Mara Lorenzi

Evidence for a physiologic role of pancreatic glucagon in human glucose homeostasis: Studies with somatostatin☆

To study the role of glucagon in human glucose homeostasis, experimental glucagon deficiency was produced by infusing somatostatin (i. v. 250 mug bolus, followed by infusion of 500 mug/hr) in six normal subjects and in two hypophysectomized patients-an insulin-dependent diabetic and a nondiabetic. In normal subjects, somatostatin lowered plasma glucagon from a mean (plus or minus SE) basal level of 85 plus or minus 15 to 33 plus or minus 10 pg/ml, p smaller than 0.001. Concurrently, plasma glucose fell from 90 plus or minus 2 to 73 plus or minus 3 mg/100 ml, p smaller than 0.001. Serum insulin and growth hormone fell slightly during somatostatin infusion, while plasma free fatty acids rose. In both hypophysectomized patients, somatostatin lowered plasma glucagon and glucose levels. In all subjects, after stopping somatostatin infusions, plasma glucagon and glucose returned promptly to control values, while serum growth hormone did not change. In additional in vitro studies, somatostatin (1 mug/ml) had no effect on muscle glucose uptake. Since it is known that somatostatin has no direct effect on hepatic glucose production, these results suggest that the fall in plasma glucose during somatostatin infusion resulted from inhibition of glucagon secretion, thus providing evidence that this hormone plays a physiologic role in the maintenance of fasting euglycemia in man.

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.

Discordance of Diabetic Microangiopathy in Identical Twins

In a pair of 19-year-old monozygotic twin girls, one developed insulin-dependent, ketosis-prone diabetes at the age of three and has required insulin for the past 16 years. Her identical twin has maintained normal oral and intravenous glucose tolerance with normal insulin release and glucagon suppression. An unequivocal hypertrophy of the muscle capillary basement membrane(1,800 ± 148 Å) was found in the diabetic twin, while a normal thickness of 1,149 ± 62 Å was present in her nondiabetic sister. Follow-up of the present subjects and data from other discordant identical twins who have reached adulthood could determine whether muscle capillary basement membrane hypertrophy is an independent marker of genetic diabetes in adults. Discordance of diabetic microangiopathy in a pair of monozygotic twins has important implications regarding the influence of heredity and environment on diabetic microangiopathy.

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.

Rapid fluctuations in glycosylated haemoglobin concentration as related to acute changes in blood glucose.

ences were detected between groups A and B. Three previous reports describe an association between BfF1 and insulin dependent diabetes [7, 8, 9] but two others found no association [10, 11]. The discrepancies may be due to geographical variations or to differences in the selection of patients studied [9]. The available data provide no evidence that HLA type or Bf allele are genetic markers for proliferative retinopathy.

Plasma glucagon suppression by phenformin in man

SummaryIn 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 ofα-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.

Inhibition by indomethacin of the glycemic response to arginine in man.

Summary We investigated the effect of indomethacin on the glucagon, glucose, and insulin responses to arginine in eight normal subjects. Glucagon secretion was not affected, but glucose and insulin responses were significantly decreased. Although inhibition of hepatic glycogenolysis is a possible reason for this effect, hepatic glycogen depletion and augmented peripheral glucose utilization are other explanations to be considered. Supported in part by Grant AM-12763(09) from the National Institutes of Health and by the Levi J. and Mary Skaggs Foundation of Oakland, California, and the Susan Greenwall Foundation of New York City.