A B S T R A C T Insulin binding to monocytes and insulin action in vivo was examined in 14 obese subjects during the postabsorptive state and after starvation and refeeding. Tissue sensitivity to insulin was evaluated with the euglycemic insulin clamp technique. The plasma insulin concentration is acutely raised and maintained 100 ,uU/ml above the fasting level, and plasma glucose is held constant by a variable glucose infusion. The amount of glucose infused is a measure of tissue sensitivity to insulin and averaged 285+15 mg/m2 per min in controls compared to 136±13 mg/ m2 per min in obese subjects (P < 0.001). 1251-Insulin binding to monocytes averaged 8.3±0.4% in controls vs. 4.6±0.5% in obese subjects (P < 0.001). Insulin binding and insulin action were highly correlated in both control (r = 0.86, P < 0.001) and obese (r = 0.94, P < 0.001) groups. Studies employing tritiated glucose to measure glucose production indicated hepatic as well as extrahepatic resistance to insulin in obesity.After 3 and 14 days of starvation, insulin sensitivity in obese subjects decreased to 69±4 and 71±7 mg/M2 per min, respectively, whereas 125I-insulin binding increased to 8.8±0.7 and 9.0±0.4%. In contrast to the basal state, there was no correlation between insulin binding and insulin action. After refeeding, tissue sensitivity increased to 168±14 mg/M2 per min (P < 0.001) whereas insulin binding fell to 5.0±0.3%.We conclude that (a) in the postabsorptive state insulin binding to monocytes provides an index of in vivo insulin action in nonobese and obese subjects and, (b) during starvation and refeeding, insulin binding and insulin action changes in opposite directions sugDr. Soman is the recipient of a Research and Development

A B S T R A C T Tissue sensitive to insulin and insulin binding to monocytes were evaluated in 15 nonobese maturity-onset diabetics and in 16 healthy controls. Insulin sensitivity was determined by the insulin clamp technique in which the plasma insulin is acutely raised and maintained 100 .U/ml above the fasting level and plasma glucose is held constant at fasting levels by a variable glucose infusion. The amount of glucose infused is a measure of overall tissue sensitivity to insulin.In the diabetic group, the fasting plasma glucose concentration (168±4 mg/dl) was 85% greater than controls (P < 0.01) whereas the plasma insulin level (15±1 ,U/ml) was similar to controls. During the insulin clamp study, comparable plasma insulin levels were achieved in the diabetics (118±5) and the controls (114±5 ,uU/ml). However, the glucose infusion rate in the diabetics (4.7±0.4 mg/kg min) was 30% below controls (P < 0.01). Among the diabetics, the glucose infusion rate correlated directly with the fasting plasma glucose level (r = 0.57, P < 0.05). In five diabetic subjects, glucose metabolism was similar to controls, and these diabetics had the highest fasting glucose levels. When they were restudied after prior normalization (with insulin) of the fasting plasma glucose (100±1 mgldl), the glucose infusion rate during the insulin clamp was 30% lower than observed in association with hyperglycemia (P < 0.01). Studies that employed tritiated glucose to measure endogenous glucose production indicated comparable 90-95% inhibition of hepatic glucose production during hyperinsulinemia in the diabetic and control subjects.1251-insulin binding to monocytes in the diabetics (5.5±0.6%) was 30% below that in controls (P < 0.01).

We studied the effect of physical training on in vivo tissue sensitivity to insulin and insulin binding to monocytes in six previously untrained healthy adults. Physical training (one hour of cycle-ergometer exercise four times per week for six weeks) failed to alter body weight but resulted in a 20 per cent increase (P less than 0.02) in maximal aerobic power (VO2 max) and a 30 per cent increase (P less than 0.01) in insulin-mediated glucose uptake (determined by the insulin clamp technique). The increase in insulin sensitivity correlated directly with the rise in VO2 max (P less than 0.05). Binding of [125I]insulin to monocytes also rose by 35 per cent after physical training (P less than 0.02), primarily because of an increase in the concentration of insulin receptors. Our data indicate that physical training increases tissue sensitivity to insulin in proportion to the improvement in physical fitness. Physical training may have a role in the management of insulin-resistant states, such as obesity and maturity-onset diabetes, that is independent of its effects on body weight.

The role of physiological hypercortisolemia in the regulation of fuel metabolism in man was examined during a 5-h primed-continuous infusion of cortisol which raised plasma cortisol levels to 40 microgram/dl. Plasma glucose increased by 15--20 mg/dl (P less than 0.005) in spite of unchanged rates of glucose production. Glucose uptake and clearance, on the other hand, fell by 15% (P less than 0.05) and 30% (P less than 0.005), respectively, thereby accounting for cortisol-induced hyperglycemia. Total blood ketones during cortisol infusion increased 3-fold above saline control values (P less than 0.01) despite comparable FFA levels in the two groups. In addition, there was a selective 40% rise in total branched chain amino acids (P less than 0.005) during cortisol infusion. These effects of cortisol on glucose, ketone, and amino acid metabolism occurred in the absence of significant changes in the plasma insulin or glucagon concentration. Furthermore, cortisol infusion had no effect on [125I]insulin binding to circulating monocytes. Our data thus suggest that acute elevations of plasma cortisol have antiinsulin effects in man which may occur independent of alterations in insulin receptors.

a (lie U'niersitiy S1bool of MeXdicine, NeXi Haven, Con necti(cut 06510 A B S T R A C 'ro investigate the role of hep)atic grlucagon recel)tors in the hypersensitivity to glticagon ob)serVed in insulin-deprived diabetics, li\er plasniia menil)ranes were prepared from1 control ratts ad(l from streptozotocin-inhuced (lialhtic rats sonic0 of whom wN7ere treated with high-dose andi low\-(lo.

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A B S T R A C T To investigate the role of glucagon and insulin receptor binding in the glucagon hypersensitivity and insulin resistance which characterize the glucose intolerance of uremia, liver plasma membranes were prepared from control rats (blood urea nitrogen [BUN] 15±1 mg/100 ml, creatinine 0.7±0.2 mg/100 ml), and from 70% nephrectomized rats (BUN 30±2 mg/100 ml, creatinine 2.2±0.2 mg/100 ml), and from 90% nephrectomized rats (BUN 46±3 mg/100 ml, creatinine 4.20+0.7 mg/100 ml), 4 wk after surgery. As compared to controls, the 90% nephrectomized rats had significantly higher levels of plasma glucose (95 ±4 vs. 125±11 mg/100 ml), plasma insulin (28±9 vs. 52±11 uU/ml), and plasma glucagon (28±5 vs. 215 ±18 pg/ml). Similar, but less marked, elevations were observed in the 70% nephrectomized animals.In liver plasma membranes from nephrectomized

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