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The metabolic and immunological effects of cyclosporin given to prevent diabetes in BB rats were examined. Diabetes-prone (BBdp) and normal (BBn) BB rats received either oral cyclosporin (10 mg X kg-1 X day-1 or its vehicle from age 30-150 days. Six of 21 (29%) vehicle-treated rats became glycosuric, with hyperglycemia, weight loss, and unremitting insulin requirements, and showed destruction of islet beta-cells. Five of 24 (21%) cyclosporin-treated rats became glycosuric, but none demonstrated weight loss, all required insulin only intermittently after onset, and all showed persistence of islet beta-cells. Cyclosporin induced hypoinsulinemic glucose intolerance in BBn rats. Cyclosporin inhibited the normal rise with age of peripheral blood lymphocyte cell numbers, identified with monoclonal antibodies. OX19+ (pan-T) and W3/25+ helper T-lymphocytes were affected, and there was an increase in the large W3/13+ OX19- population characteristic of BBdp rats; in addition, this subset appeared in BBn rats. Cyclosporin also caused the appearance and/or increase in both BBdp and BBn rats of W3/25+ OX19- and OX8+ OX19- subsets. Suppressor/cytotoxic (OX8+) T-lymphocytes and Ia+ cells were less affected. The incidence of hyperglycemia and glycosuria was therefore unaltered by cyclosporin, although the diabetic syndrome was milder. BBn rats receiving cyclosporin showed glucose intolerance, suggesting that in BBdp rats, the net effects of immunosuppression on beta-cell destruction may have been counterbalanced by the direct effect on the same cells. The attenuation of diabetes in BBdp rats occurred through further immunosuppression rather than by correction of its preexisting immunodeficiency.

Arterio-venous differences across forearm muscle in man in both prolonged starvation and in the postabsorptive state, show an uptake of glutamate and a relatively greater production of glutamine. Splanchnic arteriovenous differences in the postabsorptive state show a net uptake of glutamine and lesser rate of glutamate production. These data suggest that muscle is a major site of glutamine synthesis in man, and that the splanchnic bed is a site of its removal. The relative roles of liver and other tissues in the splanchnic circuit were not directly assessed, only the net balance. These data in man are in conflict with most previous studies in other species attributing the major proportion of glutamine production to the liver and, pari passu, to the splanchnic bed.

An in vitro system for perifusion of rat pancreas has been used to investigate the effects of diazoxide on glucose-induced insulin release. Administration of diazoxide with a stimulating concentration of glucose produced a dose-dependent suppression of insulin release. This effect was partly reversed by phentolamine. In the presence of nonstimulatory concentrations of glucose, diazoxide plus phentolamine, but neither alone, stimulated a biphasic release of insulin similar to that observed with 1-isopropyl norepinephrine. A prior period of perifusion with a low concentration of diazoxide enhanced the primary component of subsequent glucose-stimulated insulin release, an effect inhibited by addition of either phentolamine or propranolol to the diazoxide during this "prestimulation" period. These effects are similar to those observed with epinephrine. By contrast with epinephrine however, increasing the concentration of diazoxide during the period before glucose stimulation enhanced both the primary and secondary components of subsequent glucose-induced insulin release. These data suggest that at least some of the direct effects of diazoxide on the pancreas are mediated through alpha- and beta-adrenergic receptor mechanisms.

The role of glucagon in the metabolic adaptation to prolonged fasting in man has been examined. Plasma immunoreactive glucagon was determined during 6-wk fasts and during infusion of exogenous glucagon using an assay which minimized nonpancreatic immunoreactivity. Plasma glucagon concentrations rose twofold to a peak on the 3rd day of fasting and then declined thereafter to a level maintained at or above postabsorptive. Insulin concentration declined to a plateau by the 3rd day. Thus a persisting altered relationship of glucagon and insulin concentrations characterized the fasted state. A synergism of low insulin and relative or absolute elevation of glucagon levels is viewed as a hormonal mechanism controlling the rate of hepatic substrate extraction for gluconeogenesis. Glucagon was infused systemically into 4-6 wk fasted subjects at three dose levels. A marked sensitivity of individual plasma free amino acids to the induced elevations of plasma glucagon within the physiologic range was demonstrated. At higher concentrations, equivalent to those present in the portal vein, stimulation of hepatic gluconeogenesis occurred, and the effects on glucose, insulin, and growth hormone levels and on ketone metabolism were induced.

The metabolic response to human growth hormone (HGH) was studied in five obese subjects in the fed state and during prolonged (5-6 wk) starvation. In the fed state (three subjects), HGH induced an elevation in basal serum insulin concentration, a minimal increase in blood and urine ketone levels, and a marked reduction in urinary nitrogen and potassium excretion resulting in positive nitrogen and potassium balance. In prolonged fasting (four subjects), HGH administration resulted in a 2- to 3-fold increase in serum insulin which preceded a 50% elevation in blood glucose. Persistence of the lipolytic effects of HGH was indicated by a rise in free fatty acids and glycerol. The response differed markedly from the fed state in that blood beta-hydroxybutyrate and acetoacetate levels rose by 20-40%, resulting in total blood ketone acid concentrations of 10-12 mmoles/liter, ketonuria of 150-320 mmoles/day, and increased urinary potassium loss. The subjects complained of nausea, vomiting, weakness, and myalgias. Despite a 50% reduction in urea excretion during HGH administration, total nitrogen loss remained unchanged as urinary ammonia excretion rose by 50% and correlated directly with the degree of ketonuria. It is concluded that in prolonged starvation (a) HGH may have a direct insulinotropic effect on the beta cell independent of alterations in blood glucose concentration, (b) persistence of the lipolytic action of HGH results in severe exaggeration of starvation ketosis and interferes with its anticatabolic action by necessitating increased urinary ammonia loss, and (c) failure of HGH to reduce net protein catabolism in starvation suggests that this hormone does not have a prime regulatory role in conserving body protein stores during prolonged fasting.

A direct neural role in the regulation of immunoreactive glucagon (IRG) secretion has been investigated during stimulation of mixed autonomic nerves to the pancreas in anesthetized dogs. The responses were evaluated by measurement of blood flow and hormone concentration in the venous effluent from the stimulated region of pancreas. Electrical stimulation of the distal end of the discrete bundles of nerve fibers isolated along the superior pancreaticoduodenal artery was invariably followed by an increase in IRG output. With 10-min periods of nerve stimulation, the integrated response showed that the higher the control glucagon output, the greater was the increment. Atropinization did not influence the response to stimulation. That the preparation behaved in physiologic fashion was confirmed by a fall in IRG output, and a rise in immunoreactive insulin (IRI) output, during hyperglycemia induced by intravenous glucose (0.1 g/kg). The kinetics of this glucose effect on IRG showed characteristics opposite to those of nerve stimulation: the lower the control output, the less the decrement. Furthermore, during the control steady state, blood glucose concentration was tightly correlated with the IRI/IRG molar output ratio, the function relating the two parameters being markedly nonlinear. Injection or primed infusion of glucose diminished the IRG response to simultaneous nerve stimulation. Measurement of IRG was inferred to reflect response of pancreatic glucagon secretion on the basis of the site of sample collection (the superior pancreaticoduodenal vein), the absence of changes in arterial IRG, and similar responses being obtained using an antibody specific for pancreatic glucagon. THESE STUDIES SUPPORT A ROLE FOR THE AUTONOMIC NERVOUS SYSTEM IN THE CONTROL OF GLUCAGON SECRETION: direct nerve stimulation induces glucagon release. Such sympathetic activation may be interpreted as capable of shifting the sensitivity of the A cell to glucose in the direction of higher glycemia for a given glucagon output. The experimental model employed is valid for further studies of regulatory mechanisms of endocrine pancreatic function in vivo.