Victor Schneider

Prevention of human diabetic ketoacidosis by somatostatin. Evidence for an essential role of glucagon.

To evaluate the role of glucagon in the pathogenesis of diabetic ketoacidosis in man, we studied the effect of suppression of glucagon secretion by somatostatin on changes in plasma beta-hydroxybutyrate and glucose concentrations (as well as changes in their precursors) after acute withdrawal of insulin from seven patients with juvenile-type diabetes. Suppression of glucagon secretion prevented the development of ketoacidosis for 18 hours after acute insulin withdrawal, whereas in control studies mild ketoacidosis occurred 10 hours after insulin was stopped. Plasma beta-hydroxybutyrate, glucose, free fatty acid, and glycerol levels were all markedly lower during suppression of glucagon secretion (p smaller than 0.001), whereas plasma alanine levels were higher (p smaller than 0.001). These studies indicate that insulin lack per se does not lead to fulminant diabetic ketoacidosis in man and that glucagon, by means of its gluconeogenic, ketogenic, and lipolytic actions, is a prerequisite to the development of this condition.

Effects of Somatostatin on Plasma Glucose and Glucagon Levels in Human Diabetes Mellitus: Pathophysiologic and Therapeutic Implications

Abstract To evaluate the role of pancreatic alpha-cell dysfunction in human diabetes mellitus, somatostatin, an inhibitor of glucagon secretion, was infused (1 mg over two hours) in 10 insulin-dependent diabetic subjects. Fasting plasma glucagon fell from 150 ± 15 (mean ± S.E.M.) to 77 ± 10 pg per milliliter (p<0.001), and plasma glucose from 260 ± 20 to 191 ± 21 mg per 100 ml (p<0.001). Similar responses occurred in a hypophysectomized diabetic patient, indicating that these effects of somatostatin were independent of suppression of growth hormone secretion. Somatostatin (4 mg subcutaneously) was active transiently. In additional studies, somatostatin infusion combined with insulin completely abolished post-meal hyperglycemia in four diabetic patients and was more effective than insulin alone. These results indicate that excessive glucagon secretion accounts for about 25 per cent of the fasting plasmaglucose levels in such patients. Furthermore, somatostatin may be a useful adjunct to insulin in treating...

Effects of physiologic levels of glucagon and growth hormone on human carbohydrate and lipid metabolism. Studies involving administration of exogenous hormone during suppression of endogenous hormone secretion with somatostatin.

To study the individual effects of glucagon and growth hormone on human carbohydrate and lipid metabolism, endogenous secretion of both hormones was simultaneously suppressed with somatostatin and physiologic circulating levels of one or the other hormone were reproduced by exogenous infusion. The interaction of these hormones with insulin was evaluated by performing these studies in juvenile-onset, insulin-deficient diabetic subjects both during infusion of insulin and after its withdrawal. Infusion of glucagon (1 ng/kg-min) during suppression of its endogenous secretion with somatostatin produced circulating hormone levels of approximately 200 pg/ml. When glucagon was infused along with insulin, plasma glucose levels rose from 94 +/- 8 to 126 +/- 12 mg/100 ml over 1 h (P less than 0.01); growth hormone, beta-hydroxy-butyrate, alanine, FFA, and glycerol levels did not change. When insulin was withdrawn, plasma glucose, beta-hydroxybutyrate, FFA, and glycerol all rose to higher levels (P less than 0.01) than those observed under similar conditions when somatostatin alone had been infused to suppress glucagon secretion. Thus, under appropriate conditions, physiologic levels of glucagon can stimulate lipolysis and cause hyperketonemia and hyperglycemia in man; insulin antagonizes the lipolytic and ketogenic effects of glucagon more effectively than the hyperglycemic effect. Infusion of growth hormone (1 mug/kg-h) during suppression of its endogenous secretion with somastostatin produced circulating hormone levels of approximately 6 ng/ml. When growth hormone was administered along with insulin, no effects were observed. After insulin was withdrawn, plasma beta-hydroxybutyrate, glycerol, and FFA all rose to higher levels (P less than 0.01) than those observed during infusion of somatostatin alone when growth hormone secretion was suppressed; no difference in plasma glucose, alanine, and glucagon levels was evident. Thus, under appropriate conditions, physiologic levels of growth hormone can augment lipolysis and ketonemia in man, but these actions are ordinarily not apparent in the presence of physiologic levels of insulin.

Inhibition of Pancreatic Glucagon Responses to Arginine by Somatostatin in Normal Man and in Insulin-Dependent Diabetics

Somatostatin, a recently synthesized hypothalamic peptide thought to represent growth hormone-release-inhibiting factor, has been previously shown to inhibit pancreatic glucagon secretion in species other than man. To determine whether somatostatin also inhibits human glucagon secretion, plasma glucagon responses during intravenous infusion of arginine alone (250 mg. per kilogram over twenty-five minutes) and in combination with synthetic cyclic somatostatin (20,μg. per minute) were compared in six normal and six insulin-dependent diabetic subjects. Somatostatin abolished glucagon responses to arginine in both groups, with plasma glucagon declining transiently below basal levels; this occurred despite the fact that the diabetic subjects had fasting hyperglucagonemia and exaggerated glucagon responses during control arginine infusions. In both groups plasma glucose rises seen after arginine were diminished during somatostatin infusions, and, in the normal subjects, insulin responses were also inhibited. These results demonstrate that somatostatin is a potent inhibitor of glucagon secretion in man. Accordingly, it may prove useful as an adjunct to insulin therapy in treatment of insulin-requiring diabetes mellitus.

Effects of Alterations of Plasma Free Fatty Acid Levels on Pancreatic Glucagon Secretion in Man

The present investigation was undertaken to ascertain whether alterations in plasma free fatty acids (FFA) affect pancreatic glucagon secretion in man since FFA have been reported to influence pancreatic alpha cell function in other species. Elevation of plasma FFA from a mean (+/-SE) basal level of 0.478+/-0.036 mM to 0.712+/-0.055 mM after heparin administration caused plasma glucagon levels to fall approximately 50%, from a basal value of 122+/-15 pg/ml to 59+/-14 pg/ml (P < 0.001). Lowering of plasma FFA from a basal level of 0.520+/-0.046 mM to 0.252+/-0.041 mM after nicotinic acid administration raised plasma glucagon from a basal level of 113+/-18 pg/ml to 168+/-12 pg/ml (P < 0.005). Infusion of glucose elevated plasma glucose levels to the same degree that heparin raised plasma FFA levels. This resulted in suppression of plasma glucagon despite the fact that plasma FFA levels also were suppressed. Glucagon responses to arginine were diminished after elevation of plasma FFA (P < 0.01) and during infusion of glucose (P < 0.01). Diminution of plasma FFA by nicotinic acid did not augment glucagon responses to arginine. These results thus demonstrate that rather small alterations in plasma FFA within the physiologic range have a significant effect on glucagon secretion in man. Although the effects of glucose appear to predominate over those of FFA, alterations in plasma FFA may nevertheless exert an important physiologic influence over human pancreatic alpha cell function, especially in the postabsorptive state.

Effects of Acute Insulin Withdrawal and Administration on Plasma Glucagon Responses to Intravenous Arginine in Insulin-dependent Diabetic Subjects

To assess further the role of insulin in the abnormal alpha-cell dysfunction found in human diabetes mellitus, the effects of acute insulin withdrawal and administration on plasma glucagon responses to intravenous arginine were studied in eight insulin-dependent diabetic subjects. Arginine infusions (30 gm. over 30 minutes) were performed during and at one and four hours after discontinuation of a 14-hour insulin infusion (1.5 U. per hour), which had rendered the subjects euglycemic, and on another occasion before and one and four hours into a five-hour infusion of insulin (1.5 U. per hour). During the last hour of the 14-hour infusion, glucagon responses to arginine (area under the curve, nanograms per milliliter per minute) were similar to those found in normal subjects (10.3 ± 0.8 vs. 9.0 ± 0.8, respectively). After discontinuation of the insulin infusions, glucagon responses increased progressively (p < 0.01) to values (16.8 ± 1.2) that exceeded those of normal subjects by four hours (p < 0.01). These were similar to results found in the same subjects studied when their diabetes was in < optimal control (14.9 ± 1.3). Infusion of insulin under these conditions progressively decreased glucagon responses to arginine to values (9.6 ± 0.8; p < 0.01) that, at four hours, were similar to those of normal subjects and to values found at the end of the 14-hour infusion of insulin in the same diabetic individuals. These results demonstrate a rapid effect of insulin on glucagon responses to arginine and suggest that the abnormal responses seen in diabetes mellitus are the immediate result of insulin deficiency. Since abnormal glucagon responses to glucose in diabetes are not as readily corrected by insulin, the mechanisms underlying the abnormal responses to these two stimuli may differ.

Cryohypophysectomy for Acromegaly Factors Associated with Altered Endocrine Function and Carbohydrate Metabolism

Abstract After Cryohypophysectomy, fasting levels of growth hormone (GH) fell to less than 10 ng/ml in 38 (76 per cent) of 50 patients with acromegaly. Effects, including lowered serum insulin levels and improved glucose tolerance, were rapid and long-lasting. Optimal endocrine-metabolic results, defined as lowering of the GH level to 10 ng/ml or less and normal glucose tolerance (attained in 60 per cent of patients), were most often achieved when preoperative glucose tolerance was normal or mildly abnormal. Factors that favored optimal lowering of GH were preoperative GH level below 50 ng/ml and moderately, rather than greatly, enlarged sellae turcica. Factors that favored normal carbohydrate balance after treatment were postoperative fasting GH level of 10 ng/ml or less and preoperative symptom duration of 10 years or less. A family history of diabetes was not an important over-all factor in glucose intolerance. Although postoperative reduction in 24-hour urinary excretion of 17-hydroxycorticosteroids was associated with adequate GH reduction, adrenal reserve and thyroid function remained normal in most patients. In contrast to the prognostic significance of high GH levels, adrenal and thyroid function could not be related to eventual GH response or to carbohydrate metabolism.

ROLE OF GLUCAGON IN HUMAN DIABETIC KETOACIDOSIS: STUDIES USING SOMATOSTATIN

The present studies demonstrate that endogenous glucagon is hyperglycaemic, lipolytic and ketogenic in man, and that insulin deficiency is necessary, but is in itself not sufficient, to cause fulminant diabetic ketoacidosis. Furthermore, continuous elevation of endogenous glucagon secreation appears to be necessary for the maintenance and continued development of the characteristic metabolic consequences of insulin lack.