Maximal Glucose Disposal Rate Research Articles

Prolonged hypoglycaemia after insulin lispro overdose

Insulin lispro has a more rapid onset and a shorter duration of hypoglycaemic action than regular insulin. We report a 39-year-old woman, with no previous medical history, who injected 300 U of the insulin lispro (Humalog) in an attempted suicide. Half an hour later, she was found comatose and brought to our emergency department. On arrival, she was comatose, with capillary glucose of 0.4 mmol/L. She awoke after a 50 ml intravenous bolus of 50% glucose. A continuous infusion of 10% glucose was started. Intermittent hypoglycaemia with neurological signs requiring treatment with 50% glucose was recorded three times during subsequent hospitalization, the last episode being 11 h after insulin injection. The plasma insulin level 4 h after injection was 1465 mU/L, and 18 h after injection was 11 mU/L. Hypoglycaemia after an insulin lispro overdose may last for more than 11 h. Repeated hypoglycaemia after an insulin overdose could be avoided with a glucose infusion rate equivalent to the maximal glucose disposal rate.

Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance.

The insulin resistance syndrome (IRS) is associated with dyslipidemia and increased cardiovascular disease risk. A novel method for detailed analyses of lipoprotein subclass sizes and particle concentrations that uses nuclear magnetic resonance (NMR) of whole sera has become available. To define the effects of insulin resistance, we measured dyslipidemia using both NMR lipoprotein subclass analysis and conventional lipid panel, and insulin sensitivity as the maximal glucose disposal rate (GDR) during hyperinsulinemic clamps in 56 insulin sensitive (IS; mean +/- SD: GDR 15.8 +/- 2.0 mg. kg(-1). min(-1), fasting blood glucose [FBG] 4.7 +/- 0.3 mmol/l, BMI 26 +/- 5), 46 insulin resistant (IR; GDR 10.2 +/- 1.9, FBG 4.9 +/- 0.5, BMI 29 +/- 5), and 46 untreated subjects with type 2 diabetes (GDR 7.4 +/- 2.8, FBG 10.8 +/- 3.7, BMI 30 +/- 5). In the group as a whole, regression analyses with GDR showed that progressive insulin resistance was associated with an increase in VLDL size (r = -0.40) and an increase in large VLDL particle concentrations (r = -0.42), a decrease in LDL size (r = 0.42) as a result of a marked increase in small LDL particles (r = -0.34) and reduced large LDL (r = 0.34), an overall increase in the number of LDL particles (r = -0.44), and a decrease in HDL size (r = 0.41) as a result of depletion of large HDL particles (r = 0.38) and a modest increase in small HDL (r = -0.21; all P < 0.01). These correlations were also evident when only normoglycemic individuals were included in the analyses (i.e., IS + IR but no diabetes), and persisted in multiple regression analyses adjusting for age, BMI, sex, and race. Discontinuous analyses were also performed. When compared with IS, the IR and diabetes subgroups exhibited a two- to threefold increase in large VLDL particle concentrations (no change in medium or small VLDL), which produced an increase in serum triglycerides; a decrease in LDL size as a result of an increase in small and a reduction in large LDL subclasses, plus an increase in overall LDL particle concentration, which together led to no difference (IS versus IR) or a minimal difference (IS versus diabetes) in LDL cholesterol; and a decrease in large cardioprotective HDL combined with an increase in the small HDL subclass such that there was no net significant difference in HDL cholesterol. We conclude that 1) insulin resistance had profound effects on lipoprotein size and subclass particle concentrations for VLDL, LDL, and HDL when measured by NMR; 2) in type 2 diabetes, the lipoprotein subclass alterations are moderately exacerbated but can be attributed primarily to the underlying insulin resistance; and 3) these insulin resistance-induced changes in the NMR lipoprotein subclass profile predictably increase risk of cardiovascular disease but were not fully apparent in the conventional lipid panel. It will be important to study whether NMR lipoprotein subclass parameters can be used to manage risk more effectively and prevent cardiovascular disease in patients with the IRS.

TNF-alpha-induced insulin resistance in vivo and its prevention by troglitazone.

Tumor necrosis factor (TNF)-alpha may play a role in the insulin resistance of obesity and NIDDM. Troglitazone is a new orally active hypoglycemic agent that has been shown to ameliorate insulin resistance and hyperinsulinemia in both diabetic animal models and NIDDM subjects. To determine whether this drug could prevent the development of TNF-alpha-induced insulin resistance, glucose turnover was assessed in rats infused with cytokine and pretreated with troglitazone. Normal male Sprague-Dawley rats were fed normal powdered food with or without troglitazone as a food admixture (0.2%). After approximately 10 days, rats were infused with TNF-alpha for 4-5 days, producing a plasma concentration of 632 +/- 30 pg/ml. In vivo insulin action was measured by the euglycemic-hyperinsulinemic clamp technique at a submaximal (24 micromol x kg[-1] x min[-1]) and maximal insulin infusion rate (240 micromol x kg[-1] x min[-1]). TNF-alpha infusion resulted in a pronounced reduction in submaximal insulin-stimulated glucose disposal rate (GDR) (97 +/- 10 vs. 141 +/- 4 micromol x kg[-1] x min[-1], P < 0.05), maximal GDR (175 +/- 8 vs. 267 +/- 6 micromol x kg[-1] x min[-1], P < 0.01), and in insulin receptor-tyrosine kinase activity (IR-TKA) (248 +/- 39 vs. 406 +/- 32 fmol ATP/fmol IR, P < 0.05). It also led to a marked increase in basal insulin (90 +/- 24 vs. 48 +/- 6 micromol/l, P < 0.05) and free fatty acid (FFA) concentration (2.56 +/- 0.76 vs. 0.87 +/- 0.13 mmol/l, P < 0.01). Troglitazone treatment completely prevented the TNF-alpha-induced decline in submaximal GDR (133 +/- 16 vs. 141 +/- 4 micromol x kg[-1] x min[-1], NS) and maximal GDR (271 +/- 19 vs. 267 +/- 6 micromol x kg[-1] x min[-1], NS). The hyperlipidemia was partially corrected by troglitazone (1.53 +/- 0.28 vs. 0.87 +/- 0.13 mmol/l, P < 0.05), while IR-TKA and insulin concentration remained unaffected by the drug. Troglitazone restores insulin action possibly by lowering the FFA concentration of the blood and/or by stimulating glucose uptake at an intracellular point distal to insulin receptor autophosphorylation in muscle. If TNF-alpha plays a role in the development of the obesity/NIDDM syndrome, troglitazone may prove useful in its treatment.

Insulin resistance is associated with decreased clinical status in cystic fibrosis

Patients with cystic fibrosis (CF) frequently have impaired glucose tolerance and progression to diabetes (DM) with clinical features of both insulin-dependent and non-insulin-dependent diabetes. One feature of non-insulin-dependent DM is decreased insulin sensitivity, also known as insulin resistance. The goal of this study was to determine whether patients with CF exhibit insulin resistance and to determine the potential effect of insulin resistance on clinical status. We also sought to determine whether insulin resistance is associated with a specific CF genotype. We studied 18 patients with CF (8 with normal glucose tolerance, 5 with impaired glucose tolerance, 5 with DM), and 20 lean control subjects matched for age, weight, and sex. All control subjects had normal glucose tolerance. The clinical status for each CF patient was determined according to a modified National Institutes of Health scoring system. Each subject underwent a three-step hyperinsulinemic euglycemic clamp (insulin doses of 10, 40, 120 mU/m 2 per minute). Results from the 120 mU/m 2 per minute infusion defined maximal glucose disposal rate (defined in milligrams per kilogram body weight per minute) at steady state with peripheral insulin levels 195 ± 20 mU/ml. Subjects with CF demonstrated insulin resistance (control subjects = 13.6 ± 1.1, patients with CF = 10.2 ± 1.6 mg/kg per minute; p = 0.003). When each subgroup was compared separately with control subjects, all subgroups were statistically insulin resistant (glucose disposal rate, patients with CF and normal glucose tolerance = 10.8; those with impaired glucose tolerance = 8.4; those with DM = 10.1 mg/kg per minute), and the patients with CF with impaired glucose tolerance were the most insulin resistant. When plotted versus glucose disposal rate, a striking positive correlation between worsened clinical status and insulin resistance ( r = 0.85) is demonstrated. Furthermore, there is no correlation between insulin resistance and fasting blood glucose, subject age, or percent ideal body weight (all r values not significant). In conclusion, patients with CF exhibit insulin resistance that is associated with worsened clinical status. We believe it is the combination of insulin resistance and decreased insulin secretion that is responsible for the high incidence of CF-related diabetes. (J Pediatr 1997;130:948-56)

The expression of TNF alpha by human muscle. Relationship to insulin resistance.

TNFalpha is orverexpressed in the adipose tissue of obese rodents and humans, and is associated with insulin resistance. To more closely link TNF expression with whole body insulin action, we examined the expression of TNF by muscle, which is responsible for the majority of glucose uptake in vivo. Using RT-PCR, TNF was detected in human heart, in skeletal muscle from humans and rats, and in cultured human myocytes. Using competitive RT-PCR, TNF was quantitated in the muscle biopsy specimens from 15 subjects whose insulin sensitivity had been characterized using the glucose clamp. technique. TNF expression in the insulin resistant subjects and the diabetic patients was fourfold higher than in the insulin sensitive subjects, and there was a significant inverse linear relationship between maximal glucose disposal rate and muscle TNF (r = -0.60, P < 0.02). In nine subjects, muscle cells from vastus lateralis muscle biopsies were placed into tissue culture for 4 wk, and induced to differentiate into myotubes. TNF was secreted into the medium from these cells, and cells from diabetic patients expressed threefold more TNF than cells from nondiabetic subjects. Thus, TNF is expressed in human muscle, and is expressed at a higher level in the muscle tissue and in the cultured muscle cells from insulin resistant and diabetic subjects. These data suggest another mechanism by which TNF may play an important role in human insulin resistance.

Metabolic Effects of Troglitazone on Fructose-Induced Insulin Resistance in the Rat

Troglitazone is a new orally active hypoglycemic agent that has been shown to reduce insulin resistance and hyperinsulinemia in both diabetic animal models and non-insulin-dependent diabetes mellitus (NIDDM) subjects. To determine whether this drug could prevent the development of fructose-induced insulin resistance and related abnormalities, we studied the effects of troglitazone on the insulin resistance induced by fructose feeding in rats. Normal male Sprague-Dawley rats were fed a high-fructose diet for 3 weeks with and without troglitazone as a food admixture (0.2%) or were fed normal chow to serve as a control group. In vivo insulin resistnace was measured by the euglycemic hyperinsulinemic clamp technique at two different insulin infusion rates, 29 (submaximal stimulation) and 290 (maximal stimulation) pmol.kg-1.min-1. Fructose feeding markedly reduced submaximal glucose disposal rate (GDR) (113.8 +/- 8.3 vs. 176.0 +/- 5.6 mumol.kg-1.min-1, P < 0.05) and maximal GDR (255.9 +/- 5.6 vs. 313.6 +/- 10.5 mumol.kg-1.min-1, P < 0.05), reduced the suppressibility of submaximal hepatic glucose production (HGP; 45.5 +/- 5.0 vs. 11.7 +/- 5.0 mumol.kg-1.min-1, P < 0.05), and resulted in hypertriglyceridemia and hypertension. Troglitazone treatment completely restored the GDR (submaximal 158.2 +/- 5.6, maximal 305.3 +/- 6.1 mumol.kg-1.min-1) and submaximal HGP (9.4 +/- 2.8 mumol.kg-1.min-1) to control levels and also normalized the elevated plasma triglyceride concentration and systolic blood pressure levels in fructose-fed rats.(ABSTRACT TRUNCATED AT 250 WORDS)

A Modified Formula of GIK (Glucose-Insulin-Potassium) Therapy for Treatment of Extensive Burn Injury in Dogs

The effectiveness of a modified glucose-insulin-potassium (GIK) formula, which was derived from the results of a previous study (the maximal glucose disposal rate of 400 mg/M2/min required an insulin infusion rate at 1,200 mU/M2/min and KCl supplement rate at 0.08 mEq/M2/min), was evaluated in the treatment of extensive acute burn injury (EABI) in dogs. Under anesthesia initially with intravenous sodium pentobarbital 35 mg/kg followed by a maintenance dose of 5 mg/kg/hr, a third-degree burn of about 50% of the total body surface was created by acetylene torch over the ventral wall of the chest and abdomen. Cardiovascular parameters including heart rate, mean arterial blood pressure, pulmonary wedge pressure, cardiac index, and cardiac contractility (dP/dt of left ventricular pressure), as well as blood chemical data of pH value and K+ concentration were monitored. The present GIK therapy in EABI dogs effectively prevented a decrease in cardiac function, markedly enhanced cardiac function, steadily prolonged cardiac enhancement, and safely avoided hypoglycemic attack.

The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus.

We have studied the effects of 3 wk of continuous subcutaneous insulin infusion (CSII) on endogenous insulin secretion and action in a group of 14 type II diabetic subjects with a mean (+/-SEM) fasting glucose level of 286 +/- 17 mg/dl. Normal basal and postprandial glucose levels were achieved during insulin therapy at the expense of marked peripheral hyperinsulinemia. During the week of posttreatment evaluation, the subjects maintained a mean fasting glucose level of 155 +/- 11 mg/dl off insulin therapy, indicating a persistent improvement in carbohydrate homeostasis. Adipocyte insulin binding and in vivo insulin dose-response curves for glucose disposal using the euglycemic clamp technique were measured before and after therapy to assess the effect on receptor and postreceptor insulin action. Adipocyte insulin binding did not change. The insulin dose-response curve for overall glucose disposal remained right-shifted compared with age-matched controls, but the mean maximal glucose disposal rate increased by 74% from 160 +/- 14 to 278 +/- 18 mg/m2/min (P less than 0.0005). The effect of insulin treatment on basal hepatic glucose output was also assessed; the mean rate was initially elevated at 159 +/- 8 mg/m2/min but fell to 90 +/- 5 mg/m2/min in the posttreatment period (P less than 0.001), a value similar to that in control subjects. Endogenous insulin secretion was assessed in detail and found to be improved after exogenous insulin therapy. Mean 24-h integrated serum insulin and C-peptide concentrations were increased from 21,377 +/- 2766 to 35,584 +/- 4549 microU/ml/min (P less than 0.01) and from 1653 +/- 215 to 2112 +/- 188 pmol/ml/min (P less than 0.05), respectively, despite lower glycemia. Second-phase insulin response to an intravenous (i.v.) glucose challenge was enhanced from 170 +/- 53 to 1022 +/- 376 microU/ml/min (P less than 0.025), although first-phase response remained minimal. Finally, the mean insulin and C-peptide responses to an i.v. glucagon pulse were unchanged in the posttreatment period, but when glucose levels were increased by exogenous glucose infusion to approximate the levels observed before therapy and the glucagon pulse repeated, responses were markedly enhanced. Simple and multivariate correlation analysis showed that only measures of basal hepatic glucose output and the magnitude of the postbinding defect in the untreated state could be related to the respective fasting glucose levels in individual subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

Lack of in Vivo Insulin Resistance in Controlled Insulin-Dependent, Type I, Diabetic Patients*

Although type I diabetic patients are clearly insulin deficient, it is unclear whether they have normal in vivo sensitivity to insulin. Recent studies which suggested that insulin resistance is a common feature of insulin-dependent diabetics have not taken into account their degree of metabolic control or the presence of circulating antibodies. In the present study, we performed multiple euglycemic glucose clamp studies to construct insulin dose-response curves in 5 well controlled and 5 poorly controlled type I diabetic patients and 21 age-matched normal subjects. Each study was performed on a separate day at insulin infusion rates of 15, 40, 120, 240, or 1200 mU/M2 X min. During the 40 and 120 mU/M2 X min infusions, steady state insulin levels of 96 +/- 8 (+/- SE) and 285 +/- 27 microU/ml respectively, were achieved within 25 min in normal subjects. In contrast, diabetic subjects did not achieve steady state insulin levels (62 +/- 8 and 212 +/- 16 microU/ml) until 90 min of infusion, and insulin antibodies were detectable in the serum of all these patients. The dose-response curve for insulin stimulation of glucose disposal in well controlled diabetic subjects was comparable to that in normal subjects, with half-maximally effective insulin levels of 84 microU/ml in the diabetic patients compared to 70 microU/ml in normal subjects and virtually identical maximal rates of glucose disposal (433 +/- 11 vs. 411 +/- 17 mg/M2 X min in controls). In contrast, the dose-response curve for poorly controlled diabetic subjects was significantly right-shifted (half-maximally effective insulin level, 112 microU/ml), with marked reduction in the maximal glucose disposal rate (324 +/- 25 vs. 411 +/- 17 mg/M2 X min in normal subjects). Basal hepatic glucose output was increased in both poorly controlled and well controlled type I diabetic patients (132 +/- 7 and 101 +/- 16 mg/M2 X min, respectively) compared to normal subjects (76 +/- 7 mg/M2 X min). However, during each insulin infusion, hepatic glucose output was virtually 100% suppressed in all 3 groups.(ABSTRACT TRUNCATED AT 400 WORDS)

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)

Mechanisms of insulin resistance following injury.

To assess the mechanisms of insulin resistance following injury, we examined the relationship between insulin levels and glucose disposal in nine nonseptic, multiple trauma patients (average age 32 years, Injury Severity Score 22) five to 13 days postinjury. Fourteen age-matched normals served as controls. Using a modification of the euglycemic insulin clamp technique, insulin was infused in 35 two-hour studies using at least one of four infusions rates (0.5, 1.0, 2.0 or 5.0 mU/kg min). Basal glucose levels were maintained by a variable infusion of 20% dextrose using bedside glucose monitoring and a servo-control algorithm. The amount of glucose infused reflected glucose disposal (M, mg/kg.min). Tracer doses of (6,6,2D2) glucose were administered in selected subjects to determine endogenous glucose production. At plasma insulin concentrations less than 100 microU/ml, responses in both groups were similar. However, maximal glucose disposal rates were significantly less in the patients than in the controls (9.17 +/- 0.87 mg/kg . min vs. 14.3 +/- 0.78, mean +/- SEM, p less than 0.01). Insulin clearance rates in the patients were almost twice that seen in controls. To further characterize this decrease in insulin responsiveness, we studied six additional patients and 12 controls following the acute elevation of glucose 125 mg/dl above basal (hyperglycemic glucose clamp). In spite of exaggerated endogenous insulin production in the patients (80-200 microU/ml vs. 30--70 in controls), M was significantly lower (6.23 +/- 0.59 vs. 9.46 +/- 0.79, p less than 0.02). In conclusion, this study demonstrated that (1) the maximal rate of glucose disposal is reduced in trauma patients; (2) the metabolic clearance rate of insulin in the injured patients is almost twice normal and; (3) insulin resistance following injury appears to occur in peripheral tissues, probably skeletal muscle, and is consistent with a postreceptor defect.

Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus.

We have assessed the mechanisms involved in the pathogenesis of the insulin resistance associated with impaired glucose tolerance and Type II diabetes mellitus by exploring, by means of the euglycemic glucose-clamp technique, the in vivo dose-response relationship between serum insulin and the overall rate of glucose disposal in 14 control subjects; 8 subjects with impaired glucose tolerance, and 23 subjects with Type II diabetes. Each subject had at least three studies performed on separate days at insulin infusion rates of 40, 120, 240, 1,200, or 1,800 mU/M2 per min. In the subjects with impaired glucose tolerance, the dose-response curve was shifted to the right (half-maximally effective insulin level 240 vs. 135 microunits/ml for controls), but the maximal rate of glucose disposal remained normal. In patients with Type II diabetes mellitus, the dose-response curve was also shifted to the right, but in addition, there was a posal. This pattern was seen both in the 13 nonobese and the 10 obese diabetic subjects. Among these patients, an inverse linear relationship exists (r = -0.72) so that the higher the fasting glucose level, the lower the maximal glucose disposal rate. Basal rates of hepatic glucose output were 74 +/- 4, 82 +/- 7, 139 +/- 24, and 125 +/- 16 mg/M2 per min for the control subjects, subjects with impaired glucose tolerance, nonobese Type II diabetic subjects, and obese Type II diabetic subjects, respectively. Higher serum insulin levels were required to suppress hepatic glucose output in the subjects with impaired glucose tolerance and Type II diabetics, compared with controls, but hepatic glucose output could be totally suppressed in each study group. We conclude that the mechanisms of insulin resistance in patients with impaired glucose tolerance and in patients with Type II noninsulin-dependent diabetes are complex, and result from heterogeneous causes. (a) In the patients with the mildest disorders of carbohydrate homeostasis (patients with impaired glucose tolerance) the insulin resistance can be accounted for solely on the basis of decreased insulin receptors. (b) In patients with fasting hyperglycemia, insulin resistance is due to both decreased insulin receptors and postreceptor defect in the glucose mechanisms. (c) As the hyperglycemia worsens, the postreceptor defect in peripheral glucose disposal emerges and progressively increases. And (d) no postreceptor defect was detected in any of the patient groups when insulin's ability to suppress hepatic glucose output was measured.

Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects.

To assess the mechanisms of the insulin resistance in human obesity, we have determined, using a modification of the euglycemic glucose clamp technique, the shape of the in vivo insulin-glucose disposal dose-response curves in 7 control and 13 obese human subjects. Each subject had at least three euglycemic studies performed at insulin infusion rates of 15, 40, 120, 240, or 1,200 mU/M2/min. The glucose disposal rate was decreased in all obese subjects compared with controls (101 +/- 16 vs. 186 +/- 16 mg/M2/min) during the 40 mU/M2/min insulin infusion. The mean dose-response curve for the obese subjects was displaced to the right, i.e., the half-maximally effective insulin concentration was 270 +/- 27 microU/ml for the obese compared with 130 +/- 10 microU/ml for controls. In nine of the obese subjects, the dose-response curves were shifted to the right, and maximal glucose disposal rates (at a maximally effective insulin concentration) were markedly decreased, indicating both a receptor and a postreceptor defect. On the other hand, four obese patients had right-shifted dose-response curves but reached normal maximal glucose disposal rates, consistent with decreased insulin receptors as the only abnormality. When the individual data were analyzed, it was found that the lease hyperinsulinemic, least insulin-resistant patients displayed only the receptor defect, whereas those with the greatest hyperinsulinemia exhibited the largest post-receptor defect, suggesting a continuous spectrum of defects as one advances from mild to severe insulin resistance. When insulin's ability to suppress hepatic glucose output was assessed, hyperinsulinemia produced total suppresssion in all subjects. The dose-response curve for the obese subjects was shifted to the right, indicating a defect in insulin receptors. Insulin binding to isolated adipocytes obtained from the obese subjects was decreased, and a highly significant inverse linear relationship was demonstrated between insulin binding and the serum insulin concentration required for halfmaximal stimulation of glucose disposal. (a) decreased cellular insulin receptors contribute to the insulin resistance associated with human obesity in all subjects; (b) in the least hyperinsulinemic, insulin-resistant patients, decreased insulin receptors are the sole defect, whereas in the more hyperinsulinemic, insulin-resistant patients, the insulin resistance is the result of a combination of receptor and postreceptor abnormalities; (c) all obese patients were insensitive to insulin's suppressive effects on hepatic glucose output; this was entirely the result of decreased insulin receptors; no postreceptor defect in this insulin effect was demonstrated.