Summary
In order to assess whether the metabolic clearance of insulin changes overnight, 11 patients with Type 1 (insulin-dependent) diabetes and low insulin antibody titre, and 6 nondiabetic subjects were studied. In these studies insulin was always infused by a Harvard pump. Initially, the nocturnal insulin requirements were assessed in the diabetic patients by an overnight feedback insulin infusion to maintain euglycaemia. The insulin requirements decreased continuously after midnight to a nadir of 0.115 ± 0.014 mU · kg−1 · min−1 at 04.30 hours, but after 05.00 hours the insulin requirements increased nearly 40 percent to a maximum of 0.16 ±0.012 mU · kg−1 · min−1 at 07.00 hours. To assess whether plasma insulin clearance changes overnight, the diabetic patients were studied on two different occasions, from 22.00–02.30 hours and from 04.00–08.30 hours. During each of these two studies insulin was infused in sequential steps of 90 min each at the rate of 0.13, 0.40 and 0.20 mU · kg−1 · min−1. Despite changes in plasma free insulin concentration, the metabolic clearance of insulin in the interval 22.00–02.30 hours (12.6±0.17 ml · kg−1 · min−1) was no different from that of the interval 04.00–08.30 hours (12.5 ± 0.19 ml · kg−1 · min−1). The nondiabetic subjects were studied on two different occasions to assess whether the metabolic clearance of insulin changes overnight. Somatostatin (0.25 mg/h) and insulin (0.3 mU kg−1 · min−1) were infused from 22.00–02.30 hours on one occasion, and from 04.00–08.30 hours on the other. The metabolic clearance of plasma free insulin in the interval 22.00–02.30 hours was no different from that of the interval 04.00–08.30 hours (12.6 ± 0.20 vs 12.9 ± 0.25 ml · kg−1 · min−1 nor was it different from that of the diabetic patients.
It is concluded that, first, the metabolic clearance rate of insulin does not change overnight either in diabetic or in nondiabetic subjects; second, that it is independent of plasma insulin concentration; and third, that its value is comparable in nondiabetic subjects and in diabetic patients with a low titre of insulin antibodies. Thus, changes in insulin sensitivity rather than changes in insulin clearance are implicated in the pathogenesis of the dawn phenomenon.
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Clarke WL, Haymond MW, Santiago JV (1980) Overnight basal insulin requirements in fasting insulin-dependent diabetics. Diabetes 29: 78–80
Bright GM, Melton TW, Rogal AD, Clarke WL (1980) Failure of cortisol blockade to inhibit early morning increases in basal insulin requirements in fasting insulin-dependent diabetics. Diabetes 29:662–664
Skor DA, White HN, Thomas L, Shah SD, Cryer PE, Santiago JV (1983) Examination of the role of the pituitary-adrenocortical axis, counterregulatory hormones and insulin clearance in variable nocturnal insulin requirements in insulin-dependent diabetics. Diabetes 32: 403–407
Kerner W, Navascués I, Torres AA, Pfeifer EF (1984) Studies on the pathogenesis of the dawn phenomenon in insulin-dependent diabetic patients. Metabolism 33: 458–464
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
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
Bolli GB, De Feo P, De Cosmo S, Perriello G, Ventura MM, Calcinaro F, Lolli C, Campbell P, Brunetti P, Gerich JE (1984) Demonstration of a dawn phenomenon in normal human volunteers. Diabetes 33: 1150–1153
Schmidt MI, Lin QX, Gwynne JT, Jacobs S (1984) Fasting early morning rise in peripheral insulin: evidence of the dawn phenomenon in nondiabetes. Diabetes Care 7: 32–35
Campbell PJ, Bolli GB, Cryer PE, Gerich JE (1985) Pathogenesis of the dawn phenomenon in patients with insulin-dependent diabetes mellitus. N Engl J Med 312: 1473–1479
Arias P, Kerner W, Pfeiffer EF (1984) Suppression of the dawn phenomenon by somatostatin. Diabetologia 27: 252A
Orskov H, Schmitz O, Christiansen J (1985) More evidence of growth hormone's role in the dawn phenomenon. Diabetes Res Clin Pract (Suppl 1): 426
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
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
Campbell P, Cryer 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
Brennan JR, Gebhart SSP, Blackard WG (1985) Pump-induced insulin aggregation: a problem with the Biostator. Diabetes 34: 353–359
Harris M, Davidson M, Rosenberg C (1986) A simple solution to the problem of Biostator-induced insulin aggregation. Clin Res 34: 59A
Faber OK, Binder C (1977) C-peptide response to glucagon: a test for the residual β-cell function in diabetes mellitus. Diabetes 26: 605–610
Trivelli LA, Ranney HM, Lai HT (1971) Hemoglobin components in patients with diabetes mellitus. N Engl J Med 284: 353–357
Bolli GB, Dimitriadis GD, Pehling GB, Baker BA, Haymond MW, Cryer PE, Gerich JE (1984) Abnormal glucose counterregulation after subcutaneous insulin in insulin-dependent diabetes mellitus. N Engl J Med 310:1706–1711
McGuire E, Helderman J, Tobin J, Andres R, Berman M (1976) Effects of arterial versus venous sampling on analysis of glucose kinetics in man. J Appl Physiol 41: 565–573
Bolli GB, De Feo P, Perriello G, De Cosmo S, Ventura M, Campbell P, Brunetti P, Gerich JE (1985) Role of hepatic autoregulation in defense against hypoglycaemia in humans. J Clin Invest 75: 1623–1631
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
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
Shipley RA, Clark RE (1972) Tracer methods for in vivo kinetics. Theory and applications. Academic, New York
Zar JH (1984) Biostatistical analysis. Prentice-Hall, Englewood Cliffs, New Jersey
Sönksen P, Tompkins C, Srivastava M, Nabarro J (1973) A comparative study on the metabolism of human insulin and porcine proinsulin in man. Clin Sci Mol Med 45: 633–645
Waldhäusl WK, Gasić S, Bratusch-Marrain P, Kom A, Nowotny P (1982) Feedback inhibition by biosynthetic human insulin of insulin release in healthy human subjects. Am J Physiol 243: E476-E482
Sherwin RS, Kramer KJ, Tobin JD, Insel PA, Liljenquist JE, Berman M, Andres R (1974) A model of the kinetics of insulin in man. J Clin Invest 53: 1481–1492
Traneberg KG, Dencker H (1978) Modeling of plasma disappearance of unlabelled insulin in man. Am J Physiol 235: E577-E585
Ferranini E, Wahren J, Faber OK, Felig P, Binder C, De Fronzo RA (1983) Splanchnic and renal metabolism of insulin in human subjects: a does-response study. Am J Physiol 244: E517–527
Polonsky K, Jaspan J, Emmanouel D, Holmes K, Moossa AR (1983) Differences in the hepatic and renal extraction of insulin and glucagon in the dog: evidence for saturability of insulin metabolism. Acta Endocrinol 102: 420–427
Bratusch-Marrain PR, Waldhausl WK, Gasić S, Hofer A (1984) Hepatic disposal of biosynthetic human insulin and porcine C-peptide in humans. Metabolism 33: 151–157
Cobelli C, Mari A, Ferranini E (1986) On the linearity of insulin kinetics. Am J Physiol (Endocrinol Metab) E 247–E 248
Van Haeften TW, Bolli GB, Dimitriadis GD, Gottesman IS, Horwitz DL, Gerich JE (1986) Effect of insulin antibodies and their kinetic characteristics on plasma free insulin dynamics in patients with diabetes mellitus Metabolism 35: 649–656
Waldhausl W, Bratusch-Marrain P, Kruse V, Jensen I, Nowotny P, Vierhapper H (1985) Effect of insulin antibodies on insulin pharmacokinetics and glucose utilization in insulin-dependent diabetic patients. Diabetes 34: 166–173
Wahren J, Felig P (1976) Influence of somatostatin on carbohydrate disposal and absorption in diabetes mellitus. Lancet 2: 1213–1216
Jaspan JB, Polonsky KS, Lewis M, Pensler J, Pugh W, Moossa AR, Rubenstein AH (1981) Hepatic metabolism of glucagon in the dog: contribution of the liver to overall metabolic disposal of glucagon. Am J Physiol 240: E233-E244
Donner CC, Chen Y-DI, Fraze E, Moore J, Reaven GM (1985) Metabolic clearance rate of insulin in patients with noninsulin dependent diabetes mellitus. Clin Res 33: 59A (Abstract)
De Fronzo R, Hendler R, Simonson D (1982) Insulin resistance is a prominent feature of insulin-dependent diabetes. Diabetes 31: 795–801
Kolterman O, Insel J, Saekow M, Olefsky J (1980) Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects. J Clin Invest 65: 1272–1284
Rizza R, Mandarino L, Gerich J (1981) Dose-response characteristics for the effects of insulin on production and utilization of glucose in man. Am J Physiol 240: E630-E639
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De Feo, P., Perriello, G., Ventura, M.M. et al. 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 (1986). https://doi.org/10.1007/BF00453496
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DOI: https://doi.org/10.1007/BF00453496