Summary
The aim of the present studies was to test the hypothesis that the dawn phenomenon in Type 1 (insulin-de-pendent) diabetes mellitus is due to a decrease in insulin sensitivity caused by nocturnal spikes of growth hormone. Twelve subjects with Type 1 diabetes were studied on two different occasions, from 24.00 to 02.00 hours, and from 06.00 to 08.00 hours with the euglycaemic clamp technique at two plasma free insulin levels (≈25 mU/l,n=7; ≈80 mU/l,n=5). To eliminate the confounding factor of insulin waning of previous Biostator studies, prior to clamp experiments the diabetic subjects were infused with i.v. insulin by means of a syringe pump according to their minute-to-minute insulin requirements. Insulin sensitivity decreased at dawn as compared to the early night hours (≈30% increase in the rate of hepatic glucose production, ≈25% decrease in the rate of peripheral glucose utilisation). Plasma insulin clearance did not change overnight. In seven Type 1 diabetic subjects, suppression of nocturnal spikes of growth hormone secretion by somatostatin during basal glucagon and growth hormone replacement resulted in complete abolition of the increased rate of hepatic glucose production at dawn. Replacement of nocturnal spikes of growth hormone faithfully reproduced the increase in hepatic glucose production at dawn of the control study. It is concluded that the dawn phenomenon in Type 1 diabetes mellitus examined during optimal insulin replacement, first, is due solely to a decrease in insulin sensitivity and not to an increase in insulin clearance; second, that the decrease in insulin sensitivity at dawn takes place both in the liver and peripheral tissues; third, that the decrease in hepatic (and most likely extrahepatic) insulin sensitivity at dawn is caused by nocturnal spikes of growth hormone secretion.
Article PDF
Similar content being viewed by others
References
Deckert T, Lørup B (1976) Regulation of brittle diabetics by a pre-planned insulin infusion programme. Diabetologia 12: 573–579
Clarke WL, Haymond MW, Santiago JV (1980) Overnight basal requirements in fasting insulin-dependent diabetics. Diabetes 29: 78–80
De Feo P, Perriello G, Ventura MM, Calcinaro F, Basta G, Lolli C, Cruciani C, Dell'Olio A, Santeusanio F, Brunetti P, Bolli GB (1986) Studies on overnight insulin requirements and metabolic clearance rate of insulin in normal and diabetic man: relevance to the pathogenesis of the dawn phenomenon. Diabetologia 29: 475–480
Bolli GB, Gerich JE (1984) The “Dawn Phenomenon” — a common occurrence in both non-insulin-dependent and insulin-dependent diabetes mellitus. N Engl J Med 310: 746–750
Dimitriadis G, Vlachonikolis IG, Hatziagellaki E, Linos A, Kodonouri O, Alexopoulos E, Raptis S (1988) The dawn phenomenon in patients with type II diabetes mellitus. Diab Nutr Metab 1: 37–41
Schmidt MI, Lin QX, Gwynne JT, Jacob S (1984) Fasting early morning rise in peripheral insulin: evidence of the dawn phenomenon in nondiabetics. Diabetes Care 7: 32–35
Bolli GB, De Feo P, De Cosmo S, Perriello G, Ventura M, Calcinaro F, Lolli C, Campbell P, Brunetti P, Gerich JE (1984) Demonstration of a dawn phenomenon in normal human volunteers. Diabetes 33: 1150–1153
Bolli GB (1988) The dawn phenomenon: its origin and contribution to early morning hyperglycaemia in diabetes mellitus. Diabete & Metabolisme 14: 675–686
Kerner W, Navaascués I, Torres AA, Pfeiffer EF (1984) Studies on the pathogenesis of the dawn phenomenon in insulin-dependent diabetic patients. Metabolism 33: 458–464
Skor DA, White NH, Thomas L, Santiago JV (1984) Relative roles of insulin clearance and insulin sensitivity in the prebreakfast increase in insulin requirements in insulin-dependent diabetic patients. Diabetes 33: 60–63
Campbell PJ, Bolli GB, Cryer PE, Gerich JE (1985) Sequence of events during development of the dawn phenomenon in insulin-dependent diabetes mellitus. Metabolism 34: 1100–1104
Dux S, White NH, Skor DA, Santiago JV (1985) Insulin clearance contributes to the variability of nocturnal insulin requirement in insulin-dependent diabetes mellitus. Diabetes 34: 1260–1265
Campbell P, Gerich JE (1986) Occurrence of the dawn phenomenon without a change in insulin clearance in patients with insulin-dependent diabetes mellitus. Diabetes 35: 749–752
Widmer A, Keller U, Pasquel M, Berger W (1988) Alterations in insulin clearance and hepatic blood flow during the night do not contribute to the “dawn phenomenon” in Type 1 diabetes. Horm Res 29: 197–201
Campbell PJ, Bolli GB, Cryer PE, Gerich JE (1985) Pathogenesis of the dawn phenomenon in patients with insulin-dependent diabetes mellitus: accelerated glucose production and impaired glucose utilization due to nocturnal surges in growth hormone secretion. N Engl J Med 312: 1473–1479
Davidson MB, Harris MD, Ziel FH, Rosenberg CS (1988) Suppression of sleep-induced growth hormone secretion by anticholinergic agents abolishes dawn phenomenon. Diabetes 37: 166–171
Atiea JA, Creagh F, Page M, Owens DR, Scanlon MF, Peters JR (1989) Early morning hyperglycaemia in insulin-dependent diabetes: acute and sustained effects of cholinergic blockade. J Clin Endocrinol Metab 69: 390–395
Mauras N, Rogol AD, Clarke WL (1986) Failure to detect the dawn phenomenon in nondiabetic subjects with markedly different patterns of nocturnal growth hormone secretion. J Clin Endocrinol Metab 62: 975–979
Beaufrère B, Beylot M, Metz C, Ruitton A, François R, Riou JP, Mornex R (1988) Dawn phenomenon in Type 1 (insulin-dependent) diabetic adolescents: influence of the nocturnal growth hormone secretion. Diabetologia 31: 607–611
Skor DA, White NH, Thomas L, Santiago JV (1985) Influence of growth hormone on overnight insulin requirements in insulin-dependent diabetics. Diabetes 34: 135–139
Brennan JR, Gebhart SSP, Blackard WG (1985) Pump-induced insulin aggregation: a problem with the Biostator. Diabetes 34: 353–359
Koivisto VA, Yki-Järvinen H, Helve E, Karonen SL, Pelkonen R (1986) Pathogenesis and prevention of the dawn phenomenon in diabetic patients treated with CSII. Diabetes 35: 78–82
Faber O, Binder C (1977) C-peptide response to glucagon: a test for the residual B-cell function in diabetes mellitus. Diabetes 26: 605–610
Naka K, Yamazaki K, Yamamoto H (1981) Development of glycosylated hemoglobin A1c Auto-analyzer. J Clin Lab Automation 6: 22–24
Bolli GB, Dimitriadis GD, Pehling GB, Baker BA, Haymond NW, Cryer PE, Gerich JE (1984) Abnormal glucose counterregulation after subcutaneous insulin in insulin-dependent diabetes mellitus. N Engl J Med 310: 1706–1711
Francis AJ, Home PD, Hanning I, Alberti KGMM, Turnbridge WMG (1983) Intermediate acting insulin given at bedtime: effect on blood glucose concentrations before and after breakfast. Br Med J 286: 1173–1176
Bending JJ, Pickup JC, Collins ACG, Keen H (1985) Rarity of a marked “dawn phenomenon” in diabetic subjects treated by continuous insulin infusion. Diabetes Care 8: 28–33
De Feo P, Perriello G, Ventura MM, Brunetti P, Santeusanio F, Gerich J, Bolli GB (1987) The pancreatic-adrenocortical-pituitary clamp technique for study of counterregulation in humans. Am J Physiol 252: E565-E570
McGuire E, Helderman J, Tobin R, Andres R, Berman M (1976) Effects of arterial versus venous sampling on analysis of glucose kinetics in man. J Appl Physiol 41: 565–573
Rizza RA, Cryer PE, Gerich JE (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 after insulin-induced hypoglycaemia. J Clin Invest 64: 62–71
Faber O, Binder C, Markussen J, Heding L, Naithand V, Kuzuya H, Blix PM, Horwitz DL, Rubenstein A (1978) Characterization of seven C-peptide antisera. Diabetes 27 [Suppl. 1]: 170–177
Faloona G, Unger RH (1974) Glucagon. In: Jaffè B, Berman H (eds) Methods of hormone radioimmunoassay. Academic Press, New York, pp 317–330
Peake G (1974) Growth hormone. In: Jaffè B and Berman H (eds) Methods of hormone radioimmunoassay. Academic Press, New York, pp 103–121
Kuzuya H, Blix PM, Horwitz DL, Steiner DF, Rubenstein AH (1977) Determination of free and total insulin and C-peptide in insulin-treated diabetics. Diabetes 26: 22–29
Perriello G, Torlone E, Di Santo S, Fanelli C, De Feo P, Santeusanio F, Brunetti P, Bolli GB (1988) Effect of storage temperature of insulin mixtures injected subcutaneously in subjects with Type 1 (insulin-dependent) diabetes mellitus. Diabetologia 31: 811–815
De Bodo R, Steele R, Altzuler N, Dunn A, Bishop J (1963) On the hormonal regulation of carbohydrate metabolism: studies with C 14 glucose. Rec Prog Horm Res 19: 445–448
Miles J, Haymond M, Gerich JE (1982) Effects of free fatty acids, insulin, glucagon, and adrenaline on ketone body production in humans. In: Metabolic acidosis, Ciba Foundation Symposium 87. Pitman Books, London, pp 192–213
Cobelli C, Mari A, Ferrannini E (1987) The non-steady state problem: error analysis of Steele's model and new developments for glucose kinetics. Am J Physiol 252: E679-E689
De Fronzo R, Ferrannini E, Hendler R, Felig P, Wahren J (1983) Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man. Diabetes 32: 32–45
Zar J (1984) Statistical analysis. Prentice Hall, Englewood Cliffs
Anderson BN (1973) The effect of fasting on insulin secretion and the Staub-Traugott phenomenon in pigs. J Endocrinol 58: 613–625
Rizza R, Gerich J, Haymond M, Westland R, Hall L, Clemens A, Service J (1980) Control of blood sugar in insulin-dependent diabetes: comparison of an artificial endocrine pancreas, continuous subcutaneous insulin infusion and intensified conventional insulin therapy. N Engl J Med 303: 1313–1318
Calabrese G, Bueti A, Santeusanio F, Giombolini A, Zega G, Angeletti G, Cartechini MG, Brunetti P (1982) Continuous subcutaneous insulin infusion in insulin-dependent diabetic patients: a comparison with conventional optimized treatment in a long-term study. Diabetes Care 5: 457–465
Perriello G, De Feo P, Torlone E, Calcinaro F, Ventura MM, Basta G, Santeusanio F, Brunetti P, Gerich JE, Bolli GB (1988) Asymptomatic nocturnal hypoglycemia: a cause for deterioration of glycemic control in diabetes mellitus. N Engl J Med 319: 1233–1239
De Fronzo RA (1988) The triumvirate: B-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37: 667–687
McGorman L, Rizza R, Gerich J (1981) Physiological concentrations of growth hormone exert insulin-like and insulin antagonist effects on both hepatic and extra-hepatic tissues in man. J Clin Endocrinol Metab 53: 556–559
Rizza R, Mandarino L, Gerich J (1982) Effects of growth hormone on insulin action in man: mechanisms of insulin resistance, impaired suppression of glucose production and impaired stimulation of glucose utilization. Diabetes 31: 663–669
De Feo P, Perriello G, Torlone E, Ventura MM, Santeusanio F, Brunetti P, Gerich JE, Bolli GB (1989) Demonstration of a role for growth hormone in glucose counterregulation. Am J Physiol 256: E835-E843
Campbell PJ, Bolli GB, Gerich JE (1988) Prevention of the dawn phenomenon (early morning hyperglycaemia) in insulin-dependent diabetes mellitus by bedtime intranasal insulin administration of a long-acting somatostatin analogue. Metabolism 37: 34–37
Boyle PJ, Avogaro A, Smith L, Shah LD, Bier DM, Cryer PE, Santiago JU (1989) Absence of the dawn phenomenon and abnormal lipolysis in GH deficient IDDMs. Diabetes 38 [Suppl 2]: 3 A
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Perriello, G., De Feo, P., Torlone, E. et al. Nocturnal spikes of growth hormone secretion cause the dawn phenomenon in Type 1 (insulin-dependent) diabetes mellitus by decreasing hepatic (and extrahepatic) sensitivity to insulin in the absence of insulin waning. Diabetologia 33, 52–59 (1990). https://doi.org/10.1007/BF00586461
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00586461