Showing papers on "Insulin resistance published in 1991"
TL;DR: In summary, insulin resistance appears to be a syndrome that is associated with a clustering of metabolic disorders, including non-insulin-dependent diabetes mellitus, obesity, hypertension, lipid abnormalities, and atherosclerotic cardiovascular disease.
Abstract: Diabetes mellitus is commonly associated with systolic/diastolic hypertension, and a wealth of epidemiological data suggest that this association is independent of age and obesity. Much evidence indicates that the link between diabetes and essential hypertension is hyperinsulinemia. Thus, when hypertensive patients, whether obese or of normal body weight, are compared with age- and weight-matched normotensive control subjects, a heightened plasma insulin response to a glucose challenge is consistently found. A state of cellular resistance to insulin action subtends the observed hyperinsulinism. With the insulin/glucose-clamp technique, in combination with tracer glucose infusion and indirect calorimetry, it has been demonstrated that the insulin resistance of essential hypertension is located in peripheral tissues (muscle), is limited to nonoxidative pathways of glucose disposal (glycogen synthesis), and correlates directly with the severity of hypertension. The reasons for the association of insulin resistance and essential hypertension can be sought in at least four general types of mechanisms: Na+ retention, sympathetic nervous system overactivity, disturbed membrane ion transport, and proliferation of vascular smooth muscle cells. Physiological maneuvers, such as calorie restriction (in the overweight patient) and regular physical exercise, can improve tissue sensitivity to insulin; evidence indicates that these maneuvers can also lower blood pressure in both normotensive and hypertensive individuals. Insulin resistance and hyperinsulinemia are also associated with an atherogenic plasma lipid profile. Elevated plasma insulin concentrations enhance very-low-density lipoprotein (VLDL) synthesis, leading to hypertriglyceridemia. Progressive elimination of lipid and apolipoproteins from the VLDL particle leads to an increased formation of intermediate-density and low-density lipoproteins, both of which are atherogenic. Last, insulin, independent of its effects on blood pressure and plasma lipids, is known to be atherogenic. The hormone enhances cholesterol transport into arteriolar smooth muscle cells and increases endogenous lipid synthesis by these cells. Insulin also stimulates the proliferation of arteriolar smooth muscle cells, augments collagen synthesis in the vascular wall, increases the formation of and decreases the regression of lipid plaques, and stimulates the production of various growth factors. In summary, insulin resistance appears to be a syndrome that is associated with a clustering of metabolic disorders, including non-insulin-dependent diabetes mellitus, obesity, hypertension, lipid abnormalities, and atherosclerotic cardiovascular disease.
4,582 citations
TL;DR: The results confirm the existence of an insulin resistance syndrome, prevalent in South Asian populations and associated with a pronounced tendency to central obesity in this group, and control of obesity and greater physical activity offer the best chances for prevention of diabetes and CHD.
1,643 citations
TL;DR: It is hypothesized that free fatty acids and testosterone might provide a background not only to a defense reaction and primary hypertension, suggested previously, but also to a defeat reaction, which contributes to an endocrine aberration leading to metabolic aberrations and visceral fat accumulation, which in turn leads to disease.
Abstract: Insulin resistance is the cornerstone for the development of non-insulin-dependent diabetes mellitus (NIDDM). Free fatty acids (FFAs) cause insulin resistance in muscle and liver and increase hepatic gluconeogenesis and lipoprotein production and perhaps decrease hepatic clearance of insulin. It is suggested that the depressing effect of insulin on circulating FFA concentration is dependent on the fraction derived from visceral adipocytes, which have a low responsiveness to the antilipolytic effect of insulin. Elevated secretion of cortisol and/or testosterone induces insulin resistance in muscle. This also seems to be the case for low testosterone concentrations in men. In addition, cortisol increases hepatic gluconeogenesis. Cortisol and testosterone have “permissive” effect on adipose lipolysis and therefore amplify lipolytic stimulation; FFA, cortisol, and testosterone thus have powerful combined effects, resulting in insulin resistance and increased hepatic gluconeogenesis. All these factors promoting insulin resistance are active in abdominal visceral obesity, which is closely associated with insulin resistance, NIDDM, and the “ metabolic syndrome.” In addition, the endocrine aberrations may provide a cause for visceral fat accumulation, probably due to regional differences in steroid-hormone-receptor density. In addition to the increased activity along the adrenocorticosteroid axis, there also seem to be signs of increased activity from the central sympathetic nervous system. These are the established endocrine consequences of hypothalamic arousal in the defeat and defense reactions. There is some evidence that suggests an increased prevalence of psychosocial stress factors is associated with visceral distribution of body fat. Therefore, it is hypothesized that such factors might provide a background not only to a defense reaction and primary hypertension, suggested previously, but also to a defeat reaction, which contributes to an endocrine aberration leading to metabolic aberrations and visceral fat accumulation, which in turn leads to disease.
1,033 citations
TL;DR: It is concluded that the particular fatty acids and the lipid environment in which they are presented in high-fat diets determine insulin sensitivity in rats and impaired insulin action in skeletal muscle relates to triglyceride accumulation, suggesting intracellular glucose–fatty acid cycle involvement.
Abstract: High levels of some but not all dietary fats lead to insulin resistance in rats. The aim of this study was to investigate the important determinants underlying this observation. Insulin action was assessed with the euglycemic clamp. Diets high in saturated, monounsaturated (ω-9), or polyunsaturated (ω-6) fatty acids led to severe insulin resistance; glucose infusion rates [GIR] to maintain euglycemia at ∼1000 pM insulin were 6.2 ± 0.9, 8.9 ± 0.9, and 9.7 ± 0.4 mg · kg −1 · min −1 , respectively, versus 16.1 ± 1.0 mg · kg −1 · min −1 in chow-fed controls. Substituting 11% of fatty acids in the polyunsaturated fat diet with long-chain ω-3 fatty acids from fish oils normalized insulin action (GIR 15.0 ± 1.3 mg · kg −1 · min −1 ). Similar replacement with short-chain ω-3 (α-linolenic acid, 18:3ω3) was ineffective in the polyunsaturated diet (GIR 9.9 ± 0.5 mg · kg −1 · min −1 ) but completely prevented the insulin resistance induced by a saturated-fat diet (GIR 16.0 ± 1.5 mg · kg −1 · min −1 ) and did so in both the liver and peripheral tissues. Insulin sensitivity in skeletal muscle was inversely correlated with mean muscle triglyceride accumulation ( r = 0.95 and 0.86 for soleus and red quadriceps, respectively; both P = 0.01). Furthermore, percentage of long-chain ω-3 fatty acid in phospholipid measured in red quadriceps correlated highly with insulin action in that muscle ( r = 0.97). We conclude that 1 ) the particular fatty acids and the lipid environment in which they are presented in high-fat diets determine insulin sensitivity in rats; 2 ) impaired insulin action in skeletal muscle relates to triglyceride accumulation, suggesting intracellular glucose–fatty acid cycle involvement; and 3 ) long-chain ω-3 fatty acids in phospholipid of skeletal muscle may be important for efficient insulin action.
994 citations
TL;DR: It is indicated that a unique metabolic pathway exists in adipocytes that mediates desensitization of the insulin-responsive GTS, and that an early step in this pathway involves the conversion of fructose 6-phosphate to glucosamine 6- phosphate by the first and rate-limiting enzyme of the hexosamine pathway, glutamine:fructose-6-ph phosphate amidotransferase.
971 citations
TL;DR: It is concluded that insulin sensitivity, glucose tolerance, blood pressure, body fat mass and distribution, and serum lipids are a network of mutually interrelated functions and an insulin resistance syndrome underlies each and all of the six disorders carrying an increased risk of coronary artery disease.
Abstract: In a population-based survey of 2,930 subjects, prevalence rates for obesity, Type 2 (non-insulin-dependent) diabetes mellitus, impaired glucose tolerance, hypertension, hypertriglyceridaemia, and hypercholesterolaemia were 54.3, 9.3, 11.1, 9.8, 10.3 and 9.2%, respectively. The prevalence, however, of each of these conditions in its isolated form (free of the other five) was 29.0% for obesity, 1.3% for Type 2 diabetes, 1.8% for impaired glucose tolerance, 1.5% for hypertension, 1.0% for hypertriglyceridaemia, and 1.7% for hypercholesterolaemia. Two-by-two associations were even rarer. The large differences in prevalence between isolated and mixed forms indicate a major overlap among the six disorders in multiple combinations. In the isolated form, each condition was characterized by hyperinsulinaemia (both fasting and 2 h after oral glucose), suggesting the presence of insulin resistance. In addition, in any isolated condition most of the variables categorising other members of the sextet were still significantly altered in comparison with 1,049 normal subjects. In the whole of the subjects who presented with one or another disorder (1,881 of 2,930 or 64%), marked fasting and post-glucose hyperinsulinaemia was associated with higher body mass index, waist:hip ratio, fasting and post-glucose glycaemia, systolic and diastolic blood pressure, serum triglycerides and total cholesterol levels, and with lower HDL-cholesterol concentrations (all p <0.001). We conclude that (1) insulin sensitivity, glucose tolerance, blood pressure, body fat mass and distribution, and serum lipids are a network of mutually interrelated functions; and (2) an insulin resistance syndrome underlies each and all of the six disorders carrying an increased risk of coronary artery disease.
895 citations
TL;DR: This review discusses current concepts of the mechanisms of insulin action and insulin resistance and the implications of insulin resistance for a variety of disorders, including obesity, diabetes mellitus, ovarian hyperan-drogenism, and possibly hypertension.
Abstract: The past 20 years have witnessed a remarkable increase in our knowledge of the cellular and molecular mechanisms that underlie the diverse actions of insulin, the central hormone of metabolic regulation. Interest in the molecular details of insulin action has been heightened by the prevalence of insulin resistance and by the fact that insulin resistance has a key role in the pathogenesis of many disorders, including obesity, diabetes mellitus, ovarian hyperan-drogenism, and possibly hypertension. In this review, we discuss current concepts of the mechanisms of insulin action and insulin resistance and the implications of insulin resistance for a variety of . . .
792 citations
TL;DR: Urinary uric acid clearance appears to decrease in proportion to increases in insulin resistance in normal volunteers, leading to an increase in serum uric Acid concentration, which appears to be exerted at the level of the kidney.
Abstract: Objective. —To define the relationship, if any, between insulin-mediated glucose disposal and serum uric acid. Design. —Cross-sectional study of healthy volunteers. Setting.— General Clinical Research Center, Stanford (Calif) University Medical Center. Participants. —Thirty-six presumably healthy individuals, nondiabetic, without a history of gout. Measurements. —Obesity (overall and regional), plasma glucose and insulin responses to a 75-g oral glucose load, fasting uric acid concentrations, plasma triglyceride and high-density lipoprotein—cholesterol concentrations, systolic and diastolic blood pressure, insulin-mediated glucose disposal, and urinary uric acid clearance. Results. —Magnitude of insulin resistance and serum uric acid concentration were significantly related ( r =.69; P r =.57; P r = -.49; P r = -.61; P Conclusions. —Urinary uric acid clearance appears to decrease in proportion to increases in insulin resistance in normal volunteers, leading to an increase in serum uric acid concentration. Thus, it appears that modulation of serum uric concentration by insulin resistance is exerted at the level of the kidney. ( JAMA . 1991;266:3008-3011)
787 citations
TL;DR: Fat feeding induces insulin resistance in liver and adipose tissue before skeletal muscle with early metabolic changes favoring an oversupply of energy substrate to skeletal muscle relative to metabolic needs, which may generate later muscle insulin resistance.
Abstract: Muscle and hepatic insulin resistance are two major defects of non-insulin-dependent diabetes mellitus. Dietary factors may be important in the etiology of insulin resistance. We studied progressive changes in the development of high-fat–diet–induced insulin resistance in tissues of the adult male Wistar rat. In vivo insulin action was compared 3 days and 3 wk after isocaloric synthetic high-fat or high-starch feeding (59 and 10% cal as fat, respectively). Basal and insulin-stimulated glucose metabolism were assessed in the conscious 5- to 7-h fasted state with the euglycemic clamp (600 pM insulin) with a [3-3H]-glucose infusion. Fat feeding significantly reduced suppressibility of hepatic glucose output by insulin after both 3 days and 3 wk of diet (P < 0.01). However, a significant impairment of insulin-mediated peripheral glucose disposal was only present after 3 wk of diet. Further in vivo [3H]-2-deoxyglucose uptake studies supported this finding and demonstrated adipose but not muscle insulin resistance after 3 days of high-fat feeding. Muscle triglyceride accumulation due to fat feeding was not significant at 3 days but had doubled by 3 wk in red muscle ( P < 0.001) compared with starch-fed controls. By 3 wk, high-fat—fed animals had developed significant glucose intolerance. We concludethat fat feeding induces insulin resistance in liver and adipose tissue before skeletal muscle with early metabolic changes favoring an oversupply of energy substrate to skeletal muscle relative to metabolic needs. This may generate later muscle insulin resistance.
628 citations
TL;DR: These results are the first to prospectively evaluate the longitudinal changes in maternal carbohydrate metabolism from the time before conception through late gestation with newer methods such as the hyperinsulinemic-euglycemic clamp.
616 citations
TL;DR: In this article, a hypothesis based on basal hyperproinsulinemia and islet amyloid deposits in the pancreas of type II diabetes is reviewed, which leads to progressive accumulation of intracellular IAPP and pro-IAPP.
Abstract: In 1960, immunoassays of insulin first demonstrated significant quantities of circulating hormone in non-insulin-dependent (type II) diabetes and for 30 yr have fostered debate as to whether a beta-cell abnormality plays an etiological role in this syndrome. Early efforts to determine the adequacy of islet beta-cell function showed that obesity and its associated insulin resistance were major confounding variables. Subsequently, it was recognized that glucose not only directly regulated insulin synthesis and secretion but moderated all other islet signals, including other substrates, hormones, and neural factors. When both obesity and glucose are taken into account, it becomes clear that patients with fasting hyperglycemia all have abnormal islet function. Type II diabetes is characterized by a defect in first-phase or acute glucose-induced insulin secretion and a deficiency in the ability of glucose to potentiate other islet nonglucose beta-cell secretagogues. The resulting hyperglycemia compensates for the defective glucose potentiation and maintains nearly normal basal insulin levels and insulin responses to nonglucose secretagogues but does not correct the defect in first-phase glucose-induced insulin release. Before the development of fasting hyperglycemia, only first-phase glucose-induced insulin secretion is obviously defective. This is because progressive islet failure is matched by rising glucose levels to maintain basal and second-phase insulin output. The relationship between islet function and fasting plasma glucose is steeply curvilinear, so that there is a 75% loss of beta-cell function by the time the diagnostic level of 140 mg/dl is exceeded. This new steady state is characterized by glucose overproduction and inefficient utilization. Insulin resistance is also present in most patients and contributes to the hyperglycemia by augmenting the glucose levels needed for compensation. Decompensation and absolute hypoinsulinemia occur when the renal threshold for glucose is exceeded and prevents further elevation of circulating glucose. The etiology of the islet beta-cell lesion is not known, but a hypothesis based on basal hyperproinsulinemia and islet amyloid deposits in the pancreas of type II diabetes is reviewed. The recent discovery of the islet amyloid polypeptide (IAPP) or amylin, which is the major constituent of islet amyloid deposits, is integrated into this hypothesis. It is suggested that pro-IAPP and proinsulin processing and mature peptide secretion normally occur together and that abnormal processing, secondary to or in conjunction with defects in hormone secretion, lead to progressive accumulation of intracellular IAPP and pro-IAPP, which in cats, monkeys, and humans form intracellular fibrils and amyloid deposits with a loss of beta-cell mass.(ABSTRACT TRUNCATED AT 400 WORDS)
TL;DR: The increase in plasma plasminogen activator inhibitor 1 levels linked to hyperinsulinaemia is a tempting partial explanation for the association between insulin resistance and coronary disease.
Abstract: According to recent prospective studies, hypofibrinolysis due to elevated plasma plasminogen activator inhibitor 1 levels appears to be an independent risk factor for myocardial reinfarction in men, and hyperinsulinaemia, a major indicator of insulin resistance is considered as a risk factor for coronary disease. It has recently been shown that insulin resistance is accompanied by an increased plasma plasminogen activator inhibitor 1 concentration: A significant correlation coefficient was demonstrated between plasminogen activator inhibitor 1 and fasting plasma insulin in the normal population, in obese subjects, in Type 2 (non-insulin-dependent) diabetic patients and in angina pectoris. Attempts to decrease insulin resistance such as fasting, diet, or administration of an oral anti-diabetic drug such as Metformin induced a parallel decrease in plasma insulin and plasminogen activator inhibitor 1 levels. This inhibitor is produced by endothelial cells and by hepatocytes in culture. Plasminogen activator inhibitor 1 synthesis by hepatocytes in culture was stimulated by an increasing insulin concentration, or low density lipoproteins, whereas the endothelial cell synthesis was stimulated by very low density lipoproteins especially when they were obtained from hypertriglyceridaemic patients. Therefore, a direct effect of insulin or lipoprotein changes on the cells which synthesize plasminogen activator inhibitor 1 could be responsible for its increased plasma concentration in insulin resistance states. The increase in plasma plasminogen activator inhibitor 1 levels linked to hyperinsulinaemia is a tempting partial explanation for the association between insulin resistance and coronary disease.
TL;DR: The relations between insulinemia, insulin resistance, and blood pressure differ among racial groups and may be mediated by mechanisms active in whites, but not in Pima Indians or blacks.
Abstract: Background. Insulin resistance and the concomitant compensatory hyperinsulinemia have been implicated in the pathogenesis of hypertension. However, reports on the relation between insulin and blood pressure are inconsistent. This study was designed to investigate the possibility of racial differences in this relation. Methods. We studied 116 Pima Indians, 53 whites, and 42 blacks who were normotensive and did not have diabetes; the groups were comparable with respect to mean age (29, 30, and 31 years, respectively) and blood pressure (113/70, 111/68, and 113/68 mm Hg, respectively). Insulin resistance was determined by the euglycemic—hyperinsulinemic clamp technique during low-dose (40 mU per square meter of body-surface area per minute) and high-dose (400 mU per square meter per minute) insulin infusions. Results. The Pima Indians had higher fasting plasma insulin concentrations than the whites or blacks (176, 138, and 122 pmol per liter, respectively; P = 0.002) and lower rates of whole-body gl...
TL;DR: The lack of response to insulin appeared due to a suppression ofGLUT4 expression as well as a decreased intracellular content of GLUT1, which was judged to be regulated at least in part at the level of transcription.
TL;DR: The results are consistent with the hypothesis that insulin resistance is associated with a higher risk of coronary heart disease mortality, however, it is doubtful that circulating insulin per se is a direct cause of arterial complications.
Abstract: The Paris Prospective Study is a long-term, largescale study of the factors predicting coronary heart disease. The first follow-up examination included, for subjects not known as having diabetes mellitus, a 75 g oral glucose tolerance test with measurement of plasma insulin and glucose levels, fasting and 2 h post-load. Between 1968 and 1973, 6903 men aged 43–54 years were thus examined. Causes of death were ascertained within this group after 15 years of mean follow-up. The baseline variables were tested as predictors of death from coronary heart disease by a Cox regression analysis. Significant independent predictors of coronary heart disease death were: systolic blood pressure, number of cigarettes per day, plasma cholesterol level, and 2 h post-load plasma insulin level when entered as a categorical variable (below or above 452 pmol/l, i.e. the lower limit of the fifth quintile of the distribution). This dichotomization was performed to account for the non-linear univariate distribution of deaths with increasing post-load insulin values. Fasting plasma insulin level was not an independent predictor of death by coronary heart disease over this long-term follow-up. Levels of blood glucose were not significant independent predictors of death by coronary heart disease when plasma insulin levels were included in the model. The same applied to abnormalities of glucose tolerance when the 125 men with known non-insulin-treated diabetes at baseline were added to the group. Under the assumption that hyperinsulinaemia is a marker of insulin resistance, the results are consistent with the hypothesis that insulin resistance is associated with a higher risk of coronary heart disease mortality. However, it is doubtful that circulating insulin per se is a direct cause of arterial complications.
TL;DR: Resistance to insulin action on glucose uptake in peripheral tissues is a common underlying mechanism in hypertension and diabetes and may explain the unexpectedly high incidence of the development of diabetes among treated hypertensives and the poor effect on risk for coronary heart disease in intervention trials.
Abstract: The close relationship between diabetes and hypertension has been recognized for decades. New information indicates that resistance to insulin action on glucose uptake in peripheral tissues is a common underlying mechanism in hypertension and diabetes. In prospective trials, the effects of antihypertensive agents on insulin sensitivity and lipoprotein metabolism have been evaluated. Both beta-blockers and thiazide diuretics worsen insulin resistance and deteriorate lipoprotein metabolism. Angiotensin-converting enzyme (ACE) inhibitors, Ca2(+)-channel blockers, and alpha-blockers are neutral or improve these factors. These data may explain the unexpectedly high incidence of the development of diabetes among treated hypertensives and the poor effect on risk for coronary heart disease in intervention trials.
TL;DR: It is concluded that insulin resistance is associated with a reduced risk of weight gain in nondiabetic Pima Indians.
Abstract: Insulin resistance is commonly associated with obesity and noninsulin-dependent diabetes. Whereas it predicts the development of diabetes, its effect on body weight change is unknown. We measured glucose disposal rates at submaximally- and maximally-stimulating insulin concentrations in 192 nondiabetic Pima Indians and followed their weight change over 3.5 +/- 1.8 y (mean +/- SD). Results: (a) Insulin-resistant subjects gained less weight than insulin-sensitive subjects (3.1 vs. 7.6 kg, P less than 0.0001). (b) The percent weight change per year correlated with glucose disposal at submaximally-(r = 0.19, P less than 0.01) and maximally-stimulating (r = 0.34, P less than 0.0001) insulin concentrations independent of sex, age, initial weight, and 24-h energy expenditure; the correlations were stronger for glucose oxidation than for glucose storage. (c) Weight gain was associated with an increase in insulin resistance more than four times that predicted from the cross-sectional data. We conclude that insulin resistance is associated with a reduced risk of weight gain in nondiabetic Pima Indians.
TL;DR: There is evidence that the changes in glucose, insulin, and lipoprotein metabolism may play a role in the etiology and/or clinical course of patients with high blood pressure and an effort is made to marshal the evidence in support of the latter alternative.
Abstract: There is considerable evidence that abnormalities of glucose, insulin, and lipoprotein metabolism occur more frequently in untreated hypertensive patients than in normotensive control subjects. More recently, it has also become apparent that similar metabolic abnormalities occur in rodent models of hypertension. One purpose of this article is to review the experimental data that have led to the above generalizations. The second goal is to address the significance of these findings, which is certainly not clear. For example, it could be argued that the relationship between high blood pressure and the associated metabolic defects is incidental. On the other hand, there is evidence that the changes in glucose, insulin, and lipoprotein metabolism may play a role in the etiology and/or clinical course of patients with high blood pressure. Although it is impossible at this point to definitively choose between these possibilities, an effort is made to marshal the evidence in support of the latter alternative.
TL;DR: The hypothesis is advanced that in uncomplicated obesity, increased availability and oxidation of FFA leads, by the FFA/glucose cycle, to the impairment in glucose utilization, and in NIDDM, the defect in glucose usage is primary, and the enhanced rate of F FA oxidation may represent a compensatory phenomenon.
Abstract: To investigate the mechanisms of insulin resistance in obesity and noninsulin-dependent diabetes mellitus (NIDDM), we examined oxidative and nonoxidative pathways of free fatty acid (FFA) and glucose metabolism in 14 lean and 17 obese (with normal oral glucose tolerance) nondiabetic subjects and in 8 lean and 8 obese subjects with NIDDM. FFA and glucose metabolism were measured using the sequential insulin clamp technique in combination with indirect calorimetry and infusion of [3-3H]glucose and [1-14C]palmitate. Obesity was characterized by enlarged fat mass, which correlated positively with the plasma FFA concentration (r = 0.62; P less than 0.01). FFA metabolism was less sensitive to insulin in obese than in lean nondiabetic subjects, but this defect could be overcome by increasing the plasma insulin concentration. NIDDM patients showed normal sensitivity to the inhibitory action of insulin on FFA metabolism; however, maximal suppression by insulin was impaired. The combination of obesity and NIDDM was associated with a further enhancement of reesterification of FFA than observed in either condition alone. In both obesity and NIDDM, the dose-response curve for suppression of hepatic glucose production by insulin was impaired. While obesity was primarily characterized by reduced sensitivity to the stimulatory action of insulin on oxidative and nonoxidative pathways of glucose metabolism, resistance to the effect of insulin on glucose metabolism in NIDDM was characterized by a reduced maximal response. The combination of obesity and NIDDM further impaired the sensitivity of liver glucose output and glucose oxidation to insulin. The hypothesis is advanced that in uncomplicated obesity, increased availability and oxidation of FFA leads, by the FFA/glucose cycle, to the impairment in glucose utilization. In NIDDM, on the other hand, the defect in glucose utilization is primary, and the enhanced rate of FFA oxidation may represent a compensatory phenomenon.
TL;DR: It is concluded that, in obesity, insulin resistance in adipocytes is due to depletion ofGLUT 4 glucose transporters, and that the cellular content of GLUT 4 is determined by the level of encoding mRNA over a wide range of body weight.
Abstract: A major portion of insulin-mediated glucose uptake occurs via the translocation of GLUT 4 glucose transporter proteins from an intracellular depot to the plasma membrane. We have examined gene expression for the GLUT 4 transporter isoform in subcutaneous adipocytes, a classic insulin target cell, to better understand molecular mechanisms causing insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) and obesity. In subgroups of lean (body mass index [BMI] = 24 +/- 1) and obese (BMI = 32 +/- 2) controls and in obese NIDDM (BMI = 35 +/- 2) patients, the number of GLUT 4 glucose transporters was measured in total postnuclear and subcellular membrane fractions using specific antibodies on Western blots. Relative to lean controls, the cellular content of GLUT 4 was decreased 40% in obesity and 85% in NIDDM in total cellular membranes. In obesity, cellular depletion of GLUT 4 primarily involved low density microsomes (LDM), leaving fewer transporters available for insulin-mediated recruitment to the plasma membrane (PM). In NIDDM, loss of GLUT 4 was profound in all membrane subfractions, PM, LDM, as well as high density microsomes. These observations corresponded with decrements in maximally stimulated glucose transport rates in intact cells. To assess mechanisms responsible for depletion of GLUT 4, we quantitated levels of mRNA specifically hybridizing with human GLUT 4 cDNA on Northern blots. In obesity, GLUT 4 mRNA was decreased 36% compared with lean controls, and the level was well correlated (r = + 0.77) with the cellular content of GLUT 4 protein over a wide spectrum of body weight. GLUT 4 mRNA in adipocytes from NIDDM patients was profoundly reduced by 86% compared with lean controls and by 78% relative to their weight-matched nondiabetic counterparts (whether expressed per RNA, per cell, or for the amount of CHO-B mRNA). Interestingly, GLUT 4 mRNA levels in patients with impaired glucose tolerance (BMI = 34 +/- 4) were decreased to the same level as in overt NIDDM. We conclude that, in obesity, insulin resistance in adipocytes is due to depletion of GLUT 4 glucose transporters, and that the cellular content of GLUT 4 is determined by the level of encoding mRNA over a wide range of body weight. In NIDDM, more profound insulin resistance is caused by a further reduction in GLUT 4 mRNA and protein than is attributable to obesity per se. Suppression of GLUT 4 mRNA is observed in patients with impaired glucose tolerance, and therefore, may occur early in the evolution of diabetes. Thus, pretranslational suppression of GLUT 4 transporter gene expression may be an important mechanism that produces and maintains cellular insulin resistance in NIDDM.
TL;DR: The data suggest that insulin resistance during puberty is restricted to peripheral glucose metabolism, and selective insulin resistance leading to compensatory hyperinsulinemia may serve to amplify insulin's effect on amino acid metabolism, thereby facilitating protein anabolism during this period of rapid growth.
Abstract: To examine mechanisms underlying the development of insulin resistance during normal puberty, sequential 8 and 40 mU/m2·min euglycemic insulin clamp and hyperglycemic clamp studies were performed in 14 healthy prepubertal and 19 pubertal children. Both groups had comparable rates of glucose turnover and plasma levels of branched chain amino acids and FFA at baseline. The low as well as the high insulin dose stimulated peripheral glucose uptake much more effectively in prepubertal children (P < 0.05). In contrast, suppression of hepatic glucose production (60% at low dose in both groups, pNS) and lowering of substrates in response to insulin was not affected by puberty at either dose. During the hyperglycemic clamp pubertal children showed enhanced insulin responses and in turn a sharper fall in amino acids (P < 0.05 vs. prepubertals). Our data suggest that insulin resistance during puberty is restricted to peripheral glucose metabolism. Selective insulin resistance leading to compensatory hyperinsulinemia...
TL;DR: The role of insulin resistance, obesity, and independently inherited abnormalities of lipoprotein metabolism in the etiology of dyslipidemia of non-insulin-dependent (NIDDM) diabetes mellitus are complex and require further investigation as mentioned in this paper.
Abstract: Abnormalities of plasma lipid and lipoprotein concentrations are common in both insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus. In general, individuals with IDDM who are untreated or inadequately treated have elevations in both postprandial and fasting triglyceride levels in association with reduced activity of lipoprotein lipase. Low-density lipoprotein (LDL) cholesterol levels can rise when insulin deficiency impacts on LDL-receptor function. When patients with IDDM are treated and plasma glucose levels well controlled, plasma very-low-density lipoprotein (VLDL) triglyceride and LDL cholesterol levels are usually normal. In addition, plasma high-density lipoprotein (HDL) cholesterol levels are normal or elevated in well-controlled IDDM subjects. In NIDDM, increased VLDL triglyceride and reduced HDL cholesterol concentrations are common and are only partially related to glycemic control. Overproduction of VLDL leads to hypertriglyceridemia, which can be exacerbated if lipoprotein lipase activity is also reduced. The regulation of LDL levels is complex; catabolism can be reduced if significant insulin deficiency exists or increased if significant hypertriglyceridemia is present. The reduced levels of HDL cholesterol in NIDDM appear to be related to increased exchange of HDL cholesteryl esters for VLDL triglycerides, although other mechanisms may exist. The roles of insulin resistance, obesity, and independently inherited abnormalities of lipoprotein metabolism in the etiology of dyslipidemia of NIDDM are complex and require further investigation. Finally, the effects of diabetes on glycosylation of apoproteins; on other lipid enzymes, particularly hepatic triglyceride lipase; on lipoprotein surface lipids; and on hepatic uptake of remnants have only just begun to be defined. In view of the marked increase in atherosclerotic cardiovascular disease in individuals with diabetes mellitus, prompt attention to and aggressive therapy for dyslipidemia should be a central component of care for these patients.
TL;DR: Methods for accurate measurement of the amount and distribution of fat have become an important clinical consideration because of the increased mortality and morbidity associated with obesity.
Abstract: OBESITY is usually a descriptive term for excess body fat. Assessment of the presence and extent of obesity is often subjective and influenced by cosmetic and cultural considerations. However, recent interest has focused on the increased mortality and morbidity associated with both the extent and pattern of obesity (1, 2).1 Therefore, methods for accurate measurement of the amount and distribution of fat have become an important clinical consideration. The cause of the increased mortality and morbidity associated with obesity is not yet known. Obesity is associated with an increased incidence of diabetes, hypertension, increased levels of very low density lipoproteins (VLDL) triglycerides, low density lipoproteins (LDL) cholesterol, and decreased levels of high density lipoproteins (HDL) cholesterol, all of which are risk factors for the development of vascular disease. Whereas it has been known for many years that obesity is associated with insulin resistance, Reaven (3) has recently pointed out that app...
TL;DR: Evidence is summarized in support of the hypothesis that resistance to insulin-stimulated glucose uptake and hyperinsulinemia may play a central role in the cause and clinical course of patients with non-insulin-dependent diabetes mellitus, high blood pressure, abnormalities of lipoprotein metabolism, and coronary heart disease.
TL;DR: I have reviewed recent studies that shed light on the paradox of insulin-induced ovarian hyperandrogenism in insulin-resistant states and found that depending on the circumstances of the particular syndrome, insulin could act on the ovaries of diabetes patients by activating IGF-I receptor receptors, insulin receptors, hybrid insulin/IGF-I receptors, or any combination of these receptors.
Abstract: I have reviewed recent studies that shed light on the paradox of insulin-induced ovarian hyperandrogenism in insulin-resistant states Depending on the circumstances of the particular syndrome, insulin could act on the ovaries of insulin-resistant patients by activating IGF-I receptors, insulin receptors, hybrid insulin/IGF-I receptors, or any combination of these receptors Further studies will uncover precise mechanisms of insulin-induced ovarian hyperstimulation in specific syndromes of insulin resistance
TL;DR: Based on longitudinal studies in the Pima Indians, a population with the world's highest reported prevalence of NIDDM, a two-step model for development of the disease is proposed, for which insulin resistance is the main determinant and beta-cell dysfunction plays a critical role.
TL;DR: The findings reveal the quantitative nature of the reciprocal changes in insulin sensitivity and B-cell function that normally accompany late pregnancy and indicate that during the third trimester, mild gestational diabetes is characterized by an impairment of pancreatic B- cell function rather than an exaggeration of the normal insulin resistance of late pregnancy.
TL;DR: Results provide the first direct evidence that asymptomatic atherosclerosis is associated with insulin resistance, and this insulin resistance is characterized by reduced whole-body and nonoxidative glucose uptake.
Abstract: High plasma insulin has been shown to be associated with the risk of coronary heart disease in nondiabetic subjects in prospective population studies. Furthermore, insulin resistance measured by the euglycemic glucose clamp technique has been shown to be related to lipid and lipoprotein changes favoring atherosclerosis and to high blood pressure. No study, however, has demonstrated that insulin resistance per se is directly associated with atherosclerosis. With this aim, we studied 30 middle-aged nonobese subjects with asymptomatic atherosclerosis in the femoral or carotid arteries and 13 corresponding control subjects. Fasting blood glucose, insulin, and C-peptide levels were only slightly and nonsignificantly higher in subjects with atherosclerosis than in controls, and during the oral glucose tolerance test 1- and 2-hour glucose, insulin, and C-peptide levels were similar in both groups. During the euglycemic hyperinsulinemic (1,200 pmol/l) clamp studies, subjects with atherosclerosis had a 20% reduced whole-body glucose uptake (58 +/- 2 versus 71 +/- 4 mumol/kg/min, p = 0.004). Glucose oxidation, lipid oxidation, suppression of free fatty acid levels, and potassium disposal were similar in both groups. In contrast, nonoxidative glucose disposal was significantly reduced in patients compared with that in controls (37 +/- 2 versus 50 +/- 4 mumol/kg/min, p = 0.004). When glucose uptakes were matched during the hyperglycemic clamp studies, the rate of nonoxidative glucose uptake was normalized in the patients. These results provide the first direct evidence that asymptomatic atherosclerosis is associated with insulin resistance. This insulin resistance is characterized by reduced whole-body and nonoxidative glucose uptake. In contrast, glucose and lipid oxidation, potassium disposal, and suppression of free fatty acid levels during hyperinsulinemia did not differ between the subjects with and without atherosclerosis.
TL;DR: The epidemiological findings of the Paris Prospective Study and of other investigations support the hypothesis that a constellation of mild metabolic abnormalities may play a deleterious role with regard to cardiovascular disease risk.
Abstract: The Paris Prospective Study is a long-term investigation of coronary heart disease (CHD) risk factors in a large population of working men. The baseline cohort included 7028 men, 6093 who had a 75-g oral glucose tolerance test with measurement of plasma insulin and glucose levels (0 and 2 h) and 125 who were known non-insulin-treated diabetic patients. After a mean follow-up of 11 yr, 126 deaths ascribed to CHD were reported. Major independent predictors of CHD death were blood pressure, smoking, plasma cholesterol level, and fasting and 2-h postload plasma insulin level. Impairment of glucose tolerance, including overt diabetes, did not rank as an independent predictor when other baseline variables were accounted for. In the subset of the baseline cohort who presented with impaired glucose tolerance or diabetes (n = 943), 26 died from CHD during the follow-up. The strongest independent predictor of subsequent CHD death in this subsample with abnormal glucose tolerance was plasma triglyceride level. In view of the accumulating evidence that hyperinsulinemia and hypertriglyceridemia generally occur in the same type of subjects, in relation to insulin resistance and central obesity, the epidemiological findings of the Paris Prospective Study and of other investigations support the hypothesis that a constellation of mild metabolic abnormalities may play a deleterious role with regard to cardiovascular disease risk.