Hypoglycemia in adults: Clinical manifestations, definition, and causes
- F John Service, MD, PhD
F John Service, MD, PhD
- Emeritus Professor of Medicine
- Mayo Clinic College of Medicine
- Philip E Cryer, MD
Philip E Cryer, MD
- Professor of Medicine Emeritus and Adjunct Professor of Medicine
- Washington University in St. Louis
- Adrian Vella, MD
Adrian Vella, MD
- Professor of Medicine
- Mayo Clinic
In patients without diabetes, hypoglycemia is a clinical syndrome with diverse causes in which low plasma glucose concentrations lead to symptoms and signs, and there is resolution of the symptoms/signs when the plasma glucose concentration is raised . In patients with diabetes, hypoglycemia is defined as all episodes of an abnormally low plasma glucose concentration (with or without symptoms) that expose the individual to harm . In patients with diabetes, the hypoglycemia symptoms and signs occur as a consequence of therapy. The primary task in a patient without diabetes is to make an accurate diagnosis, whereas the primary task in a patient with diabetes is to alter therapy in an attempt to minimize or eliminate hypoglycemia.
This topic will review the clinical manifestations, definitions, and causes of clinical hypoglycemia. The evaluation of patients with hypoglycemia, detailed information on specific causes, and the management of hypoglycemia in patients with diabetes are reviewed elsewhere. (See "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach" and "Insulinoma" and "Factitious hypoglycemia" and "Nonislet cell tumor hypoglycemia" and "Management of hypoglycemia during treatment of diabetes mellitus".)
Patients who have only sympathoadrenal symptoms (anxiety, weakness, tremor, perspiration, or palpitations) but normal concurrent plasma glucose concentrations have a low probability of having a hypoglycemic disorder. This combination of normal glucose in the face of sympathoadrenal symptoms occurs most commonly in the postprandial state. (See "Postprandial (reactive) hypoglycemia", section on 'Postprandial syndrome'.)
Hypoglycemia is common in type 1 diabetes, especially in patients receiving intensive insulin therapy, in whom the risk of severe hypoglycemia is increased more than threefold in the Diabetes Control and Complications Trial (DCCT). Plasma glucose concentrations may be less than 50 to 60 mg/dL (2.8 to 3.3 mmol/L) as much as 10 percent of the time . Patients with type 1 diabetes may suffer an average of two episodes of symptomatic hypoglycemia per week, thousands of such episodes over a lifetime of diabetes, and one episode of severe, at least temporarily disabling hypoglycemia per year. Severe hypoglycemia events, the most reliable values albeit representing only a small fraction of the total hypoglycemic experience, have been reported to range from 62 to 320 episodes per 100 patient years in type 1 diabetes [1,3,4].
Hypoglycemia is less frequent in type 2 diabetes than it is in type 1 [3,5]. Population-based data indicate that the overall event rate for severe hypoglycemia (requiring the assistance of another individual) in insulin-treated type 2 diabetes is approximately 30 percent of that in type 1 diabetes (35 versus 115 episodes per 100 patient-years)  and that event rates for hypoglycemia requiring professional emergency medical treatment range from 40 to 100 percent of those in type 1 diabetes [7,8].
- Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2009; 94:709.
- Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. J Clin Endocrinol Metab 2013; 98:1845.
- Cryer PE. Hypoglycemia in diabetes: Pathophysiology, prevalence, and prevention, 3rd, American Diabetes Association, Alexandria, VA 2016.
- UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia 2007; 50:1140.
- Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes 2008; 57:3169.
- Donnelly LA, Morris AD, Frier BM, et al. Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: a population-based study. Diabet Med 2005; 22:749.
- Holstein A, Plaschke A, Egberts EH. Clinical characterisation of severe hypoglycaemia--a prospective population-based study. Exp Clin Endocrinol Diabetes 2003; 111:364.
- Leese GP, Wang J, Broomhall J, 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; 26:1176.
- Service FJ. Hypoglycemic disorders. N Engl J Med 1995; 332:1144.
- Service FJ. Classification of hypoglycemic disorders. Endocrinol Metab Clin North Am 1999; 28:501.
- Nirantharakumar K, Marshall T, Hodson J, et al. Hypoglycemia in non-diabetic in-patients: clinical or criminal? PLoS One 2012; 7:e40384.
- Hepburn DA, Deary IJ, Frier BM, et al. Symptoms of acute insulin-induced hypoglycemia in humans with and without IDDM. Factor-analysis approach. Diabetes Care 1991; 14:949.
- Towler DA, Havlin CE, Craft S, Cryer P. Mechanism of awareness of hypoglycemia. Perception of neurogenic (predominantly cholinergic) rather than neuroglycopenic symptoms. Diabetes 1993; 42:1791.
- 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:E32.
- Cryer PE. Hypoglycemia, functional brain failure, and brain death. J Clin Invest 2007; 117:868.
- Amiel SA, Sherwin RS, Simonson DC, Tamborlane WV. Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release. Diabetes 1988; 37:901.
- Mitrakou A, Fanelli C, Veneman T, et al. Reversibility of unawareness of hypoglycemia in patients with insulinomas. N Engl J Med 1993; 329:834.
- Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care 2005; 28:1245.
- Frier BM. Defining hypoglycaemia: what level has clinical relevance? Diabetologia 2009; 52:31.
- Swinnen SG, Mullins P, Miller M, et al. Changing the glucose cut-off values that define hypoglycaemia has a major effect on reported frequencies of hypoglycaemia. Diabetologia 2009; 52:38.
- Amiel SA, Dixon T, Mann R, Jameson K. Hypoglycaemia in Type 2 diabetes. Diabet Med 2008; 25:245.
- Cryer PE. Preventing hypoglycaemia: what is the appropriate glucose alert value? Diabetologia 2009; 52:35.
- Whipple, AO. The surgical therapy of hyperinsulinism. J Int Chir 1938; 3:237.
- Consensus statement on self-monitoring of blood glucose. Diabetes Care 1987; 10:95.
- Gambino R, Piscitelli J, Ackattupathil TA, et al. Acidification of blood is superior to sodium fluoride alone as an inhibitor of glycolysis. Clin Chem 2009; 55:1019.
- Goodenow TJ, Malarkey WB. Leukocytosis and artifactual hypoglycemia. JAMA 1977; 237:1961.
- Macaron CI, Kadri A, Macaron Z. Nucleated red blood cells and artifactual hypoglycemia. Diabetes Care 1981; 4:113.
- Theofilogiannakos EK, Giannakoulas G, Ziakas A, et al. Pseudohypoglycemia in a patient with the Eisenmenger syndrome. Ann Intern Med 2010; 152:407.
- Placzkowski KA, Vella A, Thompson GB, et al. Secular trends in the presentation and management of functioning insulinoma at the Mayo Clinic, 1987-2007. J Clin Endocrinol Metab 2009; 94:1069.
- Szoke E, Gosmanov NR, Sinkin JC, et al. Effects of glimepiride and glyburide on glucose counterregulation and recovery from hypoglycemia. Metabolism 2006; 55:78.
- Murad MH, Coto-Yglesias F, Wang AT, et al. Clinical review: Drug-induced hypoglycemia: a systematic review. J Clin Endocrinol Metab 2009; 94:741.
- Parekh TM, Raji M, Lin YL, et al. Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylureas. JAMA Intern Med 2014; 174:1605.
- Marks V, Teale JD. Drug-induced hypoglycemia. Endocrinol Metab Clin North Am 1999; 28:555.
- Krinsley JS, Grover A. Severe hypoglycemia in critically ill patients: risk factors and outcomes. Crit Care Med 2007; 35:2262.
- Miller SI, Wallace RJ Jr, Musher DM, et al. Hypoglycemia as a manifestation of sepsis. Am J Med 1980; 68:649.
- Maitra SR, Wojnar MM, Lang CH. Alterations in tissue glucose uptake during the hyperglycemic and hypoglycemic phases of sepsis. Shock 2000; 13:379.
- Metzger S, Nusair S, Planer D, et al. Inhibition of hepatic gluconeogenesis and enhanced glucose uptake contribute to the development of hypoglycemia in mice bearing interleukin-1beta- secreting tumor. Endocrinology 2004; 145:5150.
- Rich LM, Caine MR, Findling JW, Shaker JL. Hypoglycemic coma in anorexia nervosa. Case report and review of the literature. Arch Intern Med 1990; 150:894.
- Yanai H, Yoshida H, Tomono Y, Tada N. Severe hypoglycemia in a patient with anorexia nervosa. Eat Weight Disord 2008; 13:e1.
- Yamamoto T, Fukuyama J, Hasegawa K, Sugiura M. Isolated corticotropin deficiency in adults. Report of 10 cases and review of literature. Arch Intern Med 1992; 152:1705.
- Lupsa BC, Chong AY, Cochran EK, et al. Autoimmune forms of hypoglycemia. Medicine (Baltimore) 2009; 88:141.
- CLINICAL MANIFESTATIONS
- Laboratory findings
- Patients with diabetes
- Patients without diabetes
- DIFFERENTIAL DIAGNOSIS
- CAUSES OF HYPOGLYCEMIA
- Hypoglycemia in diabetes
- Hypoglycemia in patients without diabetes
- - Drugs
- - Critical illness
- - Malnourishment
- - Cortisol deficiency
- - Nonislet cell tumors
- - Endogenous hyperinsulinism
- - Accidental, surreptitious, or malicious hypoglycemia
- SOCIETY GUIDELINE LINKS
- INFORMATION FOR PATIENTS