In order to explore whether or not the negative feedback mechanism of insulin per se on insulin secretion exists in man, changes in plasma C-peptide immunoreactivity (CPR), as an index of pancreatic B cells secretory function, were studied in 6 nonobese healthy volunteers in the presence of high circulating levels of exogenous insulin. 10% glucose was infused concurrently so as to maintain blood sugar at the basal level. The insulin-glucose infusion was maintained for 120 minutes, achieving mean plasma levels of 140-180 mu1/ml. After this period, the insulin infusion was continued at the same rate for an additional 10 minutes while the glucose was omitted. Despite the elevated level of circulating insulin, no significant change in plasma CPR concentration was observed so long as the blood sugar was maintained at the basal levels. Following cessation of the glucose infusion, the plasma CPR levels declined with a decrease in blood sugar level. Under the conditions of the present study, no inhibitory effect of exogenous insulin on the secretory function of the B cells was noticed.
To clarify possible etiologie mechanisms for brittleness of diabetic control, a relationship between the degree of diabetic instability and insulinogenic reserve or insulin-binding capacity of plasma IgG was studied in 46 insulin-treated diabetics attending the outpatient clinic. Evaluation of insulinogenic reserve was based on elevations of plasma C-peptide immunoreactivity (CPR) during the oral glucose tolerance test (OGTT). The degree of instability was quantified by the standard deviations (S.D.) of 10 values of fasting blood glucose, which were determined for the last six months while subjects were attending a hospital as outpatients. An inverse correlation was evident between residual B-cell secretory capacity and blood glucose regulatory instability (r = −0.69, p < 0.005), but there was no consistent relationship of the insulin-binding capacity to the degree of diabetic instability (r = 0.15, p > 0.05). Furthermore, pancreatic A-cell functions were investigated in seven unstable and seven stable diabetics, classified according to their S.D. values. Although immunoreactive glucagon (IRG) responses to an infusion of arginine were observed, plasma IRG did not rise in unstable diabetics during insulin-induced hypoglycemia, in which condition IRG in stable diabetics rose significantly. In contrast, plasma cortisol responses to the insulin-induced hypoglycemia were demonstrated in both diabetic groups. Plasma CPR did not decrease in unstable but did in stable diabetics fol towing the insulin injection. The comparison of unstable diabetic patients with more stable ones on the basis of clinical data, such as means of age, duration of diabetes mellitus, duration of insulin therapy, and dose of insulin, revealed no significant difference. The total lack of insulinogenic reserve results inevitably in loss of the automatic regulation of circulating insulin levels, which seems to be one of the essential factors for causing the hyperla-biUty of diabetic control. The pancreatic A-cell dysfunction is also attributable in part to the metabolic variability in brittle diabetes.
Ten healthy male volunteers were studied to compare the effectiveness of intravenous and subcutaneous injections of 1 mg of glucagon on HG secretion. Plasma HGH level rose to a peak of 6 ng/ml or greater 120 minutes after the subcutaneous injection of glucagon (sc glucagon) in all subjects, whereas the intravenous injection of glucagon (iv glucagon) caused comparable increments in plasma HGH in only six out of ten subjects. Furthermore, in comparison to those in sc glucagon the periods required to show maximum responses were less consistent in iv glucagon. Plasma IRG levels reached a peak of 102.4+/-22.6 ng/ml at two minutes following iv glucagon, and a peak of 3.33+/-1.08 ng/ml at 15 minutes following sc glucagon. These fell to initial levels at 60 minutes and at 180 minutes, respectively. There was no definite correlation either between the magnitudes of changes in plasma IRG and HGH levels or between the velocities of decrement in blood sugar and HGH responsiveness. Judging from its simplicity and reproducibility it may be concluded that sc glucagon is more suitable for a clinical provocative test of HGH release than is iv glucagon. In regards to the mechanism of glucagon-induced HGH release, neither glucagon per se nor the fall of blood sugar after hyperglycemia was assumed to play any major role. The sustained elevation of plasma IRG for a certain period might be responsible for the glucagon-induced HGH release.
