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J Clin Invest. 1993 March; 91(3): 819–828.
PMCID: PMC288033

Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia.

Abstract

We hypothesize that in patients with insulin-dependent diabetes mellitus (IDDM), recent antecedent iatrogenic hypoglycemia is a major cause of hypoglycemia-associated autonomic failure, a disorder distinct from classical diabetic autonomic neuropathy (CDAN), and that hypoglycemia-associated autonomic failure, by reducing both symptoms of and defense against developing hypoglycemia, results in recurrent iatrogenic hypoglycemia, thus creating a vicious cycle. We used the hyperinsulinemic (12.0 pmol.kg-1.min-1) stepped hypoglycemic clamp technique to assess autonomic and symptomatic responses to hypoglycemia and the insulin infusion test (4.0 pmol.kg-1.min-1) to assess defense against hypoglycemia on mornings before and after clamped afternoon hypoglycemia (approximately 2.8 mmol/liter) and hyperglycemia (approximately 11.1 mmol/liter) in patients with IDDM. Compared with nondiabetic subjects, IDDM with or without CDAN exhibited reduced epinephrine (P = 0.0222 and 0.0040) and pancreatic polypeptide (P = 0.0083 and 0.0056) responses to hypoglycemia. After afternoon hypoglycemia, lower plasma glucose concentrations were required to elicit autonomic and symptomatic responses during morning hypoglycemic clamps in patients without CDAN. At the 2.8 mmol/liter step, mean (+/- SE) epinephrine levels were 1,160 +/- 270 and 2,040 +/- 270 pmol/liter (P = 0.0060), pancreatic and total symptom scores were 22 +/- 3 and 41 +/- 7 (P = 0.0475) after afternoon hypoglycemia and hyperglycemia, respectively. During morning insulin infusion tests after afternoon hypoglycemia, nadir plasma glucose concentrations were 2.6 +/- 0.2 mmol/liter compared with 3.3 +/- 0.3 mmol/liter (P < 0.001) at the corresponding time points after afternoon hyperglycemia. Thus, we conclude: (a) elevated glycemic thresholds for autonomic responses to hypoglycemia are a feature of IDDM per se, not classical diabetic autonomic neuropathy; and (b) a single episode of afternoon hypoglycemia results in both elevated glycemic thresholds for autonomic and symptomatic responses to hypoglycemia and impaired physiological defense against hypoglycemia the next morning in IDDM.

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Selected References

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  • Pramming S, Thorsteinsson B, Bendtson I, Binder C. Symptomatic hypoglycaemia in 411 type 1 diabetic patients. Diabet Med. 1991 Apr;8(3):217–222. [PubMed]
  • Cryer PE. Decreased sympathochromaffin activity in IDDM. Diabetes. 1989 Apr;38(4):405–409. [PubMed]
  • Cryer PE. Iatrogenic hypoglycemia as a cause of hypoglycemia-associated autonomic failure in IDDM. A vicious cycle. Diabetes. 1992 Mar;41(3):255–260. [PubMed]
  • White NH, Skor DA, Cryer PE, Levandoski LA, Bier DM, Santiago JV. Identification of type I diabetic patients at increased risk for hypoglycemia during intensive therapy. N Engl J Med. 1983 Mar 3;308(9):485–491. [PubMed]
  • Bolli GB, De Feo P, De Cosmo S, Perriello G, Ventura MM, Benedetti MM, Santeusanio F, Gerich JE, Brunetti P. A reliable and reproducible test for adequate glucose counterregulation in type I diabetes mellitus. Diabetes. 1984 Aug;33(8):732–737. [PubMed]
  • Sjöbom NC, Adamson U, Lin PE. The prevalence of impaired glucose counter-regulation during an insulin-infusion test in insulin-treated diabetic patients prone to severe hypoglycaemia. Diabetologia. 1989 Nov;32(11):818–825. [PubMed]
  • Heller SR, Macdonald IA, Herbert M, Tattersall RB. Influence of sympathetic nervous system on hypoglycaemic warning symptoms. Lancet. 1987 Aug 15;2(8555):359–363. [PubMed]
  • Hepburn DA, Patrick AW, Eadington DW, Ewing DJ, Frier BM. Unawareness of hypoglycaemia in insulin-treated diabetic patients: prevalence and relationship to autonomic neuropathy. Diabet Med. 1990 Sep-Oct;7(8):711–717. [PubMed]
  • Ryder RE, Owens DR, Hayes TM, Ghatei MA, Bloom SR. Unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation: no causal relation with diabetic autonomic neuropathy. BMJ. 1990 Oct 6;301(6755):783–787. [PMC free article] [PubMed]
  • Grimaldi A, Bosquet F, Davidoff P, Digy JP, Sachon C, Landault C, Thervet F, Zoghbi F, Legrand JC. Unawareness of hypoglycemia by insulin-dependent diabetics. Horm Metab Res. 1990 Feb;22(2):90–95. [PubMed]
  • Clarke WL, Gonder-Frederick LA, Richards FE, Cryer PE. Multifactorial origin of hypoglycemic symptom unawareness in IDDM. Association with defective glucose counterregulation and better glycemic control. Diabetes. 1991 Jun;40(6):680–685. [PubMed]
  • Hepburn DA, Patrick AW, Brash HM, Thomson I, Frier BM. Hypoglycaemia unawareness in type 1 diabetes: a lower plasma glucose is required to stimulate sympatho-adrenal activation. Diabet Med. 1991 Dec;8(10):934–945. [PubMed]
  • Amiel SA, Tamborlane WV, Simonson DC, Sherwin RS. Defective glucose counterregulation after strict glycemic control of insulin-dependent diabetes mellitus. N Engl J Med. 1987 May 28;316(22):1376–1383. [PubMed]
  • Amiel SA, Sherwin RS, Simonson DC, Tamborlane WV. Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release. Diabetes. 1988 Jul;37(7):901–907. [PubMed]
  • Boyle PJ, Schwartz NS, Shah SD, Clutter WE, Cryer PE. Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics. N Engl J Med. 1988 Jun 9;318(23):1487–1492. [PubMed]
  • Hirsch IB, Boyle PJ, Craft S, Cryer PE. Higher glycemic thresholds for symptoms during beta-adrenergic blockade in IDDM. Diabetes. 1991 Sep;40(9):1177–1186. [PubMed]
  • Heller SR, Cryer PE. Hypoinsulinemia is not critical to glucose recovery from hypoglycemia in humans. Am J Physiol. 1991 Jul;261(1 Pt 1):E41–E48. [PubMed]
  • Gerich JE, Langlois M, Noacco C, Karam JH, Forsham PH. Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect. Science. 1973 Oct 12;182(4108):171–173. [PubMed]
  • Bolli G, de Feo P, Compagnucci P, Cartechini MG, Angeletti G, Santeusanio F, Brunetti P, Gerich JE. Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes. 1983 Feb;32(2):134–141. [PubMed]
  • Fukuda M, Tanaka A, Tahara Y, Ikegami H, Yamamoto Y, Kumahara Y, Shima K. Correlation between minimal secretory capacity of pancreatic beta-cells and stability of diabetic control. Diabetes. 1988 Jan;37(1):81–88. [PubMed]
  • Popp DA, Shah SD, Cryer PE. Role of epinephrine-mediated beta-adrenergic mechanisms in hypoglycemic glucose counterregulation and posthypoglycemic hyperglycemia in insulin-dependent diabetes mellitus. J Clin Invest. 1982 Feb;69(2):315–326. [PMC free article] [PubMed]
  • Hirsch BR, Shamoon H. Defective epinephrine and growth hormone responses in type I diabetes are stimulus specific. Diabetes. 1987 Jan;36(1):20–26. [PubMed]
  • Heller SR, Cryer PE. Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans. Diabetes. 1991 Feb;40(2):223–226. [PubMed]
  • Davis MR, Shamoon H. Counterregulatory adaptation to recurrent hypoglycemia in normal humans. J Clin Endocrinol Metab. 1991 Nov;73(5):995–1001. [PubMed]
  • Widom B, Simonson DC. Intermittent hypoglycemia impairs glucose counterregulation. Diabetes. 1992 Dec;41(12):1597–1602. [PubMed]
  • Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest. 1987 Mar;79(3):777–781. [PMC free article] [PubMed]
  • Genovely H, Pfeifer MA. RR-variation: the autonomic test of choice in diabetes. Diabetes Metab Rev. 1988 May;4(3):255–271. [PubMed]
  • Kuzuya H, Blix PM, Horwitz DL, Steiner DF, Rubenstein AH. Determination of free and total insulin and C-peptide in insulin-treated diabetics. Diabetes. 1977 Jan;26(1):22–29. [PubMed]
  • SCHALCH DS, PARKER ML. A SENSITIVE DOUBLE ANTIBODY IMMUNOASSAY FOR HUMAN GROWTH HORMONE IN PLASMA. Nature. 1964 Sep 12;203:1141–1142. [PubMed]
  • Farmer RW, Pierce CE. Plasma cortisol determination: radioimmunoassay and competitive protein binding compared. Clin Chem. 1974 Apr;20(4):411–414. [PubMed]
  • Gingerich RL, Lacy PE, Chance RE, Johnson MG. Regional pancreatic concentration and in-vitro secretion of canine pancreatic polypeptide, insulin, and glucagon. Diabetes. 1978 Feb;27(2):96–101. [PubMed]
  • Shah SD, Clutter WE, Cryer PE. External and internal standards in the single-isotope derivative (radioenzymatic) measurement of plasma norepinephrine and epinephrine. J Lab Clin Med. 1985 Dec;106(6):624–629. [PubMed]
  • Hosaka K, Kikuchi T, Mitsuhida N, Kawaguchi A. A new colorimetric method for the determination of free fatty acids with acyl-CoA synthetase and acyl-CoA oxidase. J Biochem. 1981 Jun;89(6):1799–1803. [PubMed]
  • Pinter JK, Hayashi JA, Watson JA. Enzymic assay of glycerol, dihydroxyacetone, and glyceraldehyde. Arch Biochem Biophys. 1967 Aug;121(2):404–414. [PubMed]
  • LOWRY OH, PASSONNEAU JV, HASSELBERGER FX, SCHULZ DW. EFFECT OF ISCHEMIA ON KNOWN SUBSTRATES AND COFACTORS OF THE GLYCOLYTIC PATHWAY IN BRAIN. J Biol Chem. 1964 Jan;239:18–30. [PubMed]
  • Cahill GF, Jr, Herrera MG, Morgan AP, Soeldner JS, Steinke J, Levy PL, Reichard GA, Jr, Kipnis DM. Hormone-fuel interrelationships during fasting. J Clin Invest. 1966 Nov;45(11):1751–1769. [PMC free article] [PubMed]
  • Shah SD, Tse TF, Clutter WE, Cryer PE. The human sympathochromaffin system. Am J Physiol. 1984 Sep;247(3 Pt 1):E380–E384. [PubMed]
  • Davis MR, Mellman M, Shamoon H. Further defects in counterregulatory responses induced by recurrent hypoglycemia in IDDM. Diabetes. 1992 Oct;41(10):1335–1340. [PubMed]
  • Leveston SA, Shah SD, Cryer PE. Cholinergic stimulation of norepinephrine release in man. Evidence of a sympathetic postganglionic axonal lesion in diabetic adrenergic neuropathy. J Clin Invest. 1979 Aug;64(2):374–380. [PMC free article] [PubMed]
  • Matthews DM, Martyn CN, Riemersma RA, Clarke BF, Ewing DJ. Noradrenaline response to edrophonium (Tensilon) and its relation to other autonomic tests in diabetic subjects. Diabetes Res. 1987 Dec;6(4):175–180. [PubMed]
  • Hilsted J, Madsbad S, Krarup T, Sestoft L, Christensen NJ, Tronier B, Galbo H. Hormonal, metabolic, and cardiovascular responses to hypoglycemia in diabetic autonomic neuropathy. Diabetes. 1981 Aug;30(8):626–633. [PubMed]
  • Mitrakou A, Ryan C, Veneman T, Mokan M, Jenssen T, Kiss I, Durrant J, Cryer P, Gerich J. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol. 1991 Jan;260(1 Pt 1):E67–E74. [PubMed]
  • McCall AL, Fixman LB, Fleming N, Tornheim K, Chick W, Ruderman NB. Chronic hypoglycemia increases brain glucose transport. Am J Physiol. 1986 Oct;251(4 Pt 1):E442–E447. [PubMed]
  • Pelligrino DA, Segil LJ, Albrecht RF. Brain glucose utilization and transport and cortical function in chronic vs. acute hypoglycemia. Am J Physiol. 1990 Nov;259(5 Pt 1):E729–E735. [PubMed]
  • Cryer PE. Does central nervous system adaptation to antecedent glycemia occur in patients with insulin-dependent diabetes mellitus? Ann Intern Med. 1985 Aug;103(2):284–286. [PubMed]
  • Amiel SA, Pottinger RC, Archibald HR, Chusney G, Cunnah DT, Prior PF, Gale EA. Effect of antecedent glucose control on cerebral function during hypoglycemia. Diabetes Care. 1991 Feb;14(2):109–118. [PubMed]
  • Widom B, Simonson DC. Glycemic control and neuropsychologic function during hypoglycemia in patients with insulin-dependent diabetes mellitus. Ann Intern Med. 1990 Jun 15;112(12):904–912. [PubMed]
  • Gulan M, Perlman K, Sole M, Albisser AM, Zinman B. Counterregulatory hormone responses preserved after long-term intravenous insulin infusion compared to continuous subcutaneous insulin infusion. Diabetes. 1988 May;37(5):526–531. [PubMed]

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