Cellular Mechanisms Of Insulin Resistance Research Articles

Insulin resistance and the alterations of glucose transporter-4 in adipose cells from cachectic tumor-bearing rats.

Insulin resistance may play an important role in cancer cachexia; however, its mechanisms remain to be clarified. Cellular mechanisms of insulin resistance in tumor-bearing rats (TBR) were investigated in isolated adipose cells by measuring 3-O-[14C]methyl glucose transport activity and glucose transporter-4 (GLUT4) protein in low-density microsomes at a basal state and in the plasma membrane at an insulin-stimulated state. The insulin-stimulated glucose transport activity in adipose cells from TBR was significantly lower than that of control rats (CTR) (0.51 +/- 0.25 and 2.27 +/- 0.11 fmol/cell/min, respectively). The amount of GLUT4 in low-density microsomes at a basal state and in plasma membrane at an insulin-stimulated state was less in TBR than in CTR. These data suggest that the insulin resistance seen in the adipose cells of these tumor-bearing rats was caused in part by both a decreased amount of GLUT4 protein in a basal state and a decreased translocation of GLUT4 in response to insulin stimulation.

Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding.

To elucidate cellular mechanisms of insulin resistance induced by excess dietary fat, we studied conscious chronically high-fat-fed (HFF) and control chow diet-fed rats during euglycemic-hyperinsulinemic (560 pmol/l plasma insulin) clamps. Compared with chow diet feeding, fat feeding significantly impaired insulin action (reduced whole body glucose disposal rate, reduced skeletal muscle glucose metabolism, and decreased insulin suppressibility of hepatic glucose production [HGP]). In HFF rats, hyperinsulinemia significantly suppressed circulating free fatty acids but not the intracellular availability of fatty acid in skeletal muscle (long chain fatty acyl-CoA esters remained at 230% above control levels). In HFF animals, acute blockade of beta-oxidation using etomoxir increased insulin-stimulated muscle glucose uptake, via a selective increase in the component directed to glycolysis, but did not reverse the defect in net glycogen synthesis or glycogen synthase. In clamp HFF animals, etomoxir did not significantly alter the reduced ability of insulin to suppress HGP, but induced substantial depletion of hepatic glycogen content. This implied that gluconeogenesis was reduced by inhibition of hepatic fatty acid oxidation and that an alternative mechanism was involved in the elevated HGP in HFF rats. Evidence was then obtained suggesting that this involves a reduction in hepatic glucokinase (GK) activity and an inability of insulin to acutely lower glucose-6-phosphatase (G-6-Pase) activity. Overall, a 76% increase in the activity ratio G-6-Pase/GK was observed, which would favor net hepatic glucose release and elevated HGP in HFF rats. Thus in the insulin-resistant HFF rat 1) acute hyperinsulinemia fails to quench elevated muscle and liver lipid availability, 2) elevated lipid oxidation opposes insulin stimulation of muscle glucose oxidation (perhaps via the glucose-fatty acid cycle) and suppression of hepatic gluconeogenesis, and 3) mechanisms of impaired insulin-stimulated glucose storage and HGP suppressibility are not dependent on concomitant lipid oxidation; in the case of HGP we provide evidence for pivotal involvement of G-6-Pase and GK in the regulation of HGP by insulin, independent of the glucose source.

Can metformin reduce insulin resistance in polycystic ovary syndrome?

To examine whether metformin is able to reduce insulin resistance in polycystic ovary syndrome (PCOS). Single-blind study comprising two successive periods of treatment: 8 weeks of placebo and 10 weeks of metformin (orally, 850 mg twice daily). Clinic of endocrinology and metabolism of Cerrahpaşa Medical Faculty at Istanbul University, Istanbul, Turkey. Sixteen insulin-resistant women with PCOS. Insulin sensitivity (with an IV insulin tolerance test), plasma glucose and insulin levels during an oral glucose tolerance test (OGTT), serum androgens, and lipids were measured at baseline and after each treatment period. Insulin sensitivity, the mean fasting serum levels of glucose, insulin, total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total T, free T, androstenedione, DHEAS, and LH:FSH ratio, and the areas under the curve for plasma glucose and insulin during OGTT were not changed by either placebo or metformin treatment. Metformin does not decrease insulin resistance in PCOS. This finding suggests that cellular mechanism of insulin resistance in PCOS is different from other common insulin-resistant states such as non-insulin dependent diabetes mellitus and obesity.

Cellular mechanisms of insulin resistance in polycystic ovarian syndrome.

Insulin resistance is a predominant feature in women with polycystic ovarian syndrome (PCO). The cellular mechanisms for this insulin resistance have not been defined. In this study, major steps in the insulin action cascade, receptor binding, kinase activity, and glucose transport activity were evaluated in isolated adipocytes prepared from PCO subjects (n = 8) without acanthosis nigricans and in a group of age and weight-matched controls [normal cycling (NC) n = 8]. The PCO group was hyperinsulinemic and displayed elevated insulin responses to an iv glucose load. The binding of 125I-insulin to adipocytes was similar in cells from PCO and NC subjects. In PCO, autophosphorylation of the insulin receptor-subunit in the absence of insulin was normal but a significant decrease (30% below control) in maximal insulin stimulated autophosphorylation was observed. However, receptor kinase activity measured against the exogenous substrate poly glu:tyr (4:1) was normal. Cells from PCO subjects transported glucose at the same rate, in both the absence and presence of a maximal insulin concentration, as those from NC subjects. Strikingly, there was a large rightward shift in the insulin dose-response curve for transport stimulation in PCO cells (EC50 = 87 +/- 14 pmol in NC vs. 757 +/- 138 in PCO, P less than 0.0005); 8-fold greater insulin concentrations were required to attain comparable glucose transport rates in cells from PCO against NC. In conclusion, our results suggest that insulin resistance in PCO, as assessed in the adipocyte, is accompanied by normal function of insulin receptors, but involves a novel postreceptor defect in the insulin signal transduction chain between the receptor kinase and glucose transport.

Cellular mechanisms of insulin resistance in polycystic ovarian syndrome

Cellular mechanisms of insulin resistance in polycystic ovarian syndrome

Cellular mechanisms of insulin resistance in non-insulin-dependent (type II) diabetes

Recent studies have led to an enhanced understanding of cellular alterations that may play an important role in the pathophysiology of non-insulin-dependent diabetes mellitus (NIDDM). The insulin receptor links insulin binding at the cell surface to intracellular activation of insulin's effects. This transducer function involves the tyrosine kinase property of the beta-subunit of the receptor. It was found that adipocytes from subjects with NIDDM had a 50 to 80 percent reduction in insulin-stimulated receptor kinase activity compared with their non-diabetic counterparts. This defect was relatively specific for the diabetic state since no decrease was observed in insulin-resistant non-diabetic obese subjects. The reduction in kinase activity was accounted for by changes in the ratio of two pools of receptors, both of which bind insulin but only one of which is capable of tyrosine autophosphorylation and subsequent kinase activation; 43 percent of the receptors from non-diabetic subjects were capable of autophosphorylation compared with only 14 percent in the NIDDM group. A major component of cellular insulin resistance in NIDDM involves the glucose transport system. Exposure of cells to insulin normally results in enhanced glucose transport mediated by translocation of glucose transporters from a low-density microsomal intracellular pool to the plasma membrane. It was found that cells from NIDDM subjects had a marked depletion of glucose transporters in both plasma membranes and low-density microsomes, relative to obese non-diabetic control participants. Obese non-diabetic persons had a normal number of plasma membrane transporters but a reduced number of low-density microsome transporters in the basal state compared with lean control volunteers; insulin induced the translocation of relatively fewer transporters from the low-density microsome to the plasma membrane in the obese subgroups. In addition to the diminished number of glucose transporters, cells from both NIDDM and obese subjects had impaired functional activity of glucose carriers since decreased whole-cell glucose transport rates could not be entirely explained by the magnitude of the decrement in the number of plasma membrane transporters. Thus, impaired glucose transport is due to both a numerical and functional defect in glucose transporters. The cellular content of high-density microsomal transporters was the same in lean and obese control volunteers and NIDDM subjects, suggesting that transporter synthesis is normal and that cellular depletion results from increased protein turnover once transporters leave the high-density microsomal subfraction. Thus, the defects in NIDDM can be dissociated from those in non-diabetic obesity. In NIDDM, alterations exist at the level of the receptor kinase and the glucose transporter; in obesity, the defects include alterations in glucose transport but not in the receptor kinase.

Insulin-mediated glucose disposal in type I diabetes: evidence for insulin resistance.

To clarify whether type I diabetes is characterized by insulin resistance, insulin-mediated glucose metabolism (M; milligrams per kg/min) was estimated by means of the glucose clamp technique in five insulin-dependent diabetic patients and six normal subjects. Three glucose clamps were carried out under different metabolic conditions. Free insulin plateaux were similar during each clamp in both groups. The first clamp was performed in normal subjects after an overnight fast [blood glucose, 80 +/- 3 mg/dl (mean +/- SEM)] and in diabetic patients 18 h after insulin withdrawal (blood glucose, 366 +/- 47 mg/dl). Diabetic patients had a M value (4.25 +/- 0.74) not different from normals (5.38 +/- 0.63; P = NS). The second clamp was done with the same glycemic values (approximately 125 mg/dl) in both groups. M increased to 8.07 +/- 1.06 (P less than 0.01) in the normal subjects and decreased to 2.87 +/- 0.50 (P = NS) in the diabetic patients. The M value in the diabetic patients was lower than that in the normal subjects (P less than 0.05). The third clamp was performed in three diabetic patients after 1 month of treatment with continuous sc insulin infusion. The mean blood glucose level was 88 +/- 6 mg/dl, and M was 3.23 +/- 0.38, significantly lower than that of the normal subjects in the basal state (P less than 0.05). No differences were found in insulin binding to erythrocytes. The mean plasma clearance rate (milliliters per m2/min) of free insulin was the same in both groups (428 +/- 113 in normal subjects and 354 +/- 83 in diabetic patients). Basal endogenous glucose production was higher in the diabetics (3.13 +/- 0.48 mg/kg X min) than in the normal subjects (1.71 +/- 0.57). During the clamp, however, endogenous glucose production was similarly inhibited (approximately 95%) in both groups. Multiple glucose clamp studies were also performed at three different insulin infusion rates (21, 73, and 760 mU/m2 X min, respectively) to generate an insulin-dose response curve for glucose disposal in six diabetic patients treated with continuous sc insulin infusion for at least 6 months. This allowed investigation of the effect of chronic strict insulin therapy leading to normal glucose and intermediary metabolite levels and identification of the cellular mechanism of insulin resistance. A significant reduction of the maximal glucose disposal rate (10.7 +/- 0.5 mg/kg X min) was found in these diabetic patients compared to that in normal subjects (14.9 +/- 1.0; P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

The insulin receptor: its role in insulin resistance of obesity and diabetes.

In recent years, techniques have become available to study the interaction between insulin and its cellular receptors. This has led to an explosion of information concerning the status of insulin receptors in normal and abnormal physiologic states. Obesity and nonketotic diabetes are two common abnormal states in which insulin resistance exists, and the purpose of this review is to summarize current knowledge concerning the cellular mechanisms of insulin resistance in these conditions, with specific emphasis on insulin receptors and how they may relate to the pathogenesis of resistance to insulin action.