Prolonged fasting hypoglycemia due to insulin antibodies in patient with non-insulin-dependent diabetes mellitus: effect of insulin withdrawal on insulin-antibody-binding kinetics

Fasting hypoglycemia, which persisted for 3 days after insulin treatment was stopped, occurred in a patient with non-insulin-dependent diabetes mellitus who had inappropriate plasma free-insulin levels (18-25 microU/ml) and extremely high antibody-bound insulin (greater than 20,000 microU/ml) but normal counter-regulatory hormone secretion and plasma C-peptide levels. The amount of antibody-bound insulin decreased in a biphasic pattern over 13 mo of observation with an initial half-life of 35 days and a more gradual decrease with a half-life of 160 days. The number of high-affinity antibody binding sites was virtually identical to the amount of antibody-bound insulin in the patient's plasma. We conclude that the patient's fasting hyperinsulinemia and hypoglycemia were due to release of antibody-bound insulin.     

Insulin increases the maximum velocity for glucose uptake without altering the Michaelis constant in man. Evidence that insulin increases glucose uptake merely by providing additional transport sites.

The present studies were undertaken to assess the mechanism by which insulin increases glucose uptake in man. Because glucose uptake in most mammalian tissues occurs predominantly by a facilitated transport system that follows Michaelis-Menten kinetics, glucose uptake was measured isotopically in normal volunteers over the physiologic range of plasma glucose and insulin concentrations and was subjected to Lineweaver-Burk and Eadie-Hofstee analysis. With both methods, increases in plasma insulin from 18 microunits/ml to 80 and 150 microunits/ml were found to increase the maximum velocity (Vmax) for glucose uptake nearly three- and fivefold, respectively, (P less than 0.025 and P less than 0.001) without significantly altering the Michaelis constant (Km). Because an increase in the affinity or molecular activity of transport sites or provision of additional transport sites that differed from those present basally should have altered the Km, whereas a mere increase in the number of transport sites would have only increased the Vmax, our results indicate that in man, insulin may increase glucose uptake merely by providing additional transport sites.     

Plasma glucagon suppression by phenformin in man

Summary In an attempt to elucidate the mechanism of action of phenformin, eleven juvenile-onset, insulin-requiring diabetic subjects underwent four different treatment regimens during standard breakfast tests. These four treatments were: control (no insulin or phenformin); insulin alone (15 U regular insulin administered subcutaneously one-half hour before breakfast); phenformin alone (50 mg of the timed-release capsule given twice daily for three days before the study and two and one-half hours before breakfast on the day of study); and phenformin plus insulin (in the amounts and at the times stated above). Phenformin was found to decrease postprandial hyperglycaemia significantly when compared with control values, and its addition to insulin further decreased the postprandial glucose rise below that found with insulin alone (p<0.005). These effects were associated with a reduction in early (30-min) postprandial hyperglucagonaemia (p <0.05). Triglyceride levels, gastrin secretion, growth hormone levels, and increments of-amino nitrogen were not affected by phenformin. Thus, suppression of postprandial hyperglucagonaemia may be an additional mechanism in the reduction of postprandial hyperglycaemia after phenformin.     

Stimulation of human pancreatic polypeptide secretion by hypoglycemia is independent of adrenergic mechanisms

Human pancreatic polypeptide (HPP) increases after insulin-induced hypoglycemia. To determine whether adrenergic mechanisms contribute to this increase in normal man, six subjects were studied on two occasions: once after insulin alone and once after insulin plus simultaneous alpha (phentolamine)- and beta (propranolol)-adrenergic blockade. Despite comparable hypoglycemia (51 +/- 4 vs. 49 +/- 4 mg/dl), the increase in HPP did not differ in the presence or absence of adrenergic blockade (721 +/- 215 vs. 736 +/- 193 pg/ml, respectively). These findings suggest that HPP secretion during hypoglycemia is not dependent on adrenergic mechanisms.     

Abnormal Secretion of Insulin and Glucagon by the In Vitro Perfused Pancreas of the Genetically Diabetic Chinese Hamster

Hereditary insulin-deficient diabetes mellitus occurs in certain sublines of nonobese Chinese hamsters. Several characteristics of this syndrome are similar to those seen in insulin-deficient human diabetics. Therefore, to characterize pancreatic islet function, dynamic insulin and glucagon release from normal and nonketotic diabetic hamster pancreases in response to glucose (300 mg/100 ml) and theophylline (10 mM), infused singly and together, was studied in vitro.20-min glucose infusions of normal hamster pancreases caused biphasic insulin release, consisting of a rapid first peak and a gradually rising second phase, similar to that reported for man in vivo. Both phases were significantly reduced in the diabetic pancreases. Theophylline alone stimulated similar nonphasic insulin release in both the normal and the diabetic pancreases. Glucose and theophylline together caused greater insulin release than either stimulant alone in both normals and diabetics; however, the diabetic response was still subnormal.Glucose suppressed glucagon release from normal pancreases; suppression was significantly impaired in diabetics. Theophylline stimulated nonphasic glucagon release in both the normals and diabetics. Glucose partially suppressed the theophylline-stimulated release in both groups.Insulin/glucagon molar ratios of the diabetics were consistently subnormal, although individual hormone levels often overlapped into the normal range.IN SUMMARY, THE PANCREASES OF GENETICALLY DIABETIC CHINESE HAMSTERS PERFUSED IN VITRO SHOWED: (a) decreased first and second phase insulin release in response to glucose-containing stimuli-only partially ameliorated by theophylline-, and (b) impaired suppression of glucagon in response to glucose, resulting in (c) a decreased insulin/glucagon molar ratio. These data support the suggestion that both alpha and beta cells of diabetic pancreases may be insensitive to glucose.     

Clinical evaluation of somatostatin as a potential adjunct to insulin in the management of diabetes mellitus

Summary To determine whether somatostatin, an inhibitor of glucagon and growth hormone secretion, might be useful as an adjunct to insulin in the management of diabetic hyperglycaemia, seven insulinrequiring diabetic men were given somatostatin (100 g/h, IV) continuously for 3 days after their diabetes had been treated intensively by diet and insulin on a metabolic ward. During infusion of somatostatin and despite reduction in average insulin dose exceeding 50%, there was improvement in diabetic control as assessed by postprandial hyperglycaemia, 24-h glycosuria and the average daily serum glucose level and its fluctuation; when somatostatin was discontinued, but insulin doses held constant, diabetic control rapidly worsened. No adverse effects were observed. These results indicate that somatostatin plus insulin can be a more effective regimen than insulin alone in controlling diabetic hyperglycaemia. A longer acting and more selective somatostatin preparation may prove useful as an adjunct to insulin in the management of diabetes.