Showing papers on "Insulin resistance published in 1988"

Role of Insulin Resistance in Human Disease

Abstract: Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in ∼25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the β-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration.Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulinstimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one. However, even if insulin resistance and hyperinsulinemia are not involved in the etiology of hypertension, it is likely that the increased risk of coronary artery disease (CAD) in patients with hypertension and the fact that this risk if not reduced with antihypertensive treatment are due to the clustering of risk factors for CAD, in addition to high blood pressure, associated with insulin resistance. These include hyperinsulinemia, IGT, increased plasma triglyceride concentration, and decreased high-density lipoprotein cholesterol concentration, all of which are associated with increased risk for CAD. It is likely that the same risk factors play a significant role in the genesis of CAD in the population as a whole. Based on these considerations the possibility is raised that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases— NIDDM, hypertension, and CAD.

Diet-induced type II diabetes in C57BL/6J mice.

Abstract: We investigated the effects of diet-induced obesity on glucose metabolism in two strains of mice, C57BL/6J and A/J. Twenty animals from each strain received ad libitum exposure to a high-fat high-simple-carbohydrate diet or standard Purina Rodent Chow for 6 mo. Exposure to the high-fat, high-simple-carbohydrate, low-fiber diet produced obesity in both A/J and C57BL/6J mice. Whereas obesity was associated with only moderate glucose intolerance and insulin resistance in A/J mice, obese C57BL/6J mice showed clear-cut diabetes with fasting blood glucose levels of greater than 240 mg/dl and blood insulin levels of greater than 150 microU/ml. C57BL/6J mice showed larger glycemic responses to stress and epinephrine in the lean state than AJ mice, and these responses were exaggerated by obesity. These data suggest that the C57BL/6J mouse carries a genetic predisposition to develop non-insulin-dependent (type II) diabetes. Furthermore, altered glycemic response to adrenergic stimulation may be a biologic marker for this genetic predisposition to develop type II diabetes.

Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians

Abstract: Impaired glucose tolerance often presages the development of non-insulin-dependent diabetes mellitus. We have studied insulin action and secretion in 24 Pima Indians before and after the development of impaired glucose tolerance and in 254 other subjects representing the whole spectrum of glucose tolerance, including subjects with overt non-insulin-dependent diabetes. The transition from normal to impaired glucose tolerance was associated with a decrease in glucose uptake during hyperinsulinemia, from 0.018 to 0.016 mmol per minute (from 3.3 to 2.8 mg per kilogram of fat-free body mass per minute) (P less than 0.0003). Mean plasma insulin concentrations increased during an oral glucose-tolerance test, from 1200 to 1770 pmol per liter (from 167 to 247 microU per milliliter). In 151 subjects with normal glucose tolerance, the insulin concentration measured during an oral glucose-tolerance test correlated with the plasma glucose concentration (r = 0.48, P less than or equal to 0.0001). This relation was used to predict an insulin concentration of 1550 pmol per liter (216 microU per milliliter) in subjects with impaired glucose tolerance (actual value, 1590 pmol per liter [222 microU per milliliter]; P not significant), suggesting that these subjects had normal secretion of insulin. In contrast, plasma insulin concentrations in the diabetics decreased as glucose concentrations increased (r = -0.75, P less than or equal to 0.0001), suggesting deficient secretion of insulin. This relative insulin deficiency first appears at the lower end of the second (diabetic) mode seen in population frequency distributions of plasma glucose concentrations. Our data show that impaired glucose tolerance in our study population is primarily due to impaired insulin action. In patients with non-insulin-dependent diabetes mellitus, by contrast, impaired insulin action and insulin secretory failure are both present.

Characterization of New Oral Antidiabetic Agent CS-045: Studies in KK and ob/ob Mice and Zucker Fatty Rats

Abstract: CS-045 is a new oral antidiabetic agent that was effective in insulin-resistant diabetic animal models, including the KK mouse, the ob/ob mouse, and the Zucker fatty rat. CS-045 was not effective in the streptozocin-treated mouse, an insulin-deficient diabetic animal model. In fed KK mice, CS-045 lowered the plasma glucose levels in a dose-dependent manner after a single oral administration, and the hypoglycemic effect lasted for at least 18 h. In normal rats, however, plasma glucose levels were not changed after administration of CS-045. CS-045 when given chronically (2 wk) to diabetic KK and ob/ob mice as a 0.2% food admixture dramatically improved hyperglycemia, hyperinsulinemia, and hypertriglyceridemia to near-normal values and decreased plasma lactate, free fatty acid, and ketone body levels without reducing food intake or body weight. In the obese Zucker fatty rat, oral administration of CS-045 had a similar effect in lowering plasma glucose, insulin, triglyceride, free fatty acid, lactate, and ketone body levels. The CS-045-treated Zucker fatty rats showed increased glucose tolerance and decreased insulin secretion in response to oral glucose. After 9 days of treatment, insulin binding to adipocyte plasma membranes from both CS-045-treated Zucker fatty rats and KK mice was increased. Furthermore, 2-deoxyglucose uptake in CS-045-treated adipocytes was increased and the insulin dose-response curve was shifted to the left. These findings suggest that CS-045 increases not only insulin sensitivity but also insulin responsiveness. Based on its pharmacological profile, CS-045 is a new orally effective antidiabetic agent that may reduce abnormalities of glucose and lipid metabolism in obese and non-insulin-dependent diabetes mellitus patients with insulin resistance.

Pancreatic amylin and calcitonin gene-related peptide cause resistance to insulin in skeletal muscle in vitro

Abstract: Insulin resistance occurs in a variety of conditions, including diabetes, obesity and essential hypertension, but its underlying molecular mechanisms are unclear. In type 2 (non-insulin-dependent) diabetes mellitus, it is insulin-resistance in skeletal muscle, the chief site of insulin-mediated glucose disposal in humans, that predominantly accounts for the low rates of glucose clearance from the blood, and hence for impaired glucose tolerance. Human type 2 diabetes is characterized by a decrease in non-oxidative glucose storage (muscle glycogen synthesis), and by the deposition of amyloid in the islets of Langerhans. Amylin is a 37-amino-acid peptide which is a major component of islet amyloid and has structural similarity to human calcitonin gene-related peptide-2 (CGRP-2; ref. 8). CGRP is a neuropeptide which may be involved in motor activity in skeletal muscle. We now report that human pancreatic amylin and rat CGRP-1 are potent inhibitors of both basal and insulin-stimulated rates of glycogen synthesis in stripped rat soleus muscle in vitro. These results may provide a basis for a new understanding of the molecular mechanisms that cause insulin resistance in skeletal muscle.

The Natural History of Impaired Glucose Tolerance in the Pima Indians

Abstract: Among 384 Pima Indians with impaired glucose tolerance according to World Health Organization criteria who were followed for 1.6 to 11.5 years (median, 3.3), non-insulin-dependent diabetes mellitus (NIDDM) developed in 118 (31 percent), glucose tolerance remained impaired in 100 (26 percent), and glucose tolerance returned to normal in 166 (43 percent). The cumulative incidence of NIDDM was 25 and 61 percent at 5 and 10 years, respectively. The risk of development of diabetes was 6.3 times (95 percent confidence interval, 3.8 to 10.6) as high as in a normoglycemic control group (n = 752). Variables predicting deterioration to NIDDM were age up to the age of 40, after which increasing age had a beneficial effect; higher plasma glucose levels during fasting and after carbohydrate loading; and higher serum insulin levels after fasting and lower levels after carbohydrate loading, suggesting that insulin resistance and decreased beta-cell responsiveness are important determinants of the clinical outco...

Amylin found in amyloid deposits in human type 2 diabetes mellitus may be a hormone that regulates glycogen metabolism in skeletal muscle

Abstract: Diabetes-associated peptide has recently been isolated and characterized from the amyloid of the islets of Langerhans in type 2 (non-insulin-dependent) diabetics, and immunoreactivity with antibodies to the peptide has been demonstrated in islet B cells of both normal and type 2 diabetic subjects. In view of the evidence presented in this paper that this 37-amino acid peptide may be a hormone present in normal individuals, we now propose the name "amylin" to replace "diabetes-associated peptide." Because increased amylin, deposited as amyloid within the islets of Langerhans, is characteristic of type 2 diabetes, the study below was performed to examine the possible effects of amylin on peripheral glucose metabolism. Whole amylin was synthesized by using solid-phase techniques, with formation of the disulfide linkage by oxidation in dilute aqueous solution and recovery of the peptide by lyophilization. The effects of amylin on glucose metabolism were studied in two preparations in vitro, isolated rat soleus muscle strips and isolated rat adipocytes. In skeletal muscle exposed to 120 nM amylin for 1 hr, there was a marked decrease in both basal and submaximally insulin-stimulated rates of glycogen synthesis, which resulted in significant reduction in the rates of insulin-stimulated glucose uptake. In muscles treated with amylin there was no response at the concentration of insulin required to stimulate glucose uptake half-maximally in untreated (control) muscles. In marked contrast, amylin had no effect on either basal or insulin-stimulated rates of glucose incorporation into either CO2 or triacylglycerol in isolated adipocytes. Therefore, amylin may be a factor in the etiology of the insulin resistance in type 2 diabetes mellitus, as both deposition of the peptide in islet amyloid and decreased rates of glucose uptake and glycogen synthesis in skeletal muscle are characteristic of this condition.

Role of Gestational Hormones in the Induction of Insulin Resistance

Abstract: Pregnancy is associated with insulin resistance. We studied insulin binding and postbinding function in isolated adipocytes from pregnant and nonpregnant rats. We also used a primary culture system for female virgin rat adipocytes to assess the effects of gestational hormones in vitro on insulin binding and postbinding function. Insulin binding to adipocytes was normal during pregnancy, but [14C]3-O-methylglucose transport was reduced. When hCG or estradiol was added to the culture medium, no change in maximum [14C]3-O-methylglucose transport was found; however, maximum insulin binding was increased with estradiol. Progesterone and cortisol both decreased maximum insulin binding and [14C]3-O-methylglucose transport. PRL and placental lactogen decreased maximum [14C]3-O-methylglucose transport, but did not change insulin binding. When these hormones were added concurrently no change in insulin binding was found, but maximum [14C]3-O-methylglucose transport was reduced. We conclude that the insulin resistance of pregnancy is associated with a postbinding defect in insulin action. Estradiol increased insulin receptor binding, but during pregnancy this effect may be offset by the reduction in insulin binding induced by progesterone and cortisol. The postbinding defect in insulin action during pregnancy is probably related to increasing amounts of progesterone, cortisol, PRL, and placental lactogen.

An in vitro human muscle preparation suitable for metabolic studies. Decreased insulin stimulation of glucose transport in muscle from morbidly obese and diabetic subjects.

Abstract: We have developed an in vitro muscle preparation suitable for metabolic studies with human muscle tissue and have investigated the effects of obesity and non-insulin-dependent diabetes mellitus (NIDDM) on glucose transport. Transport of 3-O-methylglucose and 2-deoxyglucose was stimulated approximately twofold by insulin in muscle from normal nonobese subjects and stimulation occurred in the normal physiological range of insulin concentrations. In contrast to insulin stimulation of 3-O-methylglucose and 2-deoxyglucose transport in muscle from normal, nonobese subjects, tissue from morbidly obese subjects, with or without NIDDM, were not responsive to insulin. Maximal 3-O-methylglucose transport was lower in muscle of obese than nonobese subjects. Morbidly obese patients, with or without NIDDM, have a severe state of insulin resistance in glucose transport. The novel in vitro human skeletal muscle preparation herein described should be useful in investigating the mechanism of this insulin resistance.

Two mutant alleles of the insulin receptor gene in a patient with extreme insulin resistance

Abstract: Insulin receptor complementary DNA has been cloned from an insulin-resistant patient with leprechaunism whose receptors exhibited multiple abnormalities in insulin binding. The patient is a compound heterozygote, having inherited two different mutant alleles of the insulin receptor gene. One allele contains a missense mutation encoding the substitution of glutamic acid for lysine at position 460 in the alpha subunit of the receptor. The second allele has a nonsense mutation causing premature chain termination after amino acid 671 in the alpha subunit, thereby deleting both the transmembrane and tyrosine kinase domains of the receptor. Interestingly, the father is heterozygous for this nonsense mutation and exhibits a moderate degree of insulin resistance. This raises the possibility that mutations in the insulin receptor gene may account for the insulin resistance in some patients with non-insulin-dependent diabetes mellitus.

Hyperinsulinemia, upper body adiposity, and cardiovascular risk factors in non-diabetics

Abstract: Previous studies have suggested that hyperinsulinemia and upper body adiposity are each separately associated with elevated BP and triglyceride (TG) levels, and with lower high density lipoprotein (HDL) cholesterol levels. The joint effect of hyperinsulinemia and upper body adiposity on lipids, lipoproteins, and BP, however, has not been previously studied. We hypothesized that the effect of body fat distribution on cardiovascular risk factors might be mediated through hyperinsulinemia. We measured BP, lipids and lipoproteins, HDL subfractions, and insulin and glucose concentrations as part of the San Antonio Heart Study, a population-based study of diabetes and cardiovascular risk factors. Insulinemia and glycemia were assessed as the sum of the fasting, half-hour, one-hour, and two-hour insulin and glucose levels, respectively, measured during a standardized oral glucose tolerance test. Individuals who had diabetes according to National Diabetes Data Group criteria were excluded from the analyses. In univariate analyses, both hyperinsulinemia and waist-to-hip ratio (WHR), a measure of upper body adiposity, were positively associated with TG and negatively associated with total HDL and HDL2 cholesterol levels. However, when the effects of glycemia and insulinemia were controlled for by analysis of variance, WHR was no longer significantly related to TG levels. By contrast, WHR continued to be inversely related to total HDL and HDL2 cholesterol even after adjustment for glycemia and insulinemia. Hyperinsulinemia was only weakly related to HDL cholesterol. These results suggest that insulinemia and glycemia might mediate the effects of upper body adiposity on TG, although not on HDL and HDL2 cholesterol. Hyperinsulinemia was also positively associated with diastolic and systolic BP in men.

Possible role of cytosolic free calcium concentrations in mediating insulin resistance of obesity and hyperinsulinemia.

Abstract: Insulin- and glyburide-stimulated changes in cytosolic free calcium concentrations [( Ca2+]i) were studied in gluteal adipocytes obtained from six obese women (139 +/- 3% ideal body wt) and six healthy, normal weight age- and sex-matched controls. Biopsies were performed after an overnight fast and twice (at 3 and 6 h) during an insulin infusion (40 mU/m2 per min) (euglycemic clamp). In adipocytes obtained from normal subjects before insulin infusion, insulin (10 ng/ml) increased [Ca2+]i from 146 +/- 26 nM to 391 +/- 66 nM. Similar increases were evoked by 2 microM glyburide (329 +/- 41 nM). After 3 h of insulin infusion, basal [Ca2+]i rose to 234 +/- 21 nM, but the responses to insulin and glyburide were completely abolished. In vitro insulin-stimulated 2-deoxyglucose uptake was reduced by insulin and glucose infusion (25% stimulation before infusion, 5.4% at 3 h, and 0.85% at 6 h of infusion). In obese patients, basal adipocyte [Ca2+]i was increased (203 +/- 14 nM, P less than 0.05 vs. normals). The [Ca2+]i response demonstrated resistance to insulin (230 +/- 23 nM) and glyburide (249 +/- 19 nM) stimulation. Continuous insulin infusion increased basal [Ca2+]i (244 +/- 24 nM) and there was no response to either insulin or glyburide at 3 and 6 h of study. Rat adipocytes were preincubated with 1-10 mM glucose and 10 ng/ml insulin for 24 h. Measurements of 2-deoxyglucose uptake demonstrated insulin resistance in these cells. Under these experimental conditions, increased levels of [Ca2+]i that were no longer responsive to insulin were demonstrated. Verapamil in the preincubation medium prevented the development of insulin resistance.

Increased Insulin Concentrations in Nondiabetic Offspring of Diabetic Parents

Abstract: Insulin resistance is thought by many to be the primary defect that results in non-insulin-dependent diabetes mellitus (NIDDM). An implication of this theory is that prediabetic persons have higher serum insulin levels than normal subjects. We assessed serum insulin concentrations in a cohort of 1497 nondiabetic Mexican Americans, a population at high risk for NIDDM, according to whether their parents or siblings had diabetes. It was assumed that prediabetic persons would be more likely to have strong family histories of diabetes. We found a stepwise increase in fasting insulin levels in nondiabetics with neither, one, or both parents with diabetes (69.8, 77.8, and 94.6 pmol per liter, respectively; P = 0.002). Similar results were observed for insulin sum (the total of insulin concentrations in the fasting state and at 30, 60, and 120 minutes after a 75-g oral glucose load). The differences in insulin sums according to family history remained statistically significant in analyses of covariance, ...

Bed-rest-induced insulin resistance occurs primarily in muscle.

Abstract: Treatment of trauma victims and patients with severe illness may contribute to their metabolic derangements by severely restricting physical activity. We sought to quantitate the impact of absolute bed rest alone on insulin regulation of glucose metabolism in six healthy subjects. Six to seven days of strict bed rest resulted in moderate deterioration in oral glucose tolerance and increased both fasting plasma insulin concentration and the insulin response to an oral glucose challenge by more than 40%. Euglycemic insulin clamp studies demonstrated the development of resistance to insulin's stimulation of whole-body glucose utilization. This change was characterized by a rightward shift of the insulin dose-response curve (insulin concentration at which 50% of maximal stimulation occurred was 45 +/- 3 (SE) microU/mL in the base line period and 78 +/- 8 microU/mL after seven days of bed rest, P less than .01) with little alteration in the maximal response in the rate of glucose uptake (baseline 15.4 +/- 1.4 mg/kg.min and bed rest 14.0 +/- 1.3 mg/kg.min). In contrast to the shift of sensitivity of whole-body glucose utilization to insulin, suppression of hepatic glucose output by insulin was unchanged by seven days of bed rest. Insulin binding to circulating mononuclear cells was not changed by bed rest. These studies demonstrate that the limited physical activity dictated by bed rest for as little as seven days is associated with substantial resistance to insulin's effects on glucose metabolism. Further, the data suggest that these effects occur primarily in skeletal muscle with little change in insulin action on the liver.

Quantification of the relative impairment in actions of insulin on hepatic glucose production and peripheral glucose uptake in non-insulin-dependent diabetes mellitus.

Abstract: In non-insulin-dependent diabetes mellitus (NIDDM), both liver and peripheral tissues are resistant to insulin, but the relative severity and contribution of these abnormalities to fasting hyperglycemia are poorly understood. We, therefore, determined the dose-response characteristics for insulin-mediated suppression of hepatic glucose production (GP) and stimulation of peripheral glucose uptake (GU) in 14 NIDDM subjects and 14 age- and weight-matched nondiabetic volunteers (NV) using the glucose clamp sequential insulin infusion technique along with isotopic estimation of glucose flux. Postabsorptive rates of both GP (94 +/- 7 v 72 +/- 2 mg/M2/min in NV, P less than .01) and GU (88 +/- 5 v 72 +/- 2 in NV, P less than .01) were significantly increased in NIDDM subjects. The ED50 (half-maximally effective plasma insulin concentration) in NIDDM subjects for suppression of GP (64 +/- 14 microU/mL) and stimulation of GU (118 +/- 20 microU/mL were both increased more than twofold above normal (26 +/- 2 and 58 +/- 5 microU/mL, respectively, both P less than .01) and were significantly correlated with one another (r = .68, P less than .01). Although GP could be totally suppressed in the NIDDM subjects, their maximal GU was reduced 30% (287 +/- 20 v 372 +/- 15 mg/m2/min in NV, P less than .01). Nevertheless, at all physiologically relevant plasma insulin concentrations studied, there was comparable impairment in GP and GU responses. Moreover, fasting plasma glucose concentrations in NIDDM subjects were highly correlated with their increased basal rates of GP (r = .81, P less than .005) but not with their reduced GU.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin Resistance and Hyperinsulinemia in Patients with Thalassemia Major Treated by Hypertransfusion

Abstract: Diabetes mellitus in patients receiving hypertransfusion for thalassemia major is usually attributed to damage to beta cells. To determine whether iron overload leads to insulin resistance before the development of insulin deficiency, insulin was infused (by euglycemic insulin-clamp technique) into 12 children with thalassemia (4 of whom were prepubertal, and 8 pubertal) who had normal or only moderately impaired glucose tolerance and who were receiving chelation therapy. Although insulin-stimulated glucose metabolism in the prepubertal children with thalassemia was similar to that in controls (normal prepubertal children) (319 +/- 23 vs. 314 +/- 41 mg per square meter of body-surface area per minute, P not significant), the response to insulin was markedly impaired in the pubertal children with thalassemia (155 +/- 18 vs. 224 +/- 15 mg per square meter per minute in normal pubertal controls, P less than 0.01). Plasma insulin levels rose excessively after oral glucose administration in the pubertal subjects with thalassemia, but not in the prepubertal patients (P less than 0.001). Furthermore, in response to a standard hyperglycemic stimulus, insulin levels in the pubertal patients rose to two to three times greater than normal and C-peptide levels became significantly elevated. Our data suggest that insulin resistance and increased insulin secretion develop in older children with thalassemia treated with long-term hypertransfusion therapy before the development of diabetes.

Obesity and insulin resistance: Lessons learned from the Pima indians

Abstract: Diabetes and obesity are epidemic in the Pima Indians of the Southwestern United States, and the prevalence of diabetes is increasing. The most likely link between obesity and diabetes is tissue insulin resistance. If obesity is defined as an excess of body fat, then it can only be accurately assessed by measurements of body composition and not by approximations such as body mass index or percent of ideal weight. To compare the metabolic data of individuals of varying size, an accurate measure of metabolic size is needed. Total body weight is not an appropriate means of comparing individuals since obese subjects have a greater proportion of nonmetabolizing mass (triglyceride). Body surface area shows a sex difference, and this may distort data if both sexes are present. From studies of metabolic rate we have determined that metabolic rate is directly proportional to the fat-free mass plus 18 kg, and we suggest that this weight can be equated with metabolic size. Glucose storage in skeletal muscle appears to be important in the disposal of an intravenous glucose load. Consistent with its role in glycogen storage, glycogen synthase enzyme is activated in proportion to the ability to dispose of glucose during a hyperinsulinemic, euglycemic clamp. The role of glycogen synthase is most notable at supraphysiological plasma insulin concentrations; and since glucose uptake at these insulin concentrations is highly familial independent of the degree of obesity, we suggest that there may be a specific genetic defect expressed in skeletal muscle that reduces insulin responsiveness in some subjects. The lack of correlation between 24 hour respiratory quotient measured in a metabolic chamber (a measure of the proportion of fat derived calories) and degree of obesity indicates that in obese Pima Indians insulin resistance is not due to an inhibition of glucose metabolism by free fatty acids (glucose-fatty acid-ketone cycle). Obesity is associated with an increase in fat-free mass almost kilogram- for kilogram with fat mass when compared to the lean state. A role for this increase in fat-free tissue in producing insulin resistance has been given insufficient attention in the past. With an increase in fat-free mass, muscle cells are hypertrophied and capillaries in muscle are more widely spaced. We propose that these biophysical changes in muscle mediate, at least in part, the effects of obesity to produce a reduction in insulin sensitivity and the abnormal kinetics of insulin action found in the obese.(ABSTRACT TRUNCATED AT 400 WORDS)

Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin-dependent diabetes mellitus. Effect of weight loss.

Abstract: Insulin-stimulated kinase activity of adipocyte-derived insulin receptors is reduced in subjects with non-insulin-dependent diabetes mellitus (NIDDM) but normal in obese nondiabetics. To assess the reversibility of the kinase defect in NIDDM, insulin receptor kinase activity was measured before and after weight loss in 10 NIDDM and 5 obese nondiabetic subjects. Peripheral insulin action was also assessed in vivo by glucose disposal rates (GDR) measured during a hyperinsulinemic (300 mU/M2 per min) euglycemic clamp. In the NIDDMs, insulin receptor kinase activity was reduced by 50-80% and rose to approximately 65-90% (P less than 0.01) of normal after 13.2 +/- 2.0 kg (P less than 0.01) weight loss; comparable weight loss (18.2 +/- 1.5 kg, P less than 0.01) in the nondiabetics resulted in no significant change in insulin receptor kinase activity. Relative to GDR measured in lean nondiabetics, GDR in the NIDDMs was 35% of normal initially and 67% (P less than 0.01) of normal after diet therapy; weight loss in the nondiabetics resulted in an increase in GDR from 53 to 76% of normal (P less than 0.05). These results indicate that the insulin receptor kinase defect that is present in NIDDM is largely reversible after weight reduction. In contrast, the improvement in GDR, in the absence of any change in insulin receptor kinase activity in the nondiabetics, suggests that the main cause of insulin resistance in obesity lies distal to the kinase.

Ethanol causes acute inhibition of carbohydrate, fat, and protein oxidation and insulin resistance.

Abstract: To study the mechanism of the diabetogenic action of ethanol, ethanol (0.75 g/kg over 30 min) and then glucose (0.5 g/kg over 5 min) were infused intravenously into six normal males. During the 4-h study, 21.8 +/- 2.1 g of ethanol was metabolized and oxidized to CO2 and H2O. Ethanol decreased total body fat oxidation by 79% and protein oxidation by 39%, and almost completely abolished the 249% rise in carbohydrate (CHO) oxidation seen in controls after glucose infusion. Ethanol decreased the basal rate of glucose appearance (GRa) by 30% and the basal rate of glucose disappearance (GRd) by 38%, potentiated glucose-stimulated insulin release by 54%, and had no effect on glucose tolerance. In hyperinsulinemic-euglycemic clamp studies, ethanol caused a 36% decrease in glucose disposal. We conclude that ethanol was a preferred fuel preventing fat, and to lesser degrees, CHO and protein, from being oxidized. It also caused acute insulin resistance which was compensated for by hypersecretion of insulin.

Insulin resistance after oral glucose tolerance testing in patients with major depression

Abstract: An association between affective disorders and alterations in glucose utilization has been recognized. The authors administered a 5-hour oral glucose tolerance test (GTT) to 28 depressed patients and 21 healthy volunteer control subjects and measured serum glucose as well as plasma insulin and glucagon responses. Depressed patients demonstrated significantly higher basal glucose levels, greater cumulative glucose responses after the GTT, and larger cumulative insulin responses after the GTT than control subjects. Values for cumulative glucagon did not significantly differ between groups. These findings indicate the presence of a functional state of insulin resistance during major depressive illness and suggest the presence of a more generalized biological disturbance in some depressed patients.

Role of glucose transporters in the cellular insulin resistance of type II non-insulin-dependent diabetes mellitus.

Abstract: To examine the role of glucose transport proteins in cellular insulin resistance, we studied subcutaneous adipocytes isolated from lean control, obese control (body mass index [BMI] 33.4 +/- 0.9), and untreated obese non-insulin-dependent diabetes mellitus (NIDDM) patients (BMI 35.2 +/- 2.1; fasting glucose 269 +/- 20 mg/dl). Glucose transporters were measured in plasma membrane (PM), low-density (LDM), and high-density (HDM) microsomal subfractions from basal and maximally insulin-stimulated cells using the cytochalasin B binding assay, and normalized per milligram of membrane protein. In all subgroups, insulin led to an increase in PM glucose transporters and a corresponding depletion of transporters in the LDM. Insulin recruited 20% fewer transporters to the PM in the obese subgroup when compared with lean controls, and this was associated with a decline in LDM transporters with enlarging cell size in the control subjects. In NIDDM, PM, and LDM, transporters were decreased 50% in both basal and stimulated cells when compared with obese controls having similar mean adipocyte size. Cellular depletion of glucose transporters was not the only cause of insulin resistance, because the decrease in rates of [14C]-D-glucose transport (basal and insulin-stimulated) was greater than could be explained by reduced numbers of PM transporters in both NIDDM and obesity. In HDM, the number of transporters was not influenced by insulin and was similar in all subgroups. We conclude that (a) in NIDDM and obesity, both reduced numbers and impaired activity of glucose transporters contribute to cellular insulin resistance, and (b) in NIDDM, more profound cellular insulin resistance is associated primarily with a further depletion of cellular transporters.

Insulin Resistance and β-Cell Dysfunction in Aging: The Importance of Dietary Carbohydrate

Abstract: Aging is associated with a progressive decrease in glucose tolerance. This decrease is associated with insulin resistance and β-cell dysfunction. This study was performed to evaluate the possible role of dietary factors in the glucose intolerance of aging. Two groups of men were studied: one young (Y; n = 8; age range, 18–36 yr) and one elderly (E; n = 10; age range, 65–82 yr). Frequently sampled iv glucose tolerance tests were performed in random order: 1) during ad libitum home dietary conditions; 2) after a 3- to 5-day regimen of very high (85%) carbohydrate intake; and 3) after a 3- to 5-day regimen of low (30%) carbohydrate intake (Y only). From the frequently sampled iv glucose tolerance test data, we calculated the glucose disappearance rate (Kg) and metabolic parameters according to the minimal model method, including the insulin sensitivity index (S1) and the first and second phase β-cell responsivity to glucose (ϕ1 and ϕ2). The elderly men, while eating an ad libitum diet, were less tolerant to ...

Detection of an alteration in the insulin-receptor gene in a patient with insulin resistance, acanthosis nigricans, and the polycystic ovary syndrome (type A insulin resistance).

Abstract: SEVERE insulin resistance is the central metabolic feature of a number of clinically diverse syndromes,1 including the type A syndrome (young female patients with insulin resistance, acanthosis nig...

Attenuation of fructose-induced hypertension in rats by exercise training.

Abstract: This study was initiated to see if the insulin resistance, hyperinsulinemia, and hypertension that follow feeding normotensive Sprague-Dawley rats a fructose-rich diet could be prevented by letting rats run spontaneously in exercise wheel cages. Blood pressure in sedentary rats increased from (mean +/- SEM) 125 +/- 2 to 148 +/- 3 mm Hg in response to 2 weeks of a high fructose diet, and this increment was significantly (p less than 0.001) attenuated in exercising rats (from 121 +/- 1 to 131 +/- 2 mm Hg). In addition, mean (+/- SEM) plasma insulin concentration was lower in fructose-fed rats allowed to run spontaneously (44 +/- 2 vs 62 +/- 5 microU/ml; p less than 0.01). Finally, resistance to insulin-stimulated glucose uptake was assessed by determining the steady state plasma glucose response to a continuous glucose and exogenous insulin infusion during a period in which endogenous insulin secretion was suppressed. The results of these studies indicated that the mean (+/- SEM) steady state plasma glucose concentration was significantly lower in the exercise-trained rats (127 +/- 5 vs 168 +/- 6 mg/dl; p less than 0.001), despite the fact that the steady state plasma insulin levels were also lower in rats allowed to run spontaneously (75 +/- 4 vs 90 +/- 5 microU/ml; p less than 0.05). Thus, the ability of exercise-trained rats to stimulate glucose disposal was enhanced as compared with that of sedentary rats fed the same fructose-rich diet. These data demonstrate that the insulin resistance, hyperinsulinemia, and hypertension produced in normotensive rats by feeding them a high fructose diet can be attenuated if rats are allowed to run spontaneously.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between lipoprotein levels and in vivo insulin action in normal young white men

Abstract: In epidemiologic studies, hyperinsulinemia has been found to be an independent risk factor for coronary heart disease (CHD). However, the mechanisms responsible for its role in atherogenesis remain unclear. We studied the relationship of in vivo insulin action and plasma lipids and lipoproteins in 44 normotriglyceridemic white men (aged 18 to 34 years). The euglycemic, hyperinsulinemic glucose clamp technique was used to quantitate insulin-mediated glucose disposal (MI value) at a plasma insulin concentration of approximately 100 μU/mL. The MI value correlated negatively with plasma triglycerides (r = −0.553, P < .0001), as well as with fasting plasma insulin levels (r = −0.483, P < .001), independent of age, body mass index, and fasting plasma glucose levels. A negative correlation of the MI value was also observed with very low density lipoprotein (VLDL)-cholesterol (r = −0.347, P < .05), VLDL-triglycerides (r = −0.474, P < 0.005), and total cholesterol/high density lipoprotein (HDL)-cholesterol ratio (r = −0.431, P < .01). The relationship between the MI value and the total cholesterol/HDL-cholesterol ratio was independent of VLDL-cholesterol and VLDL-triglycerides, however, not independent of plasma triglycerides. No relationship was observed between insulin-mediated glucose uptake and total cholesterol, low density lipoprotein (LDL)-cholesterol, and HDL-cholesterol values. Individual differences in plasma triglycerides, fasting insulin concentration, and the total cholesterol/HDL-cholesterol ratio accounted for about half the variance observed in the MI value. In conclusion, our findings in normal healthy men support the contention that hyperinsulinemia or insulin resistance may enhance the risk of CHD by adversely affecting lipoprotein levels such as VLDL-cholesterol, VLDL-triglyceride, and the ratio of total cholesterol/HDL-cholesterol.

Etiology and Prevalence of Hypertension in Diabetic Patients

Abstract: Data from several epidemiologic studies have suggested that the prevalence of hypertension in patients with diabetes mellitus is approximately 1.5-2.0 times greater than in an appropriately matched nondiabetic population. In patients with insulin-dependent diabetes mellitus (IDDM), hypertension is generally not present at the time of diagnosis. As renal insufficiency develops, blood pressure rises and may exacerbate the progression to end-stage renal failure. In non-insulin-dependent diabetes mellitus (NIDDM), many patients are hypertensive at the time of diagnosis. The incidence of hypertension in NIDDM is related to the degree of obesity, advanced age, and extensive atherosclerosis that is typically present, and it probably includes many patients with essential hypertension. Several other pathophysiologic mechanisms also contribute to the genesis and maintenance of hypertension in the patient with diabetes. Hyperglycemia and increases in total-body exchangeable sodium may lead to extracellular fluid accumulation and expansion of the plasma volume. In some patients, alterations in the function of the renin-angiotensin-aldosterone system and vascular sensitivity to vasoactive hormones may also play a role. It has recently been suggested that hyperinsulinemia and insulin resistance may also contribute to the maintenance of an elevated blood pressure because insulin is known to promote sodium retention and enhance sympathetic nervous system activity. The evidence for these hypotheses and their respective contributions to the etiology of hypertension in IDDM and NIDDM are discussed.

Lipolysis in human adipocytes, effects of cell size, age and of regional differences.

Abstract: In man only catecholamines and insulin have pronounced and acute effects on lipolysis in fat cells. In obesity the effects of these hormones seem to be normal or even increased. When the rate of lipolysis is expressed per cell there is a strong association between hormonal effect and cell size. Indicating that catecholamines and insulin may be involved in the regulation of adipocyte volume. There are, however, site variations in the effects of the regulatory hormones, which may be of importance for the development of various regional forms of obesity. The lipolytic effect of catecholamines is more pronounced in the abdominal than in the femoral/gluteal subcutaneous fat depots, partly owing to an increased alpha 2-adrenergic receptor mediated antilipolytic effect of catecholamines in the latter region. This alteration in lipolysis favour accumulation of fat in the femoral/gluteal region and may be of importance for the development of the female type of obesity. Furthermore, in omental fat cells the lipolytic activity is higher than in subcutaneous fat cells owing in part to less marked insulin action and lower alpha 2-adrenergic receptor mediated antilipolytic effect of catecholamines. These alterations may cause elevation of the free fatty acid levels in the portal blood so that the handling of glucose and insulin is impaired in the liver which may be one mechanism behind the increased risk to develop cardiovascular complications in the male type of obesity. Age also influences hormone-induced lipolysis. Catecholamine resistance is observed at birth and at the latest stages of life. Insulin resistance is observed in old as compared to middle-aged subjects.

Glucose metabolism in obesity: influence of body fat distribution.

Abstract: The dose-response relationships between portal venous insulin concentrations and hepatic glucose production and between peripheral insulin concentrations and peripheral glucose utilization were determined in 8 nonobese and 17 obese premenopausal women with either upper or lower body fat localization. The glucose production dose-response curves for the two obese groups were shifted to the right at all levels of portal insulinemia. The upper body obese women had a greater rightward shift compared to the lower body obese women. The peripheral glucose utilization dose-response curve was shifted to the right in the lower body obese women, but maximal glucose utilization was normal. The upper body obese women had both a greater rightward shift and a marked reduction in maximal glucose utilization. The insulin concentrations that had halfmaximal effects on glucose production and utilization were similar in each group. These results indicate that the liver is not inherently more sensitive to insulin than peripher...