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.

Abstract

A B S T R A C T 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 <0.01); growth hormone, P-hydroxybutyrate, alanine, FFA, and glycerol levels did not change. When insulin was withdrawn, plasma glucose, fi-hydroxybutyrate, FFA, and glycerol all rose to higher levels (P < 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. 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 After insulin was withdrawn, plasma P-hydroxybutyrate, glycerol, and FFA all rose to higher levels (P < 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. INTRODUCTIONThe physiologic importance of glucagon and growth hormone in human carbohydrate and lipid homeostasis is poorly understood. Administration of pharmacologic amounts of glucagon can augment lipolysis (1-4), ketogenesis (1-4), and glucose production (1-5) in man, but these effects are difficult to interpret because such quantities of glucagon may promote growth hormone (6) and catecholamine (7) release. Moreover, similar results have not been consistently observed in studies using physiologic concentrations of glucagon (3,8,9). Evidence for the participation of growth hormone in human lipid and carbohydrate metabolism is based largely on results obtained after administration of pharmacologic quantities of growth hormone and on observations in hypophysectomized individuals. Growth hormone, when administered in pharmacologic doses, reportedly diminishes glucose utilization (10-15) and promotes lipolysis (10, 16) and ketosis (10, 15, 16) in man, but similar

Evidence for an important role of glucagon in the regulation of hepatic glucose production in normal man.

“…Somatostatin, however, does inhibit the release of a variety of other hormones including growth hormone (8). Although this could have influenced the results of our study, it does not seem likely, because Gerich et al (23) replaced growth hormone during somatostatin administration and noted no effect on the plasma glucose concentration. More definitive evidence emerges from our studies in the dog in which intraportal insulin and glucagon replacement during somatostatin administration results in maintenance of NSGP at basal rates (11).…”

Glucagon Immunoreactivities and Amino Acid Profile in Plasma of Duodenopancreatectomized Patients

“…The relatively benign metabolic decompensation of patient 2 after 3 d of insulin withdrawal supports the view that this form of diabetes might, in fact, be less prone to ketosis than juvenile onset-type diabetes. Similarly, Barnes et al (39) showed a much slower rise in blood glucose and ketone bodies in pancreatectomized patients after insulin deprivation than in juvenile-type diabetics, which reflects the slowed onset of ketoacidosis in the juvenile-type diabetics of Gerich et al (40) during glucagon suppression by somatostatin. The administration of glucagon accelerated the development of ketoacidosis back to where it was before somatostatin administration (40).…”

Management of Hyperglycemic Crises in Patients With Diabetes

“…In the liver, FFAs are oxidized to ketone bodies, a process predominantly stimulated by glucagon. Increased concentration of glucagon in DKA reduces the hepatic levels of malonyl-CoA by blocking the conversion of pyruvate to acetyl-CoA through inhibition of acetyl-CoA carboxylase, the first ratelimiting enzyme in de novo fatty acid synthesis (63)(64)(65)(66). Malonyl-CoA inhibits carnitine palmitoyl-transferase (CPT)-I, the rate-limiting enzyme for transesterification of fatty acyl-CoA to fatty acyl-carnitine, allowing oxidation of fatty acids to ketone bodies.…”