Basal Non-esterified Fatty Acid Research Articles

Multitissue Insulin Resistance Despite Near-Normoglycemic Remission in Africans With Ketosis-Prone Diabetes

OBJECTIVE—To characterize insulin action in Africans with ketosis-prone diabetes (KPD) during remission.RESEARCH DESIGN AND METHODS—At Saint-Louis Hospital, Paris, France, 15 African patients with KPD with an average 10.5-month insulin-free near-normoglycemic remission period (mean A1C 6.2%) were compared with 17 control subjects matched for age, sex, BMI, and geographical origin. Insulin stimulation of glucose disposal, and insulin suppression of endogenous glucose production (EGP) and nonesterified fatty acids (NEFAs), was studied using a 200-min two-step (10 mU · m−2 body surface · min−1 and 80 mU · m−2 · min −1 insulin infusion rates) euglycemic clamp with [6,6-2H2]glucose as the tracer. Early-phase insulin secretion was determined during an oral glucose tolerance test.RESULTS—The total glucose disposal was reduced in patients compared with control subjects (7.5 ± 0.8 [mean ± SE] vs. 10.5 ± 0.9 mg · kg−1 · min−1; P = 0.018). EGP rate was higher in patients than control subjects at baseline (4.0 ± 0.3 vs. 3.0 ± 0.1 mg · kg−1 · min−1; P = 0.001) and after 200-min insulin infusion (10 mU · m−2 · min−1: 1.6 ± 0.2 vs. 0.6 ± 0.1, P = 0.004; 80 mU · m−2 · min−1: 0.3 ± 0.1 vs. 0 mg · kg−1 · min−1, P = 0.007). Basal plasma NEFA concentrations were also higher in patients (1,936.7 ± 161.4 vs. 1,230.0 ± 174.1 μmol/l; P = 0.002) and remained higher after 100-min 10 mU · m−2 · min−1 insulin infusion (706.6 ± 96.5 vs. 381.6 ± 55.9 μmol/l; P = 0.015).CONCLUSIONS—The triad hepatic, adipose tissue, and skeletal muscle insulin resistance is observed in patients with KPD during near-normoglycemic remission, suggesting that KPD is a form of type 2 diabetes.

Effects of Abomasal Infusion of Linseed Oil on Responses to Glucose and Insulin in Holstein Cows

The objective was to study the effects of abomasal infusion of linseed oil, a source rich in n-3 C18:3, on whole-body response to insulin (experiment 1) and on insulin antilipolytic effects during feed restriction (experiment 2). In experiment 1, eight nonlactating, non-gestating cows were assigned to a crossover design, fed to meet maintenance requirements, and infused abomasally with either linseed oil (LIN) or tallow (TAL) at a rate of 0.54g/kg of body weight per d for 5.5 d. Infusions were performed every 8h during the first 3 d of each period and every 4h thereafter. Intravenous glucose tolerance tests (IVGTT) were performed on d 5 of each period, followed by i.v. insulin challenges (IC) 12h later. In experiment 2, six nonlactating, nongestating cows were assigned to a replicated 3×3 Latin square design. The experimental protocol included a water (WTR) treatment and feeding was suspended on d 3, leading to 50 and 62h of feed restriction before IVGTT and IC, respectively. Clearance of glucose during IVGTT and IC was not affected by treatments in either experiment. However, LIN had an insulin sensitizing effect in experiment 1, because a lower insulin concentration led to the same clearance of glucose as TAL. In experiment 1, plasma nonesterified fatty acid (NEFA) concentration was low, reflecting a postprandial state, but NEFA was greater for LIN than TAL during IVGTT (108 vs. 88±4μEq/L) and IC (133 vs. 83±9μEq/L). In experiment 2, insulin concentrations during IVGTT did not differ across treatments. Basal plasma NEFA concentration before IVGTT tended to be greater for LIN than for TAL (612 vs. 508μEq/L). Plasma NEFA clearance rate during IVGTT was greater for LIN than for TAL (2.8 vs. 2.5%/min), leading to a shorter time to reach half NEFA concentration (25 vs. 29min) and greater absolute value of NEFA response area under the curve [AUC; −64,150 vs. −46,402 (μEq/L)×180 min]. Data suggest that LIN enhanced the antilipolytic effects of insulin. Yet, other factors could have been involved because plasma NEFA concentration before IVGTT was 104μEq/L greater for LIN than TAL for unknown reasons.

A novel minimal model to describe NEFA kinetics following an intravenous glucose challenge

Dynamics of nonesterified fatty acid (NEFA) metabolism in humans requires quantification if we are to understand the etiology of such diseases as type 1 and 2 diabetes, as well as metabolic syndrome and obesity, or if we are to elucidate the mechanism of action of various interventions. We present a new compartmental model that employs the pattern of plasma glucose concentrations in healthy young adults to predict dynamic changes that occur in plasma NEFA concentrations during either a glucose-only intravenous glucose tolerance test, or an insulin-modified intravenous tolerance test, or a modified protocol during which variable-rate glucose infusions were administered to prevent plasma glucose from declining below 100 mg/dl. The model described all of the major features of NEFA response to an intravenous glucose tolerance test, including an initial latency phase, a phase during which plasma NEFA concentrations plummet to a nadir, and a rebound phase during which plasma NEFA concentrations may rise to a plateau concentration, which may be substantially higher than the initial basal NEFA concentration. This model is consistent with physiological processes and provides seven adjustable parameters that can be used to quantify NEFA production (lipolysis) and utilization (oxidation). When tested on data from the scientific literature, the range in estimated rate of lipolysis was 24-36 micromol.l(-1).min(-1) and for NEFA oxidation rate was 25-54 micromol.l(-1).min(-1). All model parameters were well identified and had coefficients of variation < 15% of their estimated values. It is concluded that this model is suitable to describe NEFA kinetics in human subjects.

Peroxisome proliferator-activated receptor (PPAR) activation induces tissue-specific effects on fatty acid uptake and metabolism in vivo--a study using the novel PPARalpha/gamma agonist tesaglitazar.

Agonists of peroxisome proliferator-activated receptors (PPARs) have emerged as important pharmacological agents for improving insulin action. A major mechanism of action of PPAR agonists is thought to involve the alteration of the tissue distribution of nonesterified fatty acid (NEFA) uptake and utilization. To test this hypothesis directly, we examined the effect of the novel PPARalpha/gamma agonist tesaglitazar on whole-body insulin sensitivity and NEFA clearance into epididymal white adipose tissue (WAT), red gastrocnemius muscle, and liver in rats with dietary-induced insulin resistance. Wistar rats were fed a high-fat diet (59% of calories as fat) for 3 wk with or without treatment with tesaglitazar (1 micromol.kg(-1).d(-1), 7 d). NEFA clearance was measured using the partially metabolizable NEFA tracer, (3)H-R-bromopalmitate, administered under conditions of basal or elevated NEFA availability. Tesaglitazar improved the insulin sensitivity of high-fat-fed rats, indicated by an increase in the glucose infusion rate during hyperinsulinemic-euglycemic clamp (P < 0.01). This improvement in insulin action was associated with decreased diglyceride (P < 0.05) and long chain acyl coenzyme A (P < 0.05) in skeletal muscle. NEFA clearance into WAT of high-fat-fed rats was increased 52% by tesaglitazar under basal conditions (P < 0.001). In addition the PPARalpha/gamma agonist moderately increased hepatic and muscle NEFA utilization and reduced hepatic triglyceride accumulation (P < 0.05). This study shows that tesaglitazar is an effective insulin-sensitizing agent in a mild dietary model of insulin resistance. Furthermore, we provide the first direct in vivo evidence that an agonist of both PPARalpha and PPARgamma increases the ability of WAT, liver, and skeletal muscle to use fatty acids in association with its beneficial effects on insulin action in this model.

Effects of the infusion of non-selective beta-, and selective beta1- or beta2-adrenergic agonists, on body fat mobilisation in underfed or overfed non-pregnant heifers.

The aim of this study was to analyse the effects of the intravenous infusion of a non-selective beta-agonist (beta-A) (isoproterenol, ISO), and selective beta1-A (dobutamine, D) or beta2-A (terbutaline, T) on body fat mobilisation in non-pregnant heifers, in a 2 x 2 crossover design with two treatments (underfeeding or overfeeding) and two periods. The effect of the duration of submission to each energy level on basal and ISO-induced fat mobilisation was also studied. ISO had a high and significant lipolytic effect whatever the energy level. Nevertheless, the response area of non-esterified fatty acids (NEFA) to ISO in underfed cows was 1.7 times greater than that in overfed cows. T had a slight but significant lipolytic effect on NEFA plasma response in the underfed group. D had no lipolytic effect. Basal and ISO-stimulated plasma NEFA levels were similar after 1 or 4 weeks of underfeeding.

Plasma non-esterified fatty acid response to a β-adrenergic challenge before or after feeding in energy underfed or overfed, dry or lactating cows

AbstractThe effects of adrenergic challenge (in order to evaluate the adipose tissue lipolytic potential) and time of challenge relative to feeding on the response curve of plasma non-esterified fatty acids (NEFA) in four underfed or overfed non-lactating non-pregnant cows were studied. Basal NEFA and NEFA response to isoproterenol (ISO; 4 nmol/kg body weight) were higher when challenged before than after feeding and higher in underfed than overfed cows. Interaction between feeding level and time of challenge was significant (P &lt; 0·001) for the rising part of NEFA response. Pooled NEFA response curves from several trials (no. = 63 challenges) were analysed in order to obtain a simplified procedure for the prediction of the NEFA response. High correlations were found between the response area or maximal NEFA response and NEFA response at 15 min (r = 0·95 and 0·98, respectively). This simplified procedure was applied on pooled data from 84 challenges in order to evaluate the effects of energy balance, physiological status, body condition score (BCS) and time of challenge relative to feeding. Energy balance had a significant effect on basal plasma NEFA and NEFA response at 15 min after ISO challenge (–7·6 and –14·2 μmol/l when the daily energy balance increased by 1 MJ, respectively). Time of ISO injection relative to feeding had a greater effect on stimulated NEFA than on basal NEFA (308 v. 239 μmol/l). There was a significant effect of BCS (41 μmol/l per unit of BCS) on the basal plasma NEFA level. The NEFA response at 15 min after ISO challenge was lower (387 μmol/l) in lactating cows than in dry cows. The NEFA response to ISO at 15 min could provide an efficient method of studying the adipose tissue lipolytic potential of cattle in vivo.

Effect of the antiobesity agent sibutramine in obese-diabetic ob/ob mice.

Sibutramine is a reuptake inhibitor of 5-hydroxytryptamine and noradrenaline, being developed as a treatment for obesity. To investigate the effect of sibutramine on glucose homeostasis in obese-hyperglycaemic insulin-resistant ob/ob mice. Sibutramine 5 mg/kg once daily was administered orally to ob/ob mice for six weeks. Sibutramine treatment decreased body weight gain by 12% without a significant overall change in daily food intake. Sibutramine reduced the hyperinsulinaemia by 31%, and lowered plasma non-esterified fatty acids (NEFA) by 17%. Basal plasma glucose concentrations were not significantly altered by sibutramine, but glucose concentrations fell more rapidly after an i.p. glucose challenge, despite lower insulin concentrations. The rate of insulin-induced glucose disappearance was increased by 10% during sibutramine treatment. First administration of sibutramine, 5 mg/kg, did not acutely alter basal plasma glucose, insulin or NEFA concentrations in ob/ob mice, although NEFA concentrations were raised after 24 h. The results indicate that chronic administration of sibutramine can reduce weight gain, lower NEFA concentrations, decrease hyperinsulinaemia and ameliorate the insulin resistance of ob/ob mice.

Lipolytic responses to catecholamines in ractopamine-treated pigs

The β-agonist ractopamine (RAC) promotes protein deposition with little effect on fat deposition in the pig. To assess whether the lack of effect on fat deposition was due to changes in response to catecholamines, crossbred pigs with venous catheters were used to examine plasma non-esterified fatty acid (NEFA) concentrations before and after intravenous (i.v.) injections of the (β1+β2)-agonist isoproterenol and the β2-agonist fenoterol during dietary RAC (0 or 20 mg/kg) treatment. In Expt 1, gilts received increasing i.v. doses of fenoterol [3, 9, 27, 81, and 243 µg/kg bodyweight (BW)] on Day 34 and blood samples were taken for metabolite analyses. The protocol was repeated on Day 36 but this time using increasing doses of isoproterenol (0·11, 0·33, 1, 3, and 9 µg/kg BW). Dietary RAC decreased basal NEFA concentrations but had no effect on plasma glucose concentrations. When the individual NEFA responses to fenoterol curves were fitted, the derived values for maximal response (Rmax) suggested that there was no difference between pigs fed 0 or 20 mg/kg RAC (1739 v. 1847 µmol/L, P = 0 ·829). However, there was an almost 10-fold increase in the dose of fenoterol required to elicit a NEFA response 50% of Rmax (ED50) in RAC-fed pigs (11·6 v. 107·0 µg/kg, P = 0·008). Intravenous fenoterol challenge increased plasma glucose linearly but this response was not altered by dietary RAC. In Expt 2, gilts received increasing i.v. doses of fenoterol (16, 80, and 400 µg/kg BW) on Day 10 and blood samples were taken for metabolite analyses. The protocol was repeated on Day 11 but this time using increasing doses of isoproterenol (6·25, 32·5, and 162·5 mg/kg BW). The derived values for Rmax suggested that there was no effect of injected β-agonist (2209 v. 2405 µmol/L for fenoterol and isoproterenol, respectively, P = 0·204) or dietary RAC (2251 v. 2363 µmol/L for 0 or 20 mg/kg RAC, respectively, P = 0·448) on Rmax. However, the ED50 was significantly lower for isoproterenol than for fenoterol (14·1 v. 31·3mg/kg, P = 0·001) and was increased by dietary RAC (18·6 v 26·9 µg/kg, P = 0·05). In conclusion, these data support the hypothesis that the lack of effect of dietary RAC on the rate of lipid deposition in the pig is due to a desensitisation of adipose tissue β-adrenergic receptors with no change in adipose tissue responsiveness.

Defects of insulin action on fatty acid and carbohydrate metabolism in familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is a common cause of premature myocardial infarction, but its metabolic basis is unknown. Insulin resistance has been suggested in some patients by the presence of fasting hyperinsulinemia. We studied insulin action on carbohydrate and fatty acid metabolism in FCHL patients and healthy control subjects by a two-step euglycemic, hyperinsulinemic clamp. During low-dose insulin infusion, steady-state nonesterified fatty acids (NEFAs) were higher in patients than in control subjects (0.36 mmol/L [95% confidence limits, 0.19, 0.53] versus 0.19 mmol/L [0.10, 0.28]; P = .05). The ratio of steady-state to basal NEFAs was increased by 88% in patients compared with control subjects (P = .005). During high-dose insulin infusion, insulin sensitivity for peripheral glucose disposal was reduced by 60% in FCHL patients compared with control subjects (P = .03). Hepatic glucose production at baseline and during the clamp was similar in the two groups. In multiple regression analysis, increased upper-body fat in the patient group accounted for the impairment of insulin-mediated glucose disposal but did not influence the defect in insulin-mediated NEFA suppression in the FCHL patients. This defect in fatty acid metabolism may be a primary defect in FCHL that contributes to abnormalities in the secretion and composition of lipoproteins in this disorder. Direct study of this defect may facilitate genetic analysis of this disorder.

Pregnancy but Not Moderate Undernutrition Attenuates Insulin Suppression of Fat Mobilization in Sheep , ,

Nonpregnant and late-pregnant ditocous ewes were fed either to maintain zero energy balance in maternal tissues (fed) or at 50% of this level (underfed) for several weeks. Plasma concentrations of nonesterified fatty acids (NEFA) and glycerol were measured under basal conditions and during infusion of various doses of insulin while maintaining euglycemia (hyperinsulinemic, euglycemic clamp technique). Pregnancy and undernutrition separately increased basal plasma NEFA concentration in an additive manner; plasma glycerol was increased by pregnancy but unaffected by undernutrition. The molar ratio of NEFA to glycerol was significantly greater in underfed ewes. Analysis of dose-response relations between plasma insulin and metabolites during insulin infusions showed that maximally insulin-suppressed concentrations of NEFA and glycerol were significantly greater in pregnant than in nonpregnant ewes but were unaffected by under-nutrition. Neither pregnancy nor undernutrition affected the maximally insulin-suppressed NEFA to glycerol ratio, or the plasma insulin concentration for 50% maximal responses to insulin of plasma NEFA, plasma glycerol, or the plasma NEFA to glycerol ratio. Thus, even in ewes at or close to zero energy balance, pregnancy seems to reduce adipose responsiveness but not sensitivity to the antilipolytic effect of insulin. This is another manifestation of the normal development of insulin resistance in maternal tissues during late pregnancy.

Lipid metabolism and insulin resistance in cirrhosis

Fasting patients with cirrhosis have high plasma non-esterified fatty acids, and a high turnover and oxidation of non-esterified fatty acids, despite high plasma insulin levels. To assess whether increased non-esterified fatty acid availability impairs utilisation of circulating glucose, and contributes to the insulin insensitivity in cirrhosis, we measured glucose, non-esterified fatty acid and glycerol flux rates, in patients with cirrhosis and controls, in the basal state and during a 0.05 U.kg-1.h-1 hyperinsulinaemic euglycaemic clamp. After an overnight fast, basal blood glucose and glucose turnover were similar in both groups. Basal plasma glycerol and non-esterified fatty acid levels were higher in patients with cirrhosis as were 1-14C-nonesterified fatty acid turnover (4.48 +/- 0.53 vs 2.54 +/- 0.45 mumol.kg-1.min-1, p < 0.05) and 2H5-glycerol turnover (3.27 +/- 0.34 vs 2.24 +/- 0.15 mumol.kg-1.min-1, p < 0.05), indicating increased lipolysis in patients with cirrhosis; metabolic clearance rate of non-esterified fatty acids and glycerol were similar in both groups, suggesting no impairment of tissue uptake in patients. The euglycaemic clamp showed patients with cirrhosis to be markedly insensitive to insulin. The glucose metabolic clearance rate increased during the clamp in controls (p < 0.005) but not in patients with cirrhosis, indicating that infused insulin had little or no effect on glucose disposal in the patients. Clamp glucose turnover in controls was higher than in the basal state (p < 0.001); in patients with cirrhosis it was lower. The profound insulin insensitivity and the clamping of blood glucose below fasting levels explains the fall in glucose turnover in patients with cirrhosis during the clamp. In both groups serum non-esterified fatty acid and glycerol levels, and their appearance rates, were suppressed during the clamp, but levels remained significantly higher in patients with cirrhosis (non-esterified fatty acids, 0.20 +/- 0.4 vs 0.10 +/- 0.01 mmol/l, p < 0.05; glycerol 74 +/- 9 vs 46 +/- 4 mumol/l, p < 0.05). This, with the high basal non-esterified fatty acid and glycerol levels seen in patients with cirrhosis, despite high insulin levels, suggests resistance of adipose tissue lipolysis to insulin. There was no correlation between glucose infusion requirements and non-esterified fatty acid turnover. The normal turnover of blood glucose in fasting patients with cirrhosis, despite increased non-esterified fatty acid turnover, suggests utilisation mainly by tissues with an obligatory requirement for glucose, which may be similar in patients with cirrhosis and controls.(ABSTRACT TRUNCATED AT 400 WORDS)

Determinants of mild fasting hypertriglyceridaemia in non‐insulin‐dependent diabetes

Factors contributing to fasting hypertriglyceridaemia were studied in 20 patients with non-insulin-dependent diabetes--nine with normal triglyceride concentrations [fasting triglyceride 0.94 (range 0.58-1.23) mmol l-1] and eleven with mild fasting hypertriglyceridaemia [fasting triglyceride 2.4 (1.82-4.0) mmol l-1]. The patients with hypertriglyceridaemia were more obese [body mass index 29.0 (24.6-33.8) vs. 25.7 (21.9-30.1) kg m-2, P less than 0.05] and demonstrated impaired glucose disposal in response to exogenous insulin at isoglycaemia [insulin sensitivity index, SIp 0.7 (0.27-2.5) vs. 2.4 (0.62-5.1) ml m-2 min per mU l-1, P less than 0.001]. Basal non-esterified fatty acid (NEFA) and glycerol concentrations were higher and were suppressed to a lesser extent during isoglycaemic hyperinsulinaemia. Fasting glucose and apolipoprotein B concentrations were higher in the hypertriglyceridaemic patients, but lipoprotein lipase activities were similar in the two groups. When the effect of obesity was removed (by weight-matching six normotriglyceridaemic with seven hypertriglyceridaemic patients) basal NEFA and glycerol concentrations and the suppression of NEFA in response to insulin remained significantly different between the two groups. We propose that defects in both the glucoregulatory and antilipolytic actions of insulin contribute to mild fasting hypertriglyceridaemia in NIDDM, and that these defects cannot be attributed solely to obesity. These disorders of insulin action may also have important implications for the postprandial metabolism of triglyceride-rich lipoproteins and hence atherogenesis.

Impaired insulin action in newly diagnosed type 1 (insulin-dependent) diabetes mellitus.

Hepatic and peripheral insulin sensitivity were investigated in five newly diagnosed Type 1 (insulin-dependent) diabetic subjects before and after 1 week of twice daily insulin therapy. Eight weight-matched control subjects were also studied. Hepatic glucose production and glucose utilization were measured basally and during two sequential 2-h insulin (25 and 40 mU X kg-1 X h-1)/ glucose infusion periods. In the untreated hyperglycaemic diabetic patients hepatic glucose production was 16.3 +/- 2.6, 8.1 +/- 1.1 and 3.6 +/- 2.8 mumol X kg-1 X min-1 respectively for each of the three periods (mean +/- SEM), and fell with treatment to 12.5 +/- 1.4, 0.5 +/- 0.5 and 0.5 +/- 0.5 mumol X kg-1 X min-1. Hepatic glucose production for normal subjects was 13.4 +/- 0.7, 2.3 +/- 0.8 and less than 0.1 mumol X kg-1 X min-1. Glucose utilization was 12.7 +/- 1.4, 18.2 +/- 0.7 and 22.1 +/- 3.4 mumol X kg-1 X min-1 before treatment in the diabetic subjects, and 11.8 +/- 1.7, 20.9 +/- 3.3 and 30.1 +/- 3.6 after treatment. These values compare with those in the euglycaemic control subjects (13.4 +/- 0.7, 18.7 +/- 1.6 and 36.3 +/- 2.7 mumol X kg-1 X min-1). The pre-treatment metabolic clearance rate of glucose in all diabetic studies with insulin levels greater than 30 mU/l was 2.6 +/- 0.4 and rose to 3.9 +/- 0.5 ml X kg-1 X min-1 following insulin therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential effects of insulin therapy on hepatic and peripheral insulin sensitivity in Type 2 (non-insulin-dependent) diabetes.

Hepatic glucose production and metabolic clearance rate of glucose were measured using (3-3H) glucose at steady state, basally and during two sequential 2 h insulin (25 and 40 mU . kg -1 . h -1)/glucose (2 and 3 mg. kg -1 . min -1) infusion periods. Eight diabetic subjects were studied before and after 1 week of twice daily insulin therapy; six control subjects matched for age, weight and degree of obesity were also studied. In the diabetic patients, pre-treatment hepatic glucose production was 20.0 +/- 2.2, 9.9 +/- 2.9, and 1.4 +/- 0.8 mu mol . kg -1 . min -1 respectively (+/- SEM) for each of the three periods, and fell significantly with treatment to 12.8 +/- 1.7, 4.0 +/- 1.5 and 1.9 +/- 1.0 mu mol . kg -1 . min -1. Hepatic glucose production in normal subjects was 13.2 +/- 0.6, 2.2 +/- 0.8 and less than 1 mu mol . kg -1 . min -1. The pre-treatment metabolic clearance rate in all diabetic studies with insulin levels greater than or equal to 30 mU/l was 1.10 +/- 0.14 ml . kg -1 . min -1 and remained virtually unchanged following insulin therapy; this was significantly lower than in the control subjects (6.83 +/- 1.02, p less than 0.001). Basal non-esterified fatty acid levels were higher (p less than 0.02) in the pre-treated diabetic patients compared to post-treated diabetic patients and control subjects. Non-esterified fatty acids in each group fell to similar levels during the insulin infusions, but the rate of fall was slower in the pre-treated diabetic patients. Insulin receptor binding to erythrocytes was normal in the diabetic subjects and unchanged by treatment. Therefore, following insulin treatment of uncontrolled Type 2 (non-insulin-dependent) diabetes, the initially increased basal hepatic glucose production, and decreased hepatic sensitivity, return towards normal. However, the glucose clearance remains low, despite good diabetic control, and appears to be a major factor in the continuing glucose intolerance. As insulin receptor binding is normal, the defect of glucose clearance in Type 2 diabetes appears compatible with a post-receptor defect of glucose metabolism.