[en] The present study aimed at investigating the hyperglycaemic, lipolytic and ketogenic effects of small doses of glucagon delivered continuously or in a pulsatile manner. The study was performed in eight healthy young volunteers (24.2 +/- 1.2 years) and in eight healthy aged subjects (69.4 +/- 2.0 years). In all the subjects, endogenous pancreatic hormone secretion was inhibited by somatostatin and only glucagon was replaced. Consequently, the effects of pulsatile and continuous glucagon delivery were studied in conditions of progressive somatostatin-induced insulin deficiency. In both the young and the aged subjects, pulsatile glucagon delivery resulted in increases in plasma glucose, non-esterified fatty acid, glycerol and beta-hydroxybutyrate levels greater than those observed when the same amount of glucagon was delivered in a continuous manner. The net increases in plasma glucose, glycerol and non-esterified fatty acid levels were similar between the young and the aged subjects when glucagon was infused continuously; in contrast, the rise in plasma beta-hydroxybutyrate in the aged was only about half that observed in the young subjects. Surprisingly, when glucagon was infused in a pulsatile manner, the rises in plasma glycerol, non-esterified fatty acid and beta-hydroxybutyrate levels were all significantly smaller in the aged subjects, while no significant differences were observed in the blood glucose responses. We conclude that, in the presence of somatostatin-induced insulin deficiency, pulsatile glucagon exerts greater effects on blood glucose, plasma non-esterified fatty acid, glycerol and beta-hydroxybutyrate levels than its continuous delivery. In the elderly, the lipolytic and ketogenic, but not the hyperglycaemic, responses to pulsatile glucagon are significantly reduced.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Paolisso, G.
Buonocore, S.
Gentile, S.
Sgambato, S.
Varricchio, M.
Scheen, André ; Université de Liège - ULiège > Département des sciences cliniques > Diabétologie, nutrition et maladie métaboliques - Médecine interne générale
D'Onofrio, F.
Lefebvre, Pierre ; Centre Hospitalier Universitaire de Liège - CHU > Diabétologie,nutrition, maladies métaboliques
Language :
English
Title :
Pulsatile glucagon has greater hyperglycaemic, lipolytic and ketogenic effects than continuous hormone delivery in man: effect of age.
Goodner C.J., Walike B.C., Koerker D.J., Ensinck J.W., Brown A.C., Chideckel E., Palmer J.C., Kalnasy L. (1977) Insulin, glucagon and glucose exhibit synchronous sustained oscillations in fasting monkeys. Science 195:177-179.
Lang D.A., Matthews D.R., Peto J., Turner R.C. (1979) Cyclic oscillations of basal plasma glucose and insulin concentrations in human beings. N Engl J Med 301:1023-1027.
Lefèbvre P.J., Paolisso G., Scheen A.J., Henquin J.C. (1987) Pulsatility of insulin and glucagon release: physiological significance and pharmacological implications. Diabetologia 30:443-452.
Matthews D.R., Naylor B.A., Jones R.G., Ward G.M., Turner R.C. (1983) Pulsatile insulin has greater hypoglycemic effect than continuous delivery. Diabetes 32:617-621.
Paolisso G., Sgambato S., Passariello N., Scheen A.J., D'Onofrio F., Lefèbvre P.J. (1987) Greater efficacy of pulsatile insulin in type I diabetics critically depends on plasma glucagon levels. Diabetes 36:566-570.
Bratusch-Marrain P.R., Komjati M., Waldhäusl W.K. (1986) Efficacy of pulsatile versus continuous insulin administration on hepatic glucose production and glucose utilization in type 1 diabetic humans. Diabetes 35:922-926.
Paolisso G., Scheen A., Lefèbvre P.J. (1987) Greater inhibition of endogenous glucose production by pulsatile insulin delivery at basal glucagon levels in normal man. Diabetologia 30:566A.
Weigle D.S., Koerker D.J., Goodner C.J. (1984) Pulsatile glucagon delivery enhances production by perifused rat hepatocytes. Am J Physiol 247:E564-E568.
Weigle D.S., Goodner C.J. (1986) Evidence that the physiological pulse frequency of glucagon secretion optimizes glucose production by perifused rat hepatocytes. Endocrinology 118:1606-1613.
Komjati M., Bratusch-Marrain P., Waldhäusl W. (1986) Superior efficacy of pulsatile versus continuous hormone exposure on hepatic glucose production in vitro. Endocrinology 118:312-319.
Paolisso G., Scheen A.J., Luyckx A.S., Lefèbvre P.J. (1987) Pulsatile hyperglucagonemia fails to increase hepatic glucose production in normal man. Am J Physiol 252:E1-E7.
Okuda Y., Kawai K., Yamashita K. (1987) Age-related change in ketone body metabolism: diminished glucagon effect on ketogenesis in adult rats. Endocrinology 120:2152-2157.
Eggstein M., Kuhlmann E. (1974) Triglycerides and glycerol; determination after alkaline hydrolysis. Methods of enzymatic analysis, Vol 4 , H.U., Bergmeyer, Verlag Chemie, Weinheim, and Academic Press Inc, New York; 1825-1831.
Williaon D.H., Mellanby J. (1974) D-(-)-3 Hydroxybutyrate. Methods of enzymatic analysis, Vol 4 , H.U., Bergmeyer, Verlag Chemie Weinheim and Academic Press Inc, New York; 1836-1839.
Dole V.P., Meinertz H. (1960) Microdetermination of long chain fatty acids in plasma and tissues. J Biol Chem 235:2595-2599.
Weigle D.S. (1987) Pulsatile secretion of fuel-regulatory hormones. Diabetes 36:764-775.
Hansen B.C., Jen K-LC, Koerker D.J., Goodner C.J., Wolfe R.A. (1982) Influence of nutritional state on periodicity in plasma insulin levels in monkeys. Am J Physiol 242:R255-R260.
Jaspan J.B., Lever E., Polonsky K.S., Van Cauter E. (1986) In vivo pulsatility of pancreatic islet peptides. Am J Physiol 251:E215-E226.
Glucagon (Handbook of experimental pharmacology, vol 66 I and II), P.J., Lefèbvre, Springer, Berlin Heidelberg New York; 1983.
Lefèbvre P.J. (1983) Glucagon and adipose tissue lipolysis. Glucagon I. Handbook of experimental pharmacology, Vol 66 , P.J., Lefèbvre, Springer, Berlin Heidelberg New York; 419-440.
McGarry J.D., Foster D.W. (1983) Glucagon and ketogenesis. Glucagon I. Handbook of experimental pharmacology, Vol 66 , P.J., Lefèbvre, Springer, Berlin Heidelberg New York; 383-398.
Holmm G., Jacobsson B., Björntorp P., Smith U. (1975) Effect of age and cell size on rat adipose tissue metabolism. J Lipid Res 16:461-464.
Cooper B., Weinblatt F., Gregerman R.I. (1977) Enhanced activity of hormone-sensitive adenylate cyclase during dietary restriction in the rat: dependance on age and relation to cell size. J Clin Invest 59:467-474.
Bertrand H.A., Masoro E.J., Byung P.Y.U. (1980) Maintenance of glucagon-promoted lipolysis in adipocytes by food restriction. Endocrinology 107:591-595.
Corvera S., Huerta-Bahena J., Pelton J.T., Hruby V.J., Trivedi D., Garcia-Sainz J.A. (1984) Metabolic effects and cyclic AMP produced by glucagon, (1-N-triitrophenylhistidine, 12-homoarginine) glucagon, and forskolin in isolated rat hepatocytes. Bioch Bioph Acta 804:434.
