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.

Insulin binding to monocytes was examined in trained athletes (long distance runners) and in sedentary control subjects in the resting state and after 3 h of exercise at 40% of maximal aerobic power. At rest, specific binding of 125-I-insulin to monocytes was 69% higher in athletes than in sedentary controls and correlated with maximal aerobic power. The increase in insulin binding was primarily due to an increase in binding capacity. During acute exercise, insulin binding fell by 31% in athletes but rose by 35% in controls. The athletes had a smaller decline in plasma glucose and a lower respiratory exchange ratio during exercise than did controls. We conclude that physical training increases insulin binding to monocytes in the resting state but results in a fall in insulin binding during acute exercise. Changes in insulin binding in athletes thus may account for augmented insulin sensitivity at rest as well as a greater shift from carbohydrate to fat usage during exercise than is observed in untrained controls.

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 muU/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 muU/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 muU/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 mg/dl), 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.(125)I-insulin binding to monocytes in the diabetics (5.5+/-0.6%) was 30% below that in controls (P < 0.01). Insulin binding to monocytes and insulin action as determined with the insulin clamp were highly correlated in both control (r = 0.67, P < 0.01), and diabetic subjects (r = 0.88, P < 0.001). We conclude that (a) tissue sensitivity to physiologic hyperinsulinemia is reduced in most maturity-onset diabetics; (b) this decrease in sensitivity is located, at least in part, in extrahepatic tissues; (c) the resistance to insulin may be mediated by a reduction in insulin binding; and (d) in maturity-onset diabetics with normal tissue sensitivity to insulin, hyperglycemia may be a contributing factor to the normal rates of insulin-mediated glucose uptake.

This chapter discusses hormonal interactions in the regulation of blood glucose. The regulation of the blood glucose concentration is a well-recognized function of the endocrine system. The efficacy of the various control mechanisms is reflected by the very limited excursions in blood glucose observed in normal humans. In normal man, the bursts of glucagon secretion precipitated by feeding pure protein prevent the inhibition in glucose production and the hypoglycemia that would otherwise accompany protein-stimulated insulin secretion. In contrast, sustained hyperglucagonemia fails to cause glucose intolerance or worsening of preexisting diabetes so long as endogenous or exogenous insulin is available. In the case of insulin, the down regulation of the insulin receptor has been observed to occur in hyperinsulinemic states. The glucagon infusion fails to alter specific binding of insulin or growth hormone, indicating the specificity of the effect of hyperglucagonemia on glucagon binding. Glucagon-induced hyperglycemia can, however, be observed either in circumstances of absolute insulin deficiency or when tissue sensitivity to this hormone is increased. The synergistic nature of these hormone–hormone interactions with respect to raising circulating plasma glucose levels may constitute the mechanism for stress hyperglycemia.

The central role of insulin lack in the pathogenesis of diabetes has been recognized since the classic studies of Minkowski in pancreatectomized dogs and the subsequent isolation of insulin by Banting and Best. However, later studies demonstrating the diabetogenic effects of growth hormone and glucocorticoids raised the possibility that in some patients diabetes may be the consequence of resistance to, rather than the absence of, insulin. Although endocrine-associated diabetes is relatively rare, evidence that insulin insensitivity is a frequent phenomenon emerged following the introduction by Berson and Yalow of radioimmunoassay for the measurement of circulating insulin. Obese patients were observed to be hyperinsulinemic yet to have a markedly increased tendency towards the development of maturity-onset diabetes. The more recent discovery that the first step in the action of insulin, as in the case of other polypeptide hormones, is its binding to a spccific cell surface receptor [I]. has led to new insights regarding the cellular mechanisms regulating tissue sensitivity to insulin in health as well as disease. Insulin receptors on target cells serve two major functions: (11 specific recognition of insulin molecules amongst other circulating hormones and substrates, and [2) the triggering of a chain of intracellular events resulting in increased transport of substrates (e.g., increased glucose uptake by fat cells] or altered enzyme activity (e.g., stimulation of glycogen synthase and inhibition of phosphorylase). Although the precise chemical structure of the insulin receptor has not been defined, it is believed to be a glycoprotein with a molecular weight of 150,000 to 300,000 daltons [2]. The number of insulin receptors per cell is estimated to vary between 50,000 (in adipocytes] and 250,000 (in hepatocytes). However, maximal biologic effects are observed when only a small proportion (less than 10 per cent] of insulin receptors are occupied. The functional significance of the existence of “spare receptors” is that in circumstances in which a reduction in the number of receptors is the rate-limiting step in insulin action, a sufficient increase in the insulin concentration should lead to an increase in the number of receptor-hormone complexes so as to achieve the critical concentration

125I-insulin binding to monocytes was examined in five children and one adult with isolated growth hormone deficiency before and after three to 12 weeks of growth hormone treatment, and in eight controls. Before treatment, mean plasma glucose was 15 mg per deciliter below controls, and plasma insulin was reduced by 40 per cent. Insulin binding to monocytes was 70 per cent greater than controls (P less than 0.005). Insulin-mediated glucose uptake (determined in the adult patient) was 25 per cent greater than mean control levels. After treatment, plasma glucose rose to control levels, plasma insulin increased to 75 per cent above controls (P less than 0.01), and insulin binding fell to 50 per cent below controls (P less than 0.01). Insulin-mediated glucose uptake fell to 30 per cent below the mean control rate. Insulin binding increases in growth hormone deficiency and falls after treatment. These changes may contribute to alterations in insulin sensitivity accompanying altered growth hormone availability.