Skip to main content
SpringerLink
Log in

Hypoglycemia in Diabetes Mellitus

  • Reference work entry
  • First Online:
Principles of Diabetes Mellitus

  • 3616 Accesses

Abstract

Hypoglycemia is a frequent occurrence for many patients with diabetes treated with insulin or insulin secretagogues. Episodes of hypoglycemia have significant morbidity and mortality and are the main limiting factor for achieving near optimal glycemic control. Risk factors including impaired glucose counterregulation and hypoglycemia unawareness are largely preventable and/or reversible. This chapter summarizes our current knowledge of the epidemiology, pathogenesis, risk factors, and complications of hypoglycemia in patients with diabetes and discusses prevention and treatment strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 699.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 899.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

CKD:

Chronic kidney disease

T1DM:

Type 1 diabetes mellitus

T2DM:

Type 2 diabetes mellitus

References

  1. Owen O, Morgan A, Kemp H, Sullivan J, Herrera M, Cahill G. Brain metabolism during fasting. J Clin Invest. 1967;46:1589–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cryer P. Banting Lecture: hypoglycemia, the limiting factor in the management of IDDM. Diabetes. 1994;43:1378–89.

    Article  CAS  PubMed  Google Scholar 

  3. Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, Heller SR, Rodriguez H, Rosenzweig J, Vigersky R. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36:1384–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gerich J. Hypoglycemia and counterregulation in type 2 diabetes. Lancet. 2000;356(9246):19467.

    Article  Google Scholar 

  5. Mokan M, Mitrakou M, Veneman T, Ryan C, Korytkowski M, Cryer P, Gerich J. Hypoglycemia unawareness in IDDM. Diabetes Care. 1994;17:1397–403.

    Article  CAS  PubMed  Google Scholar 

  6. Guillod L, Comte-Perret S, Monbaron D, Gaillard RC, Ruiz J. Nocturnal hypoglycaemias in type 1 diabetic patients: what can we learn with continuous glucose monitoring? Diabetes Metab. 2007;33:360–5.

    Article  CAS  PubMed  Google Scholar 

  7. Wentholt IM, Maran A, Masurel N, Heine RJ, Hoekstra JB, DeVries JH. Nocturnal hypoglycaemia in type 1 diabetic patients, assessed with continuous glucose monitoring: frequency, duration and associations. Diabet Med. 2007;24:527–32.

    Article  CAS  PubMed  Google Scholar 

  8. Leese GP, Wang J, Broomhall J, Kelly P, Marsden A, Morrison W, Frier BM, Morris AD. Frequency of severe hypoglycemia requiring emergency treatment in type 1 and type 2 diabetes: a population-based study of health service resource use. Diabetes Care. 2003;26:1176–80.

    Article  PubMed  Google Scholar 

  9. Hypoglycemia Study Group UK. Risk of hypoglycemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia. 2007;50:1140–7.

    Article  CAS  Google Scholar 

  10. Akram K, Pedersen-Bjergaael U, Borch-Johnson K, Thorsteinsson B. Frequency and risk factors of severe hypoglycemia in insulin-treated type 2 diabetes: a literature survey. J Diabetes Complications. 2006;20:402–8.

    Article  PubMed  Google Scholar 

  11. Amiel SA, Dixon T, Mann R, Jameson K. Hypoglycemia in type 2 diabetes. Diabet Med. 2008;25:245–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. N Engl J Med. 1993;329:977–86.

    Article  Google Scholar 

  13. van Staa T, Abenhaim L, Monette J. Rates of hypoglycemia in users of sulfonylureas. J Clin Epidemiol. 1997;50:735–41.

    Article  PubMed  Google Scholar 

  14. Gangji AS, Cukierman T, Gerstein HC, Goldsmith CH, Clase CM. A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin. Diabetes Care. 2007;30:389–94.

    Article  PubMed  Google Scholar 

  15. Holman RR, Farmer AJ, Davies MJ, Levy JC, Darbyshire JL, Keenan JF, Paul SK, 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med. 2009;361:1736–47.

    Article  CAS  PubMed  Google Scholar 

  16. Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes. Diabetes Care. 2005;28:2948–61.

    Article  PubMed  Google Scholar 

  17. Cersosimo E, Garlick P, Ferretti J. Renal glucose production during insulin-induced hypoglycemia in humans. Diabetes. 1999;48:261–6.

    Article  CAS  PubMed  Google Scholar 

  18. Meyer C, Dostou J, Gerich J. Role of the human kidney in glucose counterregulation. Diabetes. 1999;48:943–8.

    Article  CAS  PubMed  Google Scholar 

  19. Schwartz N, Clutter W, Shah S, Cryer P. The glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest. 1987;79:777–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Meyer C, Grosmann R, Mitrakou A, Mahler R, Veneman T, Gerich J, Bretzel R. Effects of autonomic neuropathy on counterregulation and awareness of hypoglycemia in type 1 diabetic patients. Diabetes Care. 1998;21:1960–6.

    Article  CAS  PubMed  Google Scholar 

  21. 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;260:E67–74.

    CAS  PubMed  Google Scholar 

  22. Fanelli C, Pampanelli S, Epifano L, Rambotti A, Ciofetta M, Modarelli F, DiVincenzo A, Annibale B, Lepore M, Lalli C, DelSindaco P, Brunetti P, Bolli G. Relative roles of insulin and hypoglycemia on induction of neuroendocrine responses to, symptoms of, and deterioration of cognitive function in hypoglycemia in male and female humans. Diabetologia. 1994;37:797–807.

    Article  CAS  PubMed  Google Scholar 

  23. DeFeo P, Perriello G, Torlone E, Ventura M, Santeusanio F, Brunetti P, Gerich J, Bolli G. Demonstration of a role of growth hormone in glucose counterregulation. Am J Physiol. 1989;256:E835–43.

    CAS  Google Scholar 

  24. DeFeo P, Perriello G, Torlone E, Ventura M, Fanelli C, Santeusanio F, Brunetti P, Gerich J, Bolli G. Contribution of cortisol to glucose counterregulation in humans. Am J Physiol. 1989;257:E35–42.

    CAS  Google Scholar 

  25. Hepburn D, Deary I, Frier B, Patrick A, Quinn J, Fisher B. Symptoms of acute insulin-induced hypoglycemia in humans with and without IDDM. Factor-analysis approach. Diabetes Care. 1991;14:949–57.

    Article  CAS  PubMed  Google Scholar 

  26. Towler D, Havlin C, Craft S, Cryer P. Mechanism of awareness of hypoglycemia: perception of neurogenic (predominantly cholinergic) rather than neuroglycopenic symptoms. Diabetes. 1993;42:1791–8.

    Article  CAS  PubMed  Google Scholar 

  27. Cox D, Gonder-Frederick L, Antoun B, Cryer P, Clarke W. Perceived symptoms in the recognition of hypoglycemia. Diabetes Care. 1993;16:519–27.

    Article  CAS  PubMed  Google Scholar 

  28. Bolli G, DeFeo P, Perriello G, DeCosmo S, Ventura M, Campbell P, Brunetti P, Gerich J. Role of hepatic autoregulation in defense against hypoglycemia in humans. J Clin Invest. 1985;75:1623–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mitrakou A, Fanelli C, Veneman T, Perriello G, Calderone S, Plantanisiotis D, Rambotti A, Raptis S, Brunetti P, Cryer P, Gerich J, Bolli G. Reversibility of unawareness of hypoglycemia in patients with insulinomas. N Engl J Med. 1993;329:834–9.

    Article  CAS  PubMed  Google Scholar 

  30. Bolli G, DeFeo P, Compagnucci P, Cartechini M, Angeletti G, Santeusanio F, Brunetti P, Gerich J. Abnormal glucose counterregulation in insulin-dependent diabetes mellitus: interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes. 1983;32:134–41.

    Article  CAS  PubMed  Google Scholar 

  31. Gerich J, Langlois M, Noacco C, Karam J, Forsham P. Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha-cell defect. Science. 1973;182:171–3.

    Article  CAS  PubMed  Google Scholar 

  32. Fukuda M, Tanaka A, Tahara Y, Ikegami H, Yamamoto Y, Kumahara Y, Shima K. Correlation between minimal secretory capacity of pancreatic ß-cells and stability of diabetic control. Diabetes. 1988;37:81–8.

    Article  CAS  PubMed  Google Scholar 

  33. Rizza R, Cryer P, Gerich J. Role of glucagon, epinephrine and growth hormone in glucose counterregulation. J Clin Invest. 1979;64:62–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hirsch B, Shamoon H. Defective epinephrine and growth hormone responses in type I diabetes are stimulus specific. Diabetes. 1987;36:20–6.

    Article  CAS  PubMed  Google Scholar 

  35. Dagogo-Jack S, Craft S, Cryer P. Hypoglycemia-associated autonomic failure in insulin dependent diabetes mellitus. J Clin Invest. 1993;91:819–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. White N, Skor D, Cryer P, Bier D, Levandoski L, Santiago J. Identification of type I diabetic patients at increased risk for hypoglycemia during intensive therapy. N Engl J Med. 1983;308:485–91.

    Article  CAS  PubMed  Google Scholar 

  37. Bolli G, DeFeo P, DeCosmo S, Perriello G, Ventura M, Benedetti M, Santeusanio F, Gerich J, Brunetti P. A reliable and reproducible test for adequate glucose counterregulation in type I diabetes mellitus. Diabetes. 1984;33:732–7.

    Article  CAS  PubMed  Google Scholar 

  38. Cersosimo E, Ferretti J, Sasvary D, Garlick P. Adrenergic stimulation of renal glucose release is impaired in type 1 diabetes. Diabetes. 2001;50 Suppl 2:A54.

    Google Scholar 

  39. Amiel S. R.D. Lawrence Lecture 1994. Limits of normality: the mechanisms of hypoglycemia unawareness. Diabet Med. 1994;11:918–24.

    Article  CAS  PubMed  Google Scholar 

  40. Gold A, MacLeod K, Frier B. Frequency of severe hypoglycemia in patients with type 1 diabetes with impaired awareness of hypoglycemia. Diabetes Care. 1994;17:697–703.

    Article  CAS  PubMed  Google Scholar 

  41. Pramming S, Thorsteinsson B, Bendtson I, Binder C. Symptomatic hypoglycemia in 411 type I diabetic patients. Diabet Med. 1991;8:217–22.

    Article  CAS  PubMed  Google Scholar 

  42. Hepburn D, Patrick A, Eadington D, Ewing D, Frier B. Unawareness of hypoglycemia in insulin-treated diabetic patients: prevalence and relationship to autonomic neuropathy. Diabet Med. 1990;7:711–7.

    Article  CAS  PubMed  Google Scholar 

  43. Macdonald PE, Marinis YZ, Ramracheya R, et al. A KATP channel-dependent pathway within alpha cells regulates glucagon release from both rodent and human islets of Langerhans. PLoS Biol. 2007;5, e143.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Munoz A, Hu M, Hussain K, Bryan J, Aguilar-Bryan L, Rajan AS. Regulation of glucagon secretion at low glucose concentrations: evidence for adenosine triphosphate-sensitive potassium channel involvement. Endocrinology. 2005;146:5514–21.

    Article  CAS  PubMed  Google Scholar 

  45. Rorsman P, Ramracheya R, Rorsman NJ, Zhang Q. ATP-regulated potassium channels and voltage-gated calcium channels in pancreatic alpha and beta cells: similar functions but reciprocal effects on secretion. Diabetologia. 2014;57(9):1749–61.

    Article  CAS  PubMed  Google Scholar 

  46. Reno CM, Litvin M, Clark AL, Fisher SJ. Defective counterregulation and hypoglycemia unawareness in diabetes: mechanisms and emerging treatments. Endocrinol Metab Clin North Am. 2013;42(1):15–38.

    Article  PubMed  Google Scholar 

  47. Korytkowski MT, Mokan M, Veneman TF, Mitrakou A, Cryer P, Gerich JE. Reduced beta-adrenergic sensitivity in patients with type 1 diabetes and hypoglycemia unawareness. Diabetes Care. 1998;21(11):1939–43.

    Article  CAS  PubMed  Google Scholar 

  48. Fritsche A, Stumvoll M, Grüb M, Sieslack S, Renn W, Schmülling RM, Häring HU, Gerich JE. Effect of hypoglycemia on beta-adrenergic sensitivity in normal and type 1 diabetic subjects. Diabetes Care. 1998;21(9):1505–10.

    Article  CAS  PubMed  Google Scholar 

  49. Trovik TS, Jaeger R, Jorde R, Sager G. Reduced beta-adrenergic sensitivity in healthy volunteers induced by hypoglycemia. Fundam Clin Pharmacol. 1995;9(2):181–6.

    Article  CAS  PubMed  Google Scholar 

  50. Heller S, MacDonald I, Tattersall R. Counterregulation in type 2 (noninsulin-dependent) diabetes mellitus: normal endocrine and glycemic responses, up to 10 years after diagnosis. Diabetologia. 1987;30:924–9.

    Article  CAS  PubMed  Google Scholar 

  51. Levy C, Kinsley B, Bajaj M, Simonson D. Effect of glycemic control on glucose counterregulation during hypoglycemia in NIDDM. Diabetes Care. 1998;21:1330–8.

    Article  CAS  PubMed  Google Scholar 

  52. Shamoon H, Friedman S, Canton C, Zacharowicz L, Hu M, Rossetti L. Increased epinephrine and skeletal muscle responses to hypoglycemia in non-insulin-dependent diabetes mellitus. J Clin Invest. 1994;93:2562–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Segel S, Paramore D, Cryer P. Hypoglycemia-associated autonomic failure in advanced type 2 diabetes. Diabetes. 2002;51:724–33.

    Article  CAS  PubMed  Google Scholar 

  54. Bolli G, Tsalikian E, Haymond M, Cryer P, Gerich J. Defective glucose counterregulation after subcutaneous insulin in noninsulin-dependent diabetes mellitus. J Clin Invest. 1984;73:1532–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Alsahli M, Gerich JE. Hypoglycemia in patients with renal disease. J Clin Med. 2015;4(5):948–64.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Alsahli M, Gerich JE. Hypoglycemia. Endocrinol Metab Clin North Am. 2013;42(4):657–76.

    Article  PubMed  Google Scholar 

  57. Murad MH, Coto-Yglesias F, Wang AT, Sheidaee N, Mullan RJ, Elamin MB, Erwin PJ, Montori VM. Drug-induced hypoglycmia: a systemic review. J Clin Endocrinol Metab. 2009;94:741–5.

    Article  CAS  PubMed  Google Scholar 

  58. Miholic J, Orskov C, Holst J, Kotzerke J, Meyer H. Emptying of the gastric substitute, glucagon-like peptide-1 (GLP-1), and reactive hypoglycemia after total gastrectomy. Dig Dis Sci. 1991;36:1361–70.

    Article  CAS  PubMed  Google Scholar 

  59. Wapnick S, Jones JJ. Changes in glucose tolerance and serum insulin following partial gastrectomy and intestinal resection. Gut. 1972;13:871–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Leichter S, Permutt M. Effect of adrenergic agents on postgastrectomy hypoglycemia. Diabetes. 1975;24:1005–10.

    Article  CAS  PubMed  Google Scholar 

  61. Shultz KT, Neelon FA, Nilsen LB, Lebovitz HE. Mechanism of postgastrectomy hypoglycemia. Arch Intern Med. 1971;128:240–6.

    Article  CAS  PubMed  Google Scholar 

  62. Guidone C, Manco M, Valera-Mora E, Iaconelli A, Gniuli D, Mari A, Nanni G, Castagneto M, Calvani M, Mingrone G. Mechanisms of recovery from type 2 diabetes after malabsorptive bariatric surgery. Diabetes. 2006;55:2025–31.

    Article  CAS  PubMed  Google Scholar 

  63. Gumbs AA, Modlin IM, Ballantyne GH. Changes in insulin resistance following bariatric surgery: role of caloric restriction and weight loss. Obes Surg. 2005;15:462–73.

    Article  PubMed  Google Scholar 

  64. Maggard MA, Shugarman LR, Suttorp M, Maglione M, Sugerman HJ, Livingston EH, Nguyen NT, Li Z, Mojica WA, Hilton L, Rhodes S, Morton SC, Shekelle PG. Meta-analysis: surgical treatment of obesity. Ann Intern Med. 2005;142:547–59.

    Article  PubMed  Google Scholar 

  65. Gebhard B, Holst JJ, Biegelmayer C, Miholic J. Postprandial GLP-1, norepinephrine, and reactive hypoglycemia in dumping syndrome. Dig Dis Sci. 2001;46:1915–23.

    Article  CAS  PubMed  Google Scholar 

  66. Lawaetz O, Blackburn AM, Bloom SR, Aritas Y, Ralphs DN. Gut hormone profile and gastric emptying in the dumping syndrome. A hypothesis concerning the pathogenesis. Scand J Gastroenterol. 1983;18:73–80.

    Article  CAS  PubMed  Google Scholar 

  67. Dube PE, Brubaker PL. Nutrient, neural and endocrine control of glucagon-like peptide secretion. Horm Metab Res. 2004;36:755–60.

    Article  CAS  PubMed  Google Scholar 

  68. Kellum JM, Kuemmerle JF, O’Dorisio TM, Rayford P, Martin D, Engle K, Wolf L, Sugerman HJ. Gastrointestinal hormone responses to meals before and after gastric bypass and vertical banded gastroplasty. Ann Surg. 1990;211:763–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med. 2002;346:1623–30.

    Article  PubMed  Google Scholar 

  70. Patti ME, McMahon G, Mun EC, Bitton A, Holst JJ, Goldsmith J, Hanto DW, Callery M, Arky R, Nose V, Bonner-Weir S, Goldfine AB. Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia. Diabetologia. 2005;48:2236–40.

    Article  CAS  PubMed  Google Scholar 

  71. Service GJ, Thompson GB, Service FJ, Andrews JC, Collazo-Clavell ML, Lloyd RV. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med. 2005;353:249–54.

    Article  CAS  PubMed  Google Scholar 

  72. Won JG, Tseng HS, Yang AH, Tang KT, Jap TS, Lee CH, Lin HD, Burcus N, Pittenger G, Vinik A. Clinical features and morphological characterization of 10 patients with noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS). Clin Endocrinol (Oxf). 2006;65:566–78.

    Article  Google Scholar 

  73. Meier JJ, Butler AE, Galasso R, Butler PC. Hyperinsulinemic hypoglycemia after gastric bypass surgery is not accompanied by islet hyperplasia or increased beta-cell turnover. Diabetes Care. 2006;29:1554–9.

    Article  PubMed  Google Scholar 

  74. McLaughlin T, Peck M, Holst J, Deacon C. Reversible hyperinsulinemic hypoglycemia after gastric bypass: a consequence of altered nutrient delivery. J Clin Endocrinol Metab. 2010;95(4):1851–5.

    Article  CAS  PubMed  Google Scholar 

  75. Campos GM, Ziemelis M, Paparodis R, Ahmed M, Davis DB. Laparoscopic reversal of Roux-en-Y gastric bypass: technique and utility for treatment of endocrine complications. Surg Obes Relat Dis. 2014;10(1):36.

    Article  PubMed  Google Scholar 

  76. Lee CJ, Brown T, Magnuson TH, Egan JM, Carlson O, Elahi D. Hormonal response to a mixed-meal challenge after reversal of gastric bypass for hypoglycemia. J Clin Endocrinol Metab. 2013;98(7):E1208–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Salehi M, Gatadelli A, D’Alessio DA. Blockade of glucagon-like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass. Gastroenterology. 2014;146(3):669–80.

    Article  CAS  PubMed  Google Scholar 

  78. Wredling R, Levander S, Adamson U, Lins P. Permanent neuropsychological impairment after recurrent episodes of severe hypoglycaemia in man. Diabetologia. 1990;33:152–7.

    Article  CAS  PubMed  Google Scholar 

  79. Patrick A, Campbell I. Fatal hypoglycaemia in insulin-treated diabetes mellitus: clinical features and neuropathological changes. Diabet Med. 1990;7:349–54.

    Article  CAS  PubMed  Google Scholar 

  80. Perros P, Frier B. The long-term sequelae of severe hypoglycemia on the brain in insulin-dependent diabetes mellitus. Horm Metab Res. 1997;29:197–202.

    Article  CAS  PubMed  Google Scholar 

  81. Deary I, Crawford J, Hepburn D, Langan S, Blackmore L, Frier B. Severe hypoglycemia and intelligence in adult patients with insulin-treated diabetes. Diabetes. 1993;42:341–4.

    Article  CAS  PubMed  Google Scholar 

  82. Reno CM, Daphna-Iken D, Chen YS, VanderWeele J, Jethi K, Fisher SJ. Severe hypoglycemia–induced lethal cardiac arrhythmias are mediated by sympathoadrenal activation. Diabetes. 2013;62(10):3570–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Frier BM. Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications. Nat Rev Endocrinol. 2014;10:711–22.

    Article  CAS  PubMed  Google Scholar 

  84. Fisher B, Quin J, Rumley A, Lennie S, Small M, MacCuish A, Lowe G. Effects of acute insulin-induced hypoglycaemia on haemostasis, fibrinolysis and haemorheology in insulin-dependent diabetic patients and control subjects. Clin Sci. 1991;80:525–31.

    Article  CAS  PubMed  Google Scholar 

  85. Joy NG, Tate DB, Younk LM, Davis SN. Effects of acute and antecedent hypoglycemia on endothelial function and markers of atherothrombotic balance in healthy humans. Diabetes. 2015;64:2571–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Duh E, Feinglos M. Hypoglycemia-induced angina pectoris in a patient with diabetes mellitus. Ann Intern Med. 1994;121:945–6.

    Article  CAS  PubMed  Google Scholar 

  87. Cryer PE. Hypoglycemia-Associated Autonomic Failure in diabetes: maladaptive, adaptive, or both? Diabetes. 2015;64(7):2322–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. VanderWeele JJ, Daphna-Iken D, Chen YS, Hoffman RS, Clark AL, Fisher SJ. Antecedent recurrent hypoglycemia reduces lethal cardiac arrhythmias induced by severe hypoglycemia in diabetic rats. Diabetes. 2014;53 Suppl 1:A39.

    Google Scholar 

  89. Gerstein HC, Miller ME, Byington RP, Goff Jr DC, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm Jr RH, Probstfield JL, Simons-Morton DG, Friedewald WT, Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.

    Article  CAS  PubMed  Google Scholar 

  90. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F, ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560–72.

    Article  CAS  PubMed  Google Scholar 

  91. Kohner E, McLeod D, Marshall J. Complications of diabetes. London: Edward Arnold; 1982.

    Google Scholar 

  92. Rhoads GG, Orsini LS, Crown W, Wang S, Getahun D, Zhang Q. Contribution of hypoglycemia to medical care expenditures and short-term disability in employees with diabetes. J Occup Environ Med. 2005;47:447–52.

    Article  PubMed  Google Scholar 

  93. Curkendall SM, Natoli JL, Alexander CM, Nathanson BH, Haidar T, Dubois RW. Economic and clinical impact of inpatient diabetic hypoglycemia. Endocr Pract. 2009;15:302–12.

    Article  PubMed  Google Scholar 

  94. Paz-Guevara A, Hsu T-H, White P. Juvenile diabetes mellitus after forty years. Diabetes. 1975;24:559–65.

    Article  CAS  PubMed  Google Scholar 

  95. Nabarro J, Mustaffa B, Morris D, Walport M, Kurtz A. Insulin deficient diabetes. Contrasts with other endocrine deficiencies. Diabetologia. 1979;16:5–12.

    Article  CAS  PubMed  Google Scholar 

  96. Seltzer H. Severe drug-induced hypoglycemia: a review. Compr Ther. 1979;5:21–9.

    CAS  PubMed  Google Scholar 

  97. Berger W, Caduff F, Pasquel M, Rump A. Die relative haufigkeit der schweren Sulfonylharnstoff- hypoglykamie in den letzten 25 Jahren in der Schweiz. Schwerz Med Wschr. 1986;116:145–51.

    CAS  Google Scholar 

  98. Gaston S. Outcomes of hypoglycemia treated by standardized protocol in a community hospital. Diabetes Educ. 1992;18:491–4.

    Article  CAS  PubMed  Google Scholar 

  99. Slama G, Traynard P, Desplanque N, Pudar H, Dhunputh I, Letanoux M, Bornet F, Tchobroutsky G. The search for an optimized treatment of hypoglycemia. Carbohydrates in tablets, solution, or gel for the correction of insulin reactions. Arch Intern Med. 1990;150:589–93.

    Article  CAS  PubMed  Google Scholar 

  100. Palatnick W, Meatherall R, Tenenbein M. Clinical spectrum of sulfonylurea overdose and experience with diazoxide therapy. Arch Intern Med. 1991;151:1859–62.

    Article  CAS  PubMed  Google Scholar 

  101. Cryer P, Gerich J. Glucose counterregulation, hypoglycemia, and intensive insulin therapy in diabetes mellitus. N Engl J Med. 1985;313:232–41.

    Article  CAS  PubMed  Google Scholar 

  102. Bolli G. How to ameliorate the problem of hypoglycemia in intensive as well as nonintensive treatment of type 1 diabetes. Diabetes Care. 1999;22 Suppl 2:B43–52.

    PubMed  Google Scholar 

  103. American Diabetes Association. Standards of medical care in diabetes 2015. Diabetes Care. 2015;38 Suppl 1:S58–66.

    Article  Google Scholar 

  104. Cox D, Ritterband L, Magee J, Clarke W, Gonder-Frederick L. Blood glucose awareness training delivered over the internet. Diabetes Care. 2008;31(8):1527–8.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Samann A, Muhlhauser I, Bender R, Kloos C, Muller UA. Glycaemic control and severe hypoglycaemia following training in flexible, intensive insulin therapy to enable dietary freedom in people with type 1 diabetes: a prospective implementation study. Diabetologia. 2005;48:1965–70.

    Article  CAS  PubMed  Google Scholar 

  106. The DAFNE Study Group. Training in flexible intensive insulin management to enable dietary freedom in people with type 1 diabetes: dose adjustment for normal eating (DAFNE) randomized controlled trial. BMJ. 2002;325:746–52.

    Article  Google Scholar 

  107. Brunelle R, Llewelyn J, Anderson J, Gale E, Koivisto V. Meta-analysis of the effect of insulin lispro on severe hypoglycemia in patients with type 1 diabetes. Diabetes Care. 1998;21:1726–31.

    Article  CAS  PubMed  Google Scholar 

  108. Home P, Bartley P, Russell-Jones D, Hanaire-Broutin H, Heeg JE, Abrams P, Landin-Olsson M, Hylleberg B, Lang H, Draeger E. Insulin detemir offers improved glycemic control compared with NPH insulin in people with type 1 diabetes: a randomized clinical trial. Diabetes Care. 2004;27:1081–7.

    Article  CAS  PubMed  Google Scholar 

  109. Rosenstock J, Dailey G, Massi-Benedetti M, Fritsche A, Lin Z, Salzman A. Reduced hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes. Diabetes Care. 2005;28:950–5.

    Article  CAS  PubMed  Google Scholar 

  110. Hermansen K, Davies M, Derezinski T, Martinez RG, Clauson P, Home P. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care. 2006;29:1269–74.

    Article  CAS  PubMed  Google Scholar 

  111. Boland E, Grey M, Oesterle A, Fredrickson L, Tamborlane W. Continuous subcutaneous insulin infusion. A new way to lower risk of severe hypoglycemia, improve metabolic control, and enhance coping in adolescents with type 1 diabetes. Diabetes Care. 1999;22:1779–84.

    Article  CAS  PubMed  Google Scholar 

  112. Pickup JC, Sutton AJ. Severe hypoglycaemia and glycaemic control in type 1 diabetes: meta-analysis of multiple daily insulin injections compared with continuous subcutaneous insulin infusion. Diabet Med. 2008;25:765–74.

    Article  CAS  PubMed  Google Scholar 

  113. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Effectiveness of continuous glucose monitoring in a clinical care environment: evidence from the Juvenile Diabetes Research Foundation Continuous Glucose Monitoring (JDRF-CGM) trial. N Engl J Med. 2010;363:311–20.

    Article  Google Scholar 

  114. Bergenstal RM, Tamborlane WV, Ahmann A, Buse JB, Dailey G, Davis SN, Joyce C, Peoples T, Perkins BA, Welsh JB, Willi SM, Wood MA, STAR 3 Study Group. Effectiveness of sensor augmented insulin-pump therapy in type 1 diabetes. N Engl J Med. 2010;363:311–20.

    Article  CAS  PubMed  Google Scholar 

  115. Battelino T, Phillip M, Bratina N, Nimri R, Oskarsson P, Bolinder J. Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes. Diabetes Care. 2011;34(4):795–800.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Dagogo-Jack S, Rattarason C, Cryer P. Reversal of hypoglycemia unawareness, but not defective glucose counterregulation in IDDM. Diabetes. 1994;43:1426–34.

    Article  CAS  PubMed  Google Scholar 

  117. Fritsche A, Stumvoll M, Haring H, Gerich J. Reversal of hypoglycemia unawareness in a long-term type 1 diabetic patient by improvement of beta-adrenergic sensitivity after prevention of hypoglycemia. J Clin Endocrinol Metab. 2000;85:523–5.

    CAS  PubMed  Google Scholar 

  118. Fanelli C, Epifano L, Rambotti A, Pampanelli S, Di Vincenzo A, Modarelli F, Lepore M, Annibale B, Ciofetta M, Bottini P, Porcellati F, Scionti L, Santeusanio F, Brunetti P, Bolli G. Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most of neuroendocrine responses to, symptoms of, and cognitive function during hypoglycemia in intensively treated patients with short-term IDDM. Diabetes. 1993;42:1683–9.

    Article  CAS  PubMed  Google Scholar 

  119. Fanelli C, Pampanelli S, Epifano L, Rambotti A, Vincenzo A, Modarelli F, Ciofetta M, Lepore M, Annibale B, Torlone E, Perriello G, DeFeo P, Santeusano F, Brunetti P, Bolli G. Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycemia, following institution of rational, intensive insulin therapy in IDDM. Diabetologia. 1994;37:1265–76.

    Article  CAS  PubMed  Google Scholar 

  120. Cranston I, Lomas J, Maran A, MacDonald I, Amiel S. Restoration of hypoglycemia unawareness in patients with long- duration insulin-dependent diabetes. Lancet. 1994;344:283–7.

    Article  CAS  PubMed  Google Scholar 

  121. Davis M, Mellman M, Friedman S, Chang C, Shamoon H. Recovery of epinephrire response but not hypoglycemic symptom threshold after intensive therapy in type 1 diabetes. Am J Med. 1994;97:535–42.

    Article  CAS  PubMed  Google Scholar 

  122. Kendall D, Teuscher A, Robertson R. Defective glucagon secretion during sustained hypoglycemia following successful islet allo- and autotransplantation in humans. Diabetes. 1997;46:23–7.

    Article  CAS  PubMed  Google Scholar 

  123. Meyer C, Hering B, Grosmann R, Brandhorst H, Brandhorst D, Gerich J, Federlin K, Bretzel R. Improved glucose counterregulation and autonomic symptoms after intraportal islet transplants alone in patients with long-standing type I diabetes mellitus. Transplantation. 1998;66:233–40.

    Article  CAS  PubMed  Google Scholar 

  124. Federlin K, Pozza G. Indications for clinical islet transplantation today and in the foreseeable future-the diabetologist's point of view. J Mol Med. 1999;77:148–52.

    Article  CAS  PubMed  Google Scholar 

  125. Choudhary RMR, Vantyghem M, Maffi P, Kay TW, Keymeulen B, Inagaki N, Saudek F, Lehmann R, Hering BJ. Evidence-informed clinical practice recommendations for treatment of type 1 diabetes complicated by problematic hypoglycemia. Diabetes Care. 2015;38:1016–29.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Robertson RP. Islet transplantation for type 1 diabetes, 2015: what have we learned from alloislet and autoislet successes? Diabetes Care. 2015;38:1030–5.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Bosi E, Piatti P, Secchi A, Monti L, Traeger J, Dubernard J, Pozza G. Response of glucagon and insulin secretion to insulin-induced hypoglycemia in diabetic patients after pancreatic transplantation. Diab Nutr Metab. 1988;1:21–7.

    Google Scholar 

  128. Diem P, Redman J, Abid M, Moran A, Sutherland D, Halter J, Robertson R. Glucagon, catecholamine, and pancreatic polypeptide secretion in type I diabetic recipients of pancreas allografts. J Clin Invest. 1990;86:2008–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Bolinder J, Wahrenberg H, Persson A, Linde B, Tyden G, Groth C, Ostman J. Effect of pancreas transplantation on glucose counterregulation in insulin-dependent diabetic patients prone to severe hypoglycaemia. J Intern Med. 1991;230:527–33.

    Article  CAS  PubMed  Google Scholar 

  130. Bolinder J, Wahrenberg H, Linde B, Tyden G, Groth C, Ostman J. Improved glucose counterregulation after pancreas transplantation in diabetic patients with unawareness of hypoglycemia. Transplant Proc. 1991;23:1667–9.

    CAS  PubMed  Google Scholar 

  131. Landgraf R, Nusser J, Riepl R, Fiedler F, Illner W, Abendroth D, Land W. Metabolic and hormonal studies of type 1 (insulin-dependent) diabetic patients after successful pancreas and kidney transplantation. Diabetologia. 1991;34 Suppl 1:S61–7.

    Article  PubMed  Google Scholar 

  132. Barrou Z, Seaquist E, Robertson R. Pancreas transplantation in diabetic humans normalizes hepatic glucose production during hypoglycemia. Diabetes. 1994;43:661–6.

    Article  CAS  PubMed  Google Scholar 

  133. Kendall D, Rooney D, Smets Y, Bolding L, Robertson R. Pancreas transplantation restores epinephrine response and symptom recognition during hypoglycemia in patients with long-standing type 1 diabetes and autonomic neuropathy. Diabetes. 1997;46:249–57.

    Article  CAS  PubMed  Google Scholar 

  134. Luzi L, Battezzati A, Perseghin G, Bianchi E, Vergani S, Secchi A, La Rocca E, Staudacher C, Spotti D, Ferrari G, Di Carlo V, Pozza G. Lack of feedback inhibition of insulin secretion in denervated human pancreas. Diabetes. 1992;41:1632–9.

    Article  CAS  PubMed  Google Scholar 

  135. Battezzati A, Luzi L, Perseghin G, Bianchi E, Spotti D, Secchi A, Vergani S, Di Carlo V, Pozza G. Persistence of counter-regulatory abnormalities in insulin-dependent diabetes mellitus after pancreas transplantation. Eur J Clin Invest. 1994;24:751–8.

    Article  CAS  PubMed  Google Scholar 

  136. Leitão CB, Tharavanij T, Cure P, Pileggi A, Baidal DA, Ricordi C, Alejandro R. Restoration of hypoglycemia awareness after islet transplantation. Diabetes Care. 2008;31(11):2113–5.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Paty BW, Ryan EA, Shapiro AM, Lakey JR, Robertson RP. Intrahepatic islet transplantation in type 1 diabetic patients does not restore hypoglycemic hormonal counterregulation or symptom recognition after insulin independence. Diabetes. 2002;51:3428–34.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Southlake Regional Health Center, Newmarket, ON, Canada

    Mazen Alsahli

  2. Department of Medicine, University of Toronto, Toronto, ON, Canada

    Mazen Alsahli

  3. Department of Medicine, University of Rochester School of Medicine, Rochester, NY, 14642, USA

    John E. Gerich

Authors
  1. Mazen Alsahli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John E. Gerich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John E. Gerich .

Editor information

Editors and Affiliations

  1. Division of Endocrinology, Gerald J. Friedman Diabetes Institute, Lenox Hill Hospital, Hofstra Northwell School of Medicine, Northwell Health, New York, New York, USA

    Leonid Poretsky

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this entry

Cite this entry

Alsahli, M., Gerich, J.E. (2017). Hypoglycemia in Diabetes Mellitus. In: Poretsky, L. (eds) Principles of Diabetes Mellitus. Springer, Cham. https://doi.org/10.1007/978-3-319-18741-9_19

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-18741-9_19

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-18740-2

  • Online ISBN: 978-3-319-18741-9

  • eBook Packages: MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation