Despite excessive glucagon responses to infusion of arginine, plasma glucagon did not rise in six juvenile-type diabetics during severe insulin-induced hypoglycemia, whereas glucagon in the controls rose significantly. Thus in diabetics pancreatic alpha cells are insensitive to glucose even in the presence of large amounts of circulating insulin. An intrinsic defect common to both alpha and beta pancreatic cells-failure to recognize (or respond to) plasma glucose fluctuations-may be operative in juvenile diabetes.

A B S T R A C T In order to characterize the influence of the adrenergic system on pancreatic glucagon secretion in man, changes in basal glucagon secretion during infusions of pure alpha and beta adrenergic agonists and their specific antagonists were studied. During infusion of isoproterenol (3 Ag/min), a beta adrenergic agonist, plasma glucagon rose from a mean (±SE) basal level of 104±10 to 171±15 pg/ml, P < 0.0002. Concomitant infusion of propranolol (80 Ag/min), a beta adrenergic antagonist, prevented the effects of isoproterenol, although propranolol itself had no effect on basal glucagon secretion. During infusion of methoxamine (0.5 mg/ min), an alpha adrenergic agonist, plasma glucagon declined from a mean basal level of 122±15 to 75±17 pg/ml, P <0.001. Infusion of phentolamine (0.5 mg/ min), an alpha adrenergic antagonist, caused a rise in plasma glucagon from a mean basal level of 118±16 to 175+21 pg/ml, P <0.0001. Concomitant infusion of methoxamine with phentolamine caused a reversal of the effects of phentolamine.The present studies thus confirm that catecholamines affect glucagon secretion in man and demonstrate that the pancreatic alpha cell possesses both alpha and beta adrenergic receptors. Beta adrenergic stimulation augments basal glucagon secretion, while alpha adrenergic stimulation diminishes basal glucagon secretion. Furthermore, since infusion of phentolamine, an alpha adrenergic antagonist, resulted in an elevation of basal plasma glucagon levels, there appears to be an inhibitory alpha adrenergic tone governing basal glucagon secretion. The above findings suggest that catecholamines may influence glucose homeostasis in man through their effects on both pancreatic alpha and beta cell function.

ABSTRA CT To examine whether abnormal pancreatic alpha-cell function found in human diabetes mellitus may represent a selective insensitivity to glucose, plasma glucagon responses to hyperglycemia and elevation of plasma free fatty acid levels (both known suppressors of glucagon secretion) were compared in juvenile-onset, insulin-requiring diabetic subjects, and in normal nondiabetic subjects. In the latter, both elevation of plasma free fatty acid levels induced by heparin administration and hyperglycemia produced by intravenous infusion of glucose resulted in a comparable 30-40% suppression of circulating glucagon levels (P < 0.01). In the diabetic subjects, glucagon suppression by hyperglycemia (< 20%) was less than that occurring in normal subjects (P < 0.01), even when accompanied by infusion of supraphysiologic amounts of insulin. However, suppression of glucagon levels by elevation of plasma free fatty acids in the diabetic group was similar to that found in normal subjects and of comparable magnitude to that due to hyperglycemia in the normal subjects. These results thus demonstrate a selective impairment of the diabetic alpha-cell response to glucose and provide further evidence for the presence of

The present investigation was undertaken to characterize glucagon responses to hypoglycemia in man. Using a highly specific antiserum, plasma immunoreactive glucagon levels were determined during episodes of insulininduced hypoglycemia in 15 normal subjects and during oral glucose tolerance tests in 4 subjects with reactive hypoglycemia. During insulininduced hypoglycemia, plasma glucagon rose from a mean ( ± S E M ) basal level of 143 ± 6.5 pg/ml to a maximum of 471 ± 15 pg/ml at 45 min, p < .001. Initial glucagon responses were evident 15 min after insulin administration and precedes those of cortisol and growth hormone. Total glucagon responses (area under curve) correlated positively with the total decrease in plasma glucose (area below basal), r = 0.852, p < 0.0005, rather than the nadir or absolute level of hypoglycemia achieved. Hyperglycemia induced by 60 min glucose infusions, which suppressed basal glucagon secretion, did not prevent glucagon responses to subsequent insulin-induced hypoglycemia. Moreover the fall in plasma glucose from a mean of 187 mg/100 ml to 112 mg/100 ml was sufficient to stimulate glucagon secretion. In all subjects with reactive hypoglycemia plasma glucagon rose at least 2 times basal.Thus, in man, hypoglycemia is a potent stimulus for glucagon secretion. The rate of fall of plasma glucose as well as the degree and duration of hypoglycemia are important determinants of the glucagon response. These findings suggest that pancreatic glucagon may function physiologically as a hypoglycemic counter-regulatory hormone, and that glucagon responses to hypoglycemia may provide an additional parameter with which to assess pancreatic alpha cell function in man. (/ Clin Endocrinol Metab 38: 77, 1974)

A B S T R A C T 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). Dimi