Long-term islet-transplanted rats were examined for their ability to secrete insulin and glucagon and maintain normal glucose homeostasis under various experimental conditions. Normal glucose tolerance and insulin secretion were noted in nonstressed transplanted animals after oral glucose loading, whereas the intravenous administration of glucose resulted in a prompt but reduced insulin release associated with a slower return to basal glucose concentrations. Both the insulin and glucagon responses of nonstressed transplanted rats to arginine were comparable to those seen in normal animals. In transplant rats, stress severely impaired glucose homeostasis, as indicated by a marked rise in plasma glucose and a significant decrease in plasma insulin under basal conditions. These abnormalities were prevented by either alpha-adrenergic blockade or adrenalectomy. Stress also severely impaired both oral and intravenous glucose tolerance tests in transplant animals and markedly inhibited insulin secretory responses to tolbutamide and theophylline. Control and transplant rats exhibited comparable plasma epinephrine and norepinephrine values under basal conditions and in response to stress. The stress-induced impairment in glucose homeostasis of transplant rats was attributed to an increased sensitivity of the transplanted A- and B-cells to catecholamines secondary to their denervated state. Transplanted islet cells exhibited appropriate adaptive responses to chronic modulating factors such as a 48-hour fast and the administration of cortisol. However, cortisol-treated rats were unable to sustain a sufficient secretion of insulin to maintain normal carbohydrate tolerance, and consequently there was a reappearance of the diabetic state.

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