Gerich, John E.

To assess the effects of endogenous somatostatin on pancreatic islet A- and B-cell function, isolated rat islets were incubated in antisomatostatin γ-globulin to bind endogenously released somatostatin, and the insulin and glucagon secretion of these islets was compared with that of islets incubated in γ-globulin isolated from nonimmune serum. Islets incubated in antisomatostatin γ-globulin released significantly more insulin at 4, 8,16, and 32 mM glucose and significantly more glucagon at 8,16, and 32 mM glucose, P < 0.05–0.005. For glucose-stimulated insulin release the threshold was decreased, the Vmax was increased, but the apparent Km was unaltered; for glucose-suppression of glucagon release the threshold was increased, maximal suppression was decreased, but the apparent Ki was unaltered. The augmentative effect of the antisomatostatin γ-globulin was most prominent at 4 mM glucose for insulin release and at 8 mM glucose for glucagon release, but was not limited to glucose since both insulin and glucagon release stimulated by arginine were also augmented by antisomatostatin γ-globulin. These results provide evidence that endogenous somatostatin may act as a physiologic local regulator of both insulin and glucagon secretion and that its effect on insulin and glucagon secretion is dependent on the prevailing glucose concentration.

SUMMARY To assess the relative contribution of overproduction and underutilization of glucose and ketone bodies to the development of diabetic ketoacidosis in man, the effects of acute insulin deficiency on glucose and ketone body turnovers were determined in seven ketosis-prone (type I) diabetic subjects. After termination of prolonged intravenous infusions of insulin, which had been maintaining the subjects euglycemic, plasma free insulin decreased from 18 ± 4 μU/ml to 7 ± 1 μU/ml, P < 0.01; plasma glucagon increased from 67 ± 6 pg/ml to 259 ± 67 pg/ml, P < 0.05, but plasma growth hormone and cortisol did not increase. Plasma glucose increased from 5.4 ± 0.3 mM to 15.6 ± 1.0 mM, P < 0.01; plasma ketone bodies (β-hydroxybutyrate plus acetoacetate) increased from 1.4 ± 0.4 mM to 7.2 ± 1.5 mM, P < 0.01. Glucose production increased abruptly from 13.2 ± 1.1 μmol/kgmin to a maximum of 26.1 ± 2.9 μmol/kg-min at 2 h but then decreased toward baseline rates; glucose utilization also increased transiently. In contrast, both ketone body production and utilization increased progressively throughout the study from 5.4 ± 1.4 and 5.5 ± 1.1 to 18.3 ± 3.9 and 14.7 ± 2.1 μmol/kg-min, respectively, P < 0.01. Clearance of both glucose and ketone bodies decreased more than 50%, P < 0.01. These results indicate that overproduction of glucose and ketone bodies is the primary process involved in the initiation of diabetic ketoacidosis in man. However, persistent overproduction of glucose and ketone bodies may not be necessary for the maintenance of hyperglycemia and hyperketonemia, since clearance of both substrates is impaired. Finally, since, of all counter-insulin hormones measured, only plasma glucagon increased coincident with increases in glucose and ketone body production, these results provide further evidence that glucagon may be the most important counter-insulin hormone involved in the genesis Of ketoacidosis.

Since little is known regarding the appropriate time for preprandial insulin administration, we compared the effects of 30-min subcutaneous insulin infusions started 60 min, 30 min, and immediately before meal ingestion on postprandial plasma glucose and insulin profiles in eight subjects with insulin-dependent diabetes mellitus. Of these three regimens, administration of insulin 60 min before meal ingestion provided plasma glucose and insulin profiles closest to normal and permitted less insulin to be used. Our results suggest that adjustments in the timing as well as in the amount of insulin administered preprandially may be used in the management of diabetes and that prolonging the interval between administration of insulin and meal ingestion may reduce insulin requirements and thus decrease the hyperinsulinemia usually associated with insulin therapy.

Glucagon normally plays a primary role in promoting glucose recovery from insulin-induced hypoglycemia. Epinephrine compensates largely for deficient glucagon secretion. Glucose recovery from hypoglycemia fails to occur only in the absence of both glucagon and epinephrine. Perhaps as a relatively early feature of autonomic neuropathy, patients with insulin-dependent diabetes mellitus commonly have blunted or absent glucagon secretory responses to hypoglycemia. However, this deficient response is commonly compensated for by epinephrine and glucose recovery occurs. In some patients, progression of adrenergic neuropathy to the point of deficient epinephrine secretory responses to hypoglycemia, coupled with deficient glucagon responses, leads to frequent, severe, and prolonged hypoglycemia. Thus, these glucose counterregulatory systems are of critical importance to patients with insulindependent diabetes mellitus. The efficacy of glucose counterregulation in a given patient may determine the degree to which euglycemia can be achieved with aggressive insulin therapy in that patient.

Although initial laboratory studies using biosynthetic human insulin (BHI) indicate little difference in the intrinsic potency of biosynthetic human and purified pork insulin (PPI) in vitro, certain in vivo observations suggest that BHI may differ pharmacokinetically from pork insulin. If further studies support these suggestions, the use of BHI may be able to provide better glycemic control and more near normal plasma insulin profiles during treatment of insulin-dependent diabetes than can be achieved with presently available insulin preparations. However, BHI appears to offer no advantage over presently available PPI in terms of prevention and treatment of insulin lipodystrophy, insulin allergy, and immune insulin resistance.

To assess the feasibility of preprogramming an open-loop device with insulin flow rates generated by the Biostator Glucose Controller, comparisons were made in 10 juvenile-onset diabetic patients between meals of equal size and composition taken in the morning, at noon, and in the evening and a bedtime snack during a 24-h period of Biostator glucose control. Four additional diabetic patients had Biostator glucose control for 72 h. Similar amounts of insulin were infused for the meals taken at differing times of the day and, except for the morning meal, for the same meal on two successive days. The meal-related glycemic patterns expressed as mean indices of meal excursions (MIME) were similar for meals of identical size and composition during a single day and for the same meal taken on two consecutive days. Preliminary results using an open-loop device preprogrammed by the Biostator system, although encouraging, underscore the deficiency of the subcutaneous route viz. the delayed entry of insulin into the circulation in achieving normal glucose levels and patterns.

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 μU/ml) and extremely high antibody-bound insulin (>20,000 μU/ml) but normal counterregulatory hormone secretion and plasma C-peptide levels. The amount of antibody-bound insulin decreased in a biphasic pattern over13 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.