subjects. During the first step of the clamp, total glucose uptake was reduced by 40% in cirrhotic patients versus controls (4.42 ± 1.39 v 7.63 ± 1.60 mg/kg/min, P = .002). By increasing insulin to pharmacological levels, glucose disposal increased in both groups. However, the maximum rate of glucose metabolism achieved in cirrhotic patients was lower than in controls at all times (10.29 ± 2.04 v 12.82 ± 0.51 mg/kg/min, P = .012). Glucose oxidation was lower in cirrhotics in the basal state, but similar in both groups during insulin/glucose infusion. On the other hand, the reduced nonoxidative glucose disposal observed in cirrhotic patients was not normalized even by increasing insulin to pharmacological levels. In conclusion, in liver cirrhosis a reduced insulin sensitivity is associated with a reduced insulin responsiveness that is mainly caused by defective nonoxidative glucose disposal.

Mechanisms Behind Insulin Resistance in Rat Skeletal Muscle After Oophorectomy and Additional Testosterone Treatment

The absence of female sex hormones, as well as testosterone treatment of oophorectomized (OVX) female rats has been demonstrated to result in decreased whole-body insulin-mediated glucose uptake. The cellular mechanism behind this insulin resistance and the role of low levels of female sex hormones as a risk factor for development of peripheral insulin resistance are not yet fully clarified. We assessed the protein expression of GLUT4 and glycogen synthase, as well as insulin-induced translocation of GLUT4 to the plasma membrane, in soleus skeletal muscle from control rats, OVX rats, and OVX rats treated for 8 weeks with testosterone (OVX + T). Whole-body insulin-mediated glucose uptake assessed by the hyperinsulinemic-euglycemic clamp procedure was 25% lower in OVX rats (P < 0.001) and addition of testosterone treatment further decreased insulin-mediated glucose uptake in OVX + T rats by 48% (P < 0.001) compared with controls. GLUT4 protein expression in soleus muscles was unaltered in the OVX and OVX + T rats compared with controls. Insulin induced a 3.7-fold increase (P < 0.05) in the plasma membrane content of GLUT4 in soleus muscle from control rats, whereas plasma membrane content of GLUT4 in soleus muscle from OVX or OVX + T rats was unaltered in response to insulin. Glycogen synthase protein expression in muscle homogenates was decreased by 25% in the OVX group (P < 0.05) and by 37% in the OVX + T group (P < 0.05) when compared with the control group. Insulin receptor and tyrosine kinase activities in the basal and insulin-stimulated states did not differ between the OVX and OVX + T rats. In conclusion, the absence of female sex hormones appears to decrease insulin-mediated whole-body glucose uptake via an impaired insulin-stimulated translocation of GLUT4 to the plasma membrane and by decreased protein expression of glycogen synthase. Testosterone treatment further impairs whole-body insulin-mediated glucose uptake, presumably by additional impairment of glycogen synthase expression.

Insulin Action on Glucose Transport in Isolated Skeletal Muscle from Patients with Liver Cirrhosis

Insulin resistance, associated with liver cirrhosis, has been suggested to be localized in skeletal muscle. We used an in vitro incubation technique to determine insulin action on glucose transport in skeletal muscle obtained from seven patients with clinically stable alcoholic cirrhosis and seven healthy age- and sex-matched individuals. In addition, a euglycemic-hyperinsulinemic clamp procedure was performed to assess whole-body insulin-mediated glucose uptake. Insulin-mediated peripheral glucose utilization was 40% lower (p < 0.05) in the cirrhotic patients than in the healthy individuals. Intact skeletal muscle from the vastus lateralis portion of the quadriceps femoris muscle was obtained from each study participant. Thereafter, smaller skeletal muscle strips (approximately 18 mg) were dissected free and incubated in vitro to assess the rate of non-insulin- and insulin-stimulated 3-O-methylglucose transport. Insulin increased the rate of 3-O-methylglucose transport in a dose-dependent manner, with a maximal response observed in the presence of 200 microU/ml in skeletal muscle obtained from the cirrhotic patients and healthy individuals. The dose-response curve for insulin-stimulated 3-O-methylglucose transport did not differ between the groups. Furthermore, muscle glycogen content of needle biopsy specimens was comparable in the two groups. In conclusion, the present group of patients, with liver cirrhosis on an alcoholic basis, had a normal insulin-stimulated capacity for glucose transport at the cellular level irrespective of the degree of whole-body insulin resistance. The mechanism for the divergence between the in vivo and in vitro responses to insulin remains to be elucidated.