Summary
To determine the effects of prolonged hyperglycaemia on pancreatic islet A- and B-cell function, plasma glucose was clamped for 12 h at approximately 11 and 5 mmol/l in control experiments by infusing glucose and somatostatin along with replacement amounts of insulin, glucagon, and growth hormone in seven normal volunteers. Following restitution of euglycaemia for 1 h after prolonged hyperglycaemia, termination of the somatostatin-replacement hormone infusions resulted in a sustained decrease in plasma glucose to 3 mmol/l (p<0.01). Despite this, plasma glucagon did not increase above values observed in control experiments in which plasma glucose did not decrease; moreover, there was a persistent increase in insulin secretion nearly threefold above that observed in control experiments (p<0.01). Plasma growth hormone, cortisol and adrenaline responses were appropriate. This failure of a decrement in plasma glucose to suppress insulin secretion and to stimulate glucagon secretion was not observed when comparable hypoglycaemia was induced by exogenous insulin after a prolonged euglycaemic clamp. Our results indicate that hyperglycaemia can induce altered sensitivity of pancreatic A and B cells to glucose and suggest that abnormal A- and B-cell responses to glucose in diabetes mellitus may not represent a wholly intrinsic defect.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Kipnis D (1969) Insulin secretion in diabetes mellitus. Ann Int Med 69: 981–901
Gerich J, Langlois M, Noacco D, Karam J, Forsham P (1973) Lack of glucagon response to hypoglycaemia in diabetes: evidence for an intrinsic pancreatic alpha-cell defect. Science 182: 171–173
Varsano-Aharon N, Echemedia E, Yalow R, Berson S (1970) Early insulin responses to glucose and tolbutamide in maturity-onset diabetes. Metabolism 19: 409–417
Robertson R, Porte D (1973) The glucose receptor: A defective mechanism in diabetes mellitus distinct from the beta adrenergic receptor. J Clin Invest 52: 87–876
Deckert T, Lauridsen U, Madsen S, Morgensen P (1972) Insulin response to glucose, tolbutamide, secretin, and isoprenaline in maturity onset diabetes mellitus. Dan Med Bull 19: 222–226
Turner R, Schneelock B, Nabarro J (1971) Biphasic insulin secretory response to intravenous xylitol and glucose in normal, diabetic and obese subjects. J Clin Endocrinol Metab 33: 301–307
Palmer J, Benson J, Walter R, Ensinck J (1976) Arginine-stimulated acute phase of insulin and glucagon secretion in diabetic subjects. J Clin Invest 58: 565–570
Unger R, Aguilar-Parada E, Muller W, Eisentraut A (1970) Studies of pancreatic alpha cell function in normal and diabetic subjects. J Clin Invest 49: 837–848
Gerich J, Langlois M, Noacco C, Lorenzi M, Karam J, Forsham P (1976) Comparison of suppressive effects of hyperglycaemia and elevation of plasma free fatty acid levels on glucagon secretion in normal and insulin-dependent subjects: Evidence for selective alpha cell sensitivity to glucose in diabetes mellitus. J Clin Invest 58: 320–325
Unger R, Madison L, Muller W (1972) Abnormal alpha cell function in diabetes: Response to insulin. Diabetes 21: 301–309
Cerasi R, Luft R, Efendic S (1972) Decreased sensitivity of the pancreatic beta cells to glucose in prediabetic and diabetic subjects: A glucose dose-response study. Diabetes 21: 224–234
Niki A, Niki H (1975) Is diabetes a disorder of the glucoreceptor? Lancet 2: 658–659
Kahn C, Baird K, Flier J, Grunfeld C, Harmon J, Harrison L, Karlsson F, Kasuga M, King G, Lang U, Podskalny J, Obberghen E (1981) Insulin receptors, insulin antibodies and the mechanism of insulin action. Rec Prog Horm Res 37: 477–538
Verdonk C, Rizza R, Westland R, Service J, Nelson R, Gerich J (1980) Glucose clamping using the biostator. Horm Metab Res 12: 133–136
Faber O, Binder C, Markussen J, Heding L, Naithani V, Kuzuya H, Blix P, Horwitz D, Rubenstein A (1978) Characterization of seven C-peptide antisera. Diabetes 27 (Suppl 1): 170–177
Herbert V, Lau K, Gottlieb C, Bleicher S (1965) Coated charcoal immunoassay of insulin. J Clin Endocrinol Metab 25: 1375–1384
Faloona G, Unger R (1974) Glucagon. In: Jaffe B, Behrman H (eds) Methods of hormone radioimmunoassay. Academic Press, New York, pp 317–330
Peake G (1974) Growth hormone. In: Jaffe B, Behrman H (eds) Methods of hormone radioimmunoassay. Academic Press, New York, pp 103–121
Murphy B (1967) Some studies of the protein-binding steroids and their application to the routine micro- and ultramicromeasurement of various steroids in body fluids by competitive protein-binding radioassay. J Clin Endocrinol Metab 27: 973–990
Cryer P (1976) Isotope-derivative measurements of plasma norepinephrine and epinephrine in man. Diabetes 25: 1071–1082
Bolli G, Gottesman I, Cryer P, Gerich J (1984) Glucose counter-regulation during prolonged hypoglycaemia in normal man. Am J Physiol 247: E206–214
Eaton R, Allen R, Schade D, Erickson K, Standefer J (1980) Prehepatic insulin production in man: kinetic analysis using peripheral connecting peptide behavior. J Clin Endocrinol Metab 51: 520–528
Andersson A, Westman J, Hellerström C (1974) Effects of glucose on the ultrastructure and insulin biosynthesis of isolated mouse pancreatic islets maintained in tissue culture. Diabetologia 10: 743–753
Porte D, Pupo A (1969) Insulin responses to glucose: evidence for a two pool system in man. J Clin Invest 48: 2309–2319
Goldfine I, Cerasi E, Luft R (1972) Glucagon stimulation of insulin release in man: inhibition during hypoglycaemia. J Clin Endocrinol Metab 35: 312–315
Efendic S, Cerasi E, Luft R (1971) Role of glucose in arginine-induced insulin release in man. Metabolism 20: 568–578
Horwitz D, Rubenstein A, Reynolds C, Molnar G, Yanaihara N (1975) Prolonged suppression of insulin release by insulin-induced hypoglyaemia: demonstration by C-peptide assay. Horm Metab Res 7: 449–452
Santeusanio F, Bolli G, Massi-Benedetti M, DeFeo P, Angeletti G, Compagnucci P, Calabrese G, Brunetti P (1981) Counterregulatory hormones during moderate, insulin-induced, blood glucose decrements in man. J Clin Endocrinol Metab 52: 477–482
Santiago J, Clarke W, Shah S, Cryer P (1980) Epinephrine, norepinephrine, glucagon and growth hormone release in association with physiological decrements in the plasma glucose concentration in normal and diabetic man. J Clin Endocrinol Metab 51: 877–883
Sacca L, Sherwin R, Hendler R, Felig P (1979) Influence of continuous physiologic hyperinsulinemia on glucose kinetics and counterregulatory hormones in normal and diabetic man. J Clin Invest 63: 849–857
Rizza R, Cryer P, Gerich J (1979) Role of glucagon, catecholamines, and growth hormone in human glucose counterregulation: effects of somatostatin and combined α and β adrenergic blockade on plasma glucose recovery and glucose flux rates following insulin-induced hypoglycaemia. J Clin Invest 64: 62–71
Bolli G, Tsalikian E, Haymond M, Cryer P, Gerich J (1984). Defective glucose counterregulation after subcutaneous insulin in non-insulin-dependent diabetes mellitus. Paradoxical suppression of glucose utilization and lack of compensatory increase in glucose production, roles of insulin resistance, abnormal neuroendocrine responses, and islet paracrine interactions. J Clin Invest 73: 1532–1541
Kosaka K, Kuzuya T, Akanuma Y, Hagura R (1980) Increase in insulin response after treatment of overt maturity-onset diabetes is independent of the mode of treatment. Diabetologia 18: 23–28
Savage P, Bennion L, Flock E, Nagulesparan M, Mott D, Roth J, Unger R, Bennett P (1979) Diet-induced improvement of abnormalities in insulin and glucagon secretion and in insulin receptor binding in diabetes mellitus. J Clin Endocrinol Metab. 48: 999–1007
Berger D, Floyd J, Pek S (1981) The effect of treatment of Type 2 (insulin-independent) diabetes mellitus on plasma concentrations of pancreatic polypeptide and glucagon. Diabetologia 21: 120–125
Raskin P, Pietri A, Unger R (1979) Changes in glucagon levels after four to five weeks of glucoregulation by portable insulin infusion pumps. Diabetes 28: 1033–1035
Vague P, Moulin J (1982) The defective glucose sensitivity of the B-cell in noninsulin dependent diabetes: improvement after twenty-four hours of normoglycaemia. Metabolism 31: 139–142
Schmeltz R, Wendorff H, Field J (1978) Effect of control of blood glucose on plasma insulin responses to various stimuli in secondary failures to oral hypoglycaemic agents and in newly diagnosed maturity onset, ketosis-resistant diabetics. J Clin Endocrinol Metab 46: 519–527
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Dimitriadis, G., Cryer, P. & Gerich, J. Prolonged hyperglycaemia during infusion of glucose and somatostatin impairs pancreatic A- and B-cell responses to decrements in plasma glucose in normal man: evidence for induction of altered sensitivity to glucose. Diabetologia 28, 63–69 (1985). https://doi.org/10.1007/BF00279917
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00279917