Hypoglycemia is uncommon in the general, nondiabetic population but occurs frequently in persons with diabetes treated with insulin or insulin secretagogues. Thus, iatrogenic hypoglycemia explains the majority of cases among persons with type 1 diabetes (T1DM). Since T1DM is characterized by absolute insulin dependence, the current imperfections in insulin replacement therapies often lead to a mismatch between caloric supply and circulating insulin levels, thus increasing the risk for glycemic fluctuations. Hypoglycemia is the limiting factor to excellent glycemic control in insulin-treated subjects. Intensification of glycemic control was associated with a 300 % increase in the rate of hypoglycemia in the Diabetes Control and Complications Trial. Recent measurements using continuous glucose monitoring reveal an alarming rate of daytime and nocturnal episodes of hypoglycemia in patients with T1DM. Etiological factors underlying hypoglycemia in T1DM include predictable triggers (skipped meals, exercise, insulin over dosage) as well as defective counterregulation, a component of hypoglycemia-associated autonomic failure.
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Crofford OB. Diabetes control and complications. Annu Rev Med. 1995;46:267–79.
Dagogo-Jack S. Hypoglycemia in type 1 diabetes mellitus: pathophysiology and prevention. Treat Endocrinol. 2004;3(2):91–103.
O'Connell SM, Cooper MN, Bulsara MK, Davis EA, Jones TW. Reducing rates of severe hypoglycemia in a population-based cohort of children and adolescents with type 1 diabetes over the decade 2000-2009. Diabetes Care. 2011;34(11):2379–80.
• Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and diabetes: a report of a workgroup of the american diabetes association and the endocrine society. Diabetes Care. 2013;36(5):1384–95. This recent report provides a comprehensive review on hypoglycemia in diabetes, addressing not only the clinical implications, but also the conventional and emerging strategies for its prevention.
Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes. 2008;57(12):3169–76.
Cryer PE. Hypoglycemia in type 1 diabetes mellitus. Endocrinol Metab Clin North Am. 2010;39(3):641–54.
Workgroup on Hypoglycemia ADA. Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 2005;28(5):1245–9.
Cryer PE. Banting Lecture. Hypoglycemia: the limiting factor in the management of IDDM. Diabetes. 1994;43(11):1378–89.
McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. Diabet Med. 2001;18(9):690–705.
Cryer PE. Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes. Diabetologia. 2002;45(7):937–48.
Cryer PE. Hypoglycemia risk reduction in type 1 diabetes. Exp Clin Endocrinol Diabetes. 2001;109 Suppl 2:S412–23.
Epidemiology of severe hypoglycemia in the diabetes control and complications trial. The DCCT Research Group. Am J Med. 1991;90(4):450–9.
Bulsara MK, Holman CD, Davis EA, Jones TW. The impact of a decade of changing treatment on rates of severe hypoglycemia in a population-based cohort of children with type 1 diabetes. Diabetes Care. 2004;27(10):2293–8.
Leese GP, Wang J, Broomhall J, Kelly P, Marsden A, Morrison W, et al. 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(4):1176–80.
Group UKHS. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia. 2007;50(6):1140–7.
Donnelly LA, Morris AD, Frier BM, Ellis JD, Donnan PT, Durrant R, et al. Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: a population-based study. Diabet Med. 2005;22(6):749–55.
Cryer PE. Hypoglycemia-associated autonomic failure in diabetes. Am J Physiol Endocrinol Metab. 2001;281(6):E1115–21.
Pedersen-Bjergaard U, Agerholm-Larsen B, Pramming S, Hougaard P, Thorsteinsson B. Prediction of severe hypoglycaemia by angiotensin-converting enzyme activity and genotype in type 1 diabetes. Diabetologia. 2003;46(1):89–96.
Pedersen-Bjergaard U, Agerholm-Larsen B, Pramming S, Hougaard P, Thorsteinsson B. Activity of angiotensin-converting enzyme and risk of severe hypoglycaemia in type 1 diabetes mellitus. Lancet. 2001;357(9264):1248–53.
Bulsara MK, Holman CD, van Bockxmeer FM, Davis EA, Gallego PH, Beilby JP, et al. The relationship between ACE genotype and risk of severe hypoglycaemia in a large population-based cohort of children and adolescents with type 1 diabetes. Diabetologia. 2007;50(5):965–71.
Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009;94(3):709–28.
Harjutsalo V, Forsblom C, Groop PH. Time trends in mortality in patients with type 1 diabetes: nationwide population based cohort study. BMJ. 2011;343:d5364.
Asao K, Sarti C, Forsen T, Hyttinen V, Nishimura R, Matsushima M, et al. Long-term mortality in nationwide cohorts of childhood-onset type 1 diabetes in Japan and Finland. Diabetes Care. 2003;26(7):2037–42.
The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329(14):977–86.
Shafiee G, Mohajeri-Tehrani M, Pajouhi M, Larijani B. The importance of hypoglycemia in diabetic patients. J Diabetes Metab Disord. 2012;11(1):17.
Ha WC, Oh SJ, Kim JH, Lee JM, Chang SA, Sohn TS, et al. Severe hypoglycemia is a serious complication and becoming an economic burden in diabetes. Diabetes Metab J. 2012;36(4):280–4.
Ginde AA, Espinola JA, Camargo Jr CA. Trends and disparities in U.S. emergency department visits for hypoglycemia, 1993-2005. Diabetes Care. 2008;31(3):511–3.
Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011;365(21):2002–12.
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(5):447–52.
Snell-Bergeon JK, Wadwa RP. Hypoglycemia, diabetes, and cardiovascular disease. Diabetes Technol Ther. 2012;14 Suppl 1:S51–8.
Marques JL, George E, Peacey SR, Harris ND, Macdonald IA, Cochrane T, et al. Altered ventricular repolarization during hypoglycaemia in patients with diabetes. Diabet Med. 1997;14(8):648–54.
Frier BM. Morbidity of hypoglycemia in type 1 diabetes. Diabetes Res Clin Pract. 2004;65 Suppl 1:S47–52.
Gill GV, Woodward A, Casson IF, Weston PJ. Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes–the 'dead in bed' syndrome revisited. Diabetologia. 2009;52(1):42–5.
Razavi Nematollahi L, Kitabchi AE, Stentz FB, Wan JY, Larijani BA, Tehrani MM, et al. Proinflammatory cytokines in response to insulin-induced hypoglycemic stress in healthy subjects. Metabolism. 2009;58(4):443–8.
Gimenez M, Gilabert R, Monteagudo J, Alonso A, Casamitjana R, Pare C, et al. Repeated episodes of hypoglycemia as a potential aggravating factor for preclinical atherosclerosis in subjects with type 1 diabetes. Diabetes Care. 2011;34(1):198–203.
Wright RJ, Frier BM. Vascular disease and diabetes: is hypoglycaemia an aggravating factor? Diabetes Metab Res Rev. 2008;24(5):353–63.
Oyer DS. The science of hypoglycemia in patients with diabetes. Curr Diabetes Rev. 2013;9(3):195–208.
Fidler C, Elmelund Christensen T, Gillard S. Hypoglycemia: an overview of fear of hypoglycemia, quality-of-life, and impact on costs. J Med Econ. 2011;14(5):646–55.
Cox DJ, Kovatchev B, Vandecar K, Gonder-Frederick L, Ritterband L, Clarke W. Hypoglycemia preceding fatal car collisions. Diabetes Care. 2006;29(2):467–8.
Brod M, Christensen T, Thomsen TL, Bushnell DM. The impact of non-severe hypoglycemic events on work productivity and diabetes management. Value Health. 2011;14(5):665–71.
Noguchi R, Kubota H, Yugi K, Toyoshima Y, Komori Y, Soga T, et al. The selective control of glycolysis, gluconeogenesis and glycogenesis by temporal insulin patterns. Mol Syst Biol. 2013;9:664.
Choi SM, Tucker DF, Gross DN, Easton RM, DiPilato LM, Dean AS, et al. Insulin regulates adipocyte lipolysis via an Akt-independent signaling pathway. Mol Cell Biol. 2010;30(21):5009–20.
Habegger KM, Heppner KM, Geary N, Bartness TJ, DiMarchi R, Tschop MH. The metabolic actions of glucagon revisited. Nat Rev Endocrinol. 2010;6(12):689–97.
Pegorier JP, Garcia-Garcia MV, Prip-Buus C, Duee PH, Kohl C, Girard J. Induction of ketogenesis and fatty acid oxidation by glucagon and cyclic AMP in cultured hepatocytes from rabbit fetuses. Evidence for a decreased sensitivity of carnitine palmitoyltransferase I to malonyl-CoA inhibition after glucagon or cyclic AMP treatment. Biochem J. 1989;264(1):93–100.
Cryer PE. Minireview: Glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes. Endocrinology. 2012;153(3):1039–48.
Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care. 2003;26(6):1902–12.
Mitrakou A, Ryan C, Veneman T, Mokan M, Jenssen T, Kiss I, et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol. 1991;260(1 Pt 1):E67–74.
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;40(6):680–5.
Bakatselos SO. Hypoglycemia unawareness. Diabetes Res Clin Pract. 2011;93 Suppl 1:S92–6.
Raju B, Cryer PE. Loss of the decrement in intraislet insulin plausibly explains loss of the glucagon response to hypoglycemia in insulin-deficient diabetes: documentation of the intraislet insulin hypothesis in humans. Diabetes. 2005;54(3):757–64.
Cryer PE. Hypoglycemia in diabetes: pathophysiological mechanisms and diurnal variation. Prog Brain Res. 2006;153:361–5.
Dagogo-Jack SE, Craft S, Cryer PE. Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia. J Clin Invest. 1993;91(3):819–28.
Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes. Diabetes. 2005;54(12):3592–601.
Cryer PE. Hypoglycemia unawareness in IDDM. Diabetes Care. 1993;16 Suppl 3:40–7.
DeRosa MA, Cryer PE. Hypoglycemia and the sympathoadrenal system: neurogenic symptoms are largely the result of sympathetic neural, rather than adrenomedullary, activation. Am J Physiol Endocrinol Metab. 2004;287(1):E32–41.
Cryer PE. Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes. J Clin Invest. 2006;116(6):1470–3.
• 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. This article provides a thorough review of the pathophysiologic mechanisms implicated in defective counterregulation and hypoglycemia unawareness, as well as emerging treatment options.
Banarer S, Cryer PE. Sleep-related hypoglycemia-associated autonomic failure in type 1 diabetes: reduced awakening from sleep during hypoglycemia. Diabetes. 2003;52(5):1195–203.
McGregor VP, Greiwe JS, Banarer S, Cryer PE. Limited impact of vigorous exercise on defenses against hypoglycemia: relevance to hypoglycemia-associated autonomic failure. Diabetes. 2002;51(5):1485–92.
Davis SN, Shavers C, Costa F, Mosqueda-Garcia R. Role of cortisol in the pathogenesis of deficient counterregulation after antecedent hypoglycemia in normal humans. J Clin Invest. 1996;98(3):680–91.
Flanagan DE, Keshavarz T, Evans ML, Flanagan S, Fan X, Jacob RJ, et al. Role of corticotrophin-releasing hormone in the impairment of counterregulatory responses to hypoglycemia. Diabetes. 2003;52(3):605–13.
Raju B, McGregor VP, Cryer PE. Cortisol elevations comparable to those that occur during hypoglycemia do not cause hypoglycemia-associated autonomic failure. Diabetes. 2003;52(8):2083–9.
Koranyi L, Bourey RE, James D, Mueckler M, Fiedorek Jr FT, Permutt MA. Glucose transporter gene expression in rat brain: Pretranslational changes associated with chronic insulin-induced hypoglycemia, fasting, and diabetes. Mol Cell Neurosci. 1991;2(3):244–52.
Segel SA, Fanelli CG, Dence CS, Markham J, Videen TO, Paramore DS, et al. Blood-to-brain glucose transport, cerebral glucose metabolism, and cerebral blood flow are not increased after hypoglycemia. Diabetes. 2001;50(8):1911–7.
Boyle PJ, Nagy RJ, O'Connor AM, Kempers SF, Yeo RA, Qualls C. Adaptation in brain glucose uptake following recurrent hypoglycemia. Proc Natl Acad Sci U S A. 1994;91(20):9352–6.
Levin BE, Becker TC, Eiki J, Zhang BB, Dunn-Meynell AA. Ventromedial hypothalamic glucokinase is an important mediator of the counterregulatory response to insulin-induced hypoglycemia. Diabetes. 2008;57(5):1371–9.
McCrimmon RJ, Fan X, Ding Y, Zhu W, Jacob RJ, Sherwin RS. Potential role for AMP-activated protein kinase in hypoglycemia sensing in the ventromedial hypothalamus. Diabetes. 2004;53(8):1953–8.
Chan O, Paranjape S, Czyzyk D, Horblitt A, Zhu W, Ding Y, et al. Increased GABAergic output in the ventromedial hypothalamus contributes to impaired hypoglycemic counterregulation in diabetic rats. Diabetes. 2011;60(5):1582–9.
Matveyenko AV, Bohland M, Saberi M, Donovan CM. Portal vein hypoglycemia is essential for full induction of hypoglycemia-associated autonomic failure with slow-onset hypoglycemia. Am J Physiol Endocrinol Metab. 2007;293(3):E857–64.
Arbelaez AM, Powers WJ, Videen TO, Price JL, Cryer PE. Attenuation of counterregulatory responses to recurrent hypoglycemia by active thalamic inhibition: a mechanism for hypoglycemia-associated autonomic failure. Diabetes. 2008;57(2):470–5.
Szepietowska B, Zhu W, Chan O, Horblitt A, Dziura J, Sherwin RS. Modulation of beta-adrenergic receptors in the ventromedial hypothalamus influences counterregulatory responses to hypoglycemia. Diabetes. 2011;60(12):3154–8.
Realsen JM, Chase HP. Recent advances in the prevention of hypoglycemia in type 1 diabetes. Diabetes Technol Ther. 2011;13(12):1177–86.
Gold AE, MacLeod KM, Frier BM. Frequency of severe hypoglycemia in patients with type I diabetes with impaired awareness of hypoglycemia. Diabetes Care. 1994;17(7):697–703.
Dagogo-Jack S, Rattarasarn C, Cryer PE. Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM. Diabetes. 1994;43(12):1426–34.
Yeh HC, Brown TT, Maruthur N, Ranasinghe P, Berger Z, Suh YD, et al. Comparative effectiveness and safety of methods of insulin delivery and glucose monitoring for diabetes mellitus: a systematic review and meta-analysis. Ann Intern Med. 2012;157(5):336–47.
Cryer PE. Preventing hypoglycaemia: what is the appropriate glucose alert value? Diabetologia. 2009;52(1):35–7.
Standards of medical care in diabetes--2013. Diabetes Care. 2013;36 Suppl 1:S11–66.
Kovatchev BP, Cox DJ, Farhy LS, Straume M, Gonder-Frederick L, Clarke WL. Episodes of severe hypoglycemia in type 1 diabetes are preceded and followed within 48 hours by measurable disturbances in blood glucose. J Clin Endocrinol Metab. 2000;85(11):4287–92.
Tamborlane WV, Beck RW, Bode BW, Buckingham B, Chase HP, Clemons R, et al. Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med. 2008;359(14):1464–76.
Kaufman FR, Austin J, Neinstein A, Jeng L, Halvorson M, Devoe DJ, et al. Nocturnal hypoglycemia detected with the Continuous Glucose Monitoring System in pediatric patients with type 1 diabetes. J Pediatr. 2002;141(5):625–30.
Beck RW, Hirsch IB, Laffel L, Tamborlane WV, Bode BW, Buckingham B, et al. The effect of continuous glucose monitoring in well-controlled type 1 diabetes. Diabetes Care. 2009;32(8):1378–83.
Cox DJ, Gonder-Frederick L, Ritterband L, Clarke W, Kovatchev BP. Prediction of severe hypoglycemia. Diabetes Care. 2007;30(6):1370–3.
Cox DJ, Gonder-Frederick L, Polonsky W, Schlundt D, Kovatchev B, Clarke W. Blood glucose awareness training (BGAT-2): long-term benefits. Diabetes Care. 2001;24(4):637–42.
Cox DJ, Kovatchev B, Koev D, Koeva L, Dachev S, Tcharaktchiev D, et al. Hypoglycemia anticipation, awareness and treatment training (HAATT) reduces occurrence of severe hypoglycemia among adults with type 1 diabetes mellitus. Int J Behav Med. 2004;11(4):212–8.
Cox D, Clarke W, Gonder-Frederick L, Kovatchev B. Driving mishaps and hypoglycaemia: risk and prevention. Int J Clin Pract Suppl. 2001;123:38–42.
Franz MJ, Bantle JP, Beebe CA, Brunzell JD, Chiasson JL, Garg A, et al. Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care. 2003;26 Suppl 1:S51–61.
Cryer PE, Fisher JN, Shamoon H. Hypoglycemia. Diabetes Care. 1994;17(7):734–55.
Detlofson I, Kroon M, Aman J. Oral bedtime cornstarch supplementation reduces the risk for nocturnal hypoglycaemia in young children with type 1 diabetes. Acta Paediatr. 1999;88(6):595–7.
Kaufman FR, Halvorson M, Kaufman ND. A randomized, blinded trial of uncooked cornstarch to diminish nocturnal hypoglycemia at diabetes camp. Diabetes Res Clin Pract. 1995;30(3):205–9.
Chipkin SR, Klugh SA, Chasan-Taber L. Exercise and diabetes. Cardiol Clin. 2001;19(3):489–505.
Zinman B, Ruderman N, Campaigne BN, Devlin JT, Schneider SH. Physical activity/exercise and diabetes mellitus. Diabetes Care. 2003;26 Suppl 1:S73–7.
Heller SR, Colagiuri S, Vaaler S, Wolffenbuttel BH, Koelendorf K, Friberg HH, et al. Hypoglycaemia with insulin aspart: a double-blind, randomised, crossover trial in subjects with Type 1 diabetes. Diabet Med. 2004;21(7):769–75.
Brunelle BL, Llewelyn J, Anderson Jr JH, Gale EA, Koivisto VA. Meta-analysis of the effect of insulin lispro on severe hypoglycemia in patients with type 1 diabetes. Diabetes Care. 1998;21(10):1726–31.
Linkeschova R, Raoul M, Bott U, Berger M, Spraul M. Less severe hypoglycaemia, better metabolic control, and improved quality of life in Type 1 diabetes mellitus with continuous subcutaneous insulin infusion (CSII) therapy; an observational study of 100 consecutive patients followed for a mean of 2 years. Diabet Med. 2002;19(9):746–51.
Cranston I, Lomas J, Maran A, Macdonald I, Amiel SA. Restoration of hypoglycaemia awareness in patients with long-duration insulin-dependent diabetes. Lancet. 1994;344(8918):283–7.
Paty BW, Lanz K, Kendall DM, Sutherland DE, Robertson RP. Restored hypoglycemic counterregulation is stable in successful pancreas transplant recipients for up to 19 years after transplantation. Transplantation. 2001;72(6):1103–7.
Leitao CB, Tharavanij T, Cure P, Pileggi A, Baidal DA, Ricordi C, et al. Restoration of hypoglycemia awareness after islet transplantation. Diabetes Care. 2008;31(11):2113–5.
Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006;355(13):1318–30.
Meloche RM. Transplantation for the treatment of type 1 diabetes. World J Gastroenterol. 2007;13(47):6347–55.
Dr. Samuel Dagogo-Jack is supported in part by grants from NIH (DK67269, DK62203, DK48411, DK 98246).
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Omodele Awoniyi, Rabia Rehman, and Samuel Dagogo-Jack declare that they have no conflict of interest.
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This article does not contain any studies with human or animal subjects performed by any of the authors.
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Awoniyi, O., Rehman, R. & Dagogo-Jack, S. Hypoglycemia in Patients with Type 1 Diabetes: Epidemiology, Pathogenesis, and Prevention. Curr Diab Rep 13, 669–678 (2013). https://doi.org/10.1007/s11892-013-0411-y
- Type 1 diabetes mellitus
- Hemoglobin A1c
- Iatrogenic hypoglycemia
- Risk factors
- Defective counterregulation
- Hypoglycemia unawareness
- Hypoglycemia-associated autonomic failure