Physiologic response to hypoglycemia in normal subjects and patients with diabetes mellitus
- Philip E Cryer, MD
Philip E Cryer, MD
- Professor of Endocrinology and Metabolism in Medicine
- Washington University in St. Louis
The brain relies almost exclusively on glucose as a fuel, but cannot synthesize or store much of it. As a result, adequate uptake of glucose from the plasma is essential for normal brain function and survival. Given the survival value of maintenance of the plasma glucose concentration, it is not surprising that very effective physiological and behavioral mechanisms that normally prevent or rapidly correct hypoglycemia have evolved. As a result, hypoglycemia is an uncommon clinical event except in patients who use drugs that lower glucose levels, particularly those with diabetes who use insulin, a sulfonylurea, or a glinide. In addition to being at increased risk for hypoglycemia, diabetic patients treated with insulin often have impaired neurohumoral responses to and few early symptoms of low blood glucose concentrations [1-4].
This topic card will review glucose metabolism and the response to hypoglycemia in normal subjects and in patients with diabetes. The therapeutic approach to hypoglycemia in diabetic patients is discussed separately. (See "Management of hypoglycemia during treatment of diabetes mellitus".)
REGULATION OF GLUCOSE HOMEOSTASIS
In normal subjects, the extracellular supply of glucose is carefully regulated primarily by insulin and glucagon (figure 1) [1-4]. As plasma glucose concentrations rise after a meal, glucose enters the pancreatic beta-cells. In the cells, the enzyme glucokinase, which phosphorylates glucose to glucose-6-phosphate, may act as the glucose sensor, initiating a sequence of events leading to entry of calcium and insulin release. (See "Insulin secretion and pancreatic beta cell function".)
Insulin acts to restore normoglycemia primarily through the following two mechanisms:
●It decreases hepatic glucose production by diminishing both glycogenolysis and gluconeogenesis. It does so directly and indirectly by diminishing delivery of the gluconeogenic precursors, lactate and alanine, among other amino acids, and glycerol to the liver via its antiglycolytic, antiproteolytic, and antilipolytic actions.
- Cryer PE. Hypoglycemia in Diabetes: Pathophysiology, Prevalence and Prevention, 3rd ed, American Diabetes Association, Alexandria, VA 2016.
- Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes 2008; 57:3169.
- Dunning BE, Gerich JE. The role of alpha-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications. Endocr Rev 2007; 28:253.
- Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 2013; 369:362.
- Cooperberg BA, Cryer PE. Insulin reciprocally regulates glucagon secretion in humans. Diabetes 2010; 59:2936.
- Cryer PE. Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes. J Clin Invest 2006; 116:1470.
- 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; 91:819.
- Segel SA, Paramore DS, Cryer PE. Hypoglycemia-associated autonomic failure in advanced type 2 diabetes. Diabetes 2002; 51:724.
- 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; 54:757.
- Gosmanov NR, Szoke E, Israelian Z, et al. Role of the decrement in intraislet insulin for the glucagon response to hypoglycemia in humans. Diabetes Care 2005; 28:1124.
- Heller SR, Cryer PE. Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans. Diabetes 1991; 40:223.
- White NH, Skor DA, Cryer PE, et al. Identification of type I diabetic patients at increased risk for hypoglycemia during intensive therapy. N Engl J Med 1983; 308:485.
- Bolli GB, De Feo P, De Cosmo S, et al. A reliable and reproducible test for adequate glucose counterregulation in type I diabetes mellitus. Diabetes 1984; 33:732.
- Geddes J, Schopman JE, Zammitt NN, Frier BM. Prevalence of impaired awareness of hypoglycaemia in adults with Type 1 diabetes. Diabet Med 2008; 25:501.
- Bottini P, Boschetti E, Pampanelli S, et al. Contribution of autonomic neuropathy to reduced plasma adrenaline responses to hypoglycemia in IDDM: evidence for a nonselective defect. Diabetes 1997; 46:814.
- Meyer C, Grossmann R, Mitrakou A, et al. Effects of autonomic neuropathy on counterregulation and awareness of hypoglycemia in type 1 diabetic patients. Diabetes Care 1998; 21:1960.
- U.K. prospective diabetes study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes 1995; 44:1249.
- Raju B, Arbelaez AM, Breckenridge SM, Cryer PE. Nocturnal hypoglycemia in type 1 diabetes: an assessment of preventive bedtime treatments. J Clin Endocrinol Metab 2006; 91:2087.
- Jones TW, Porter P, Sherwin RS, et al. Decreased epinephrine responses to hypoglycemia during sleep. N Engl J Med 1998; 338:1657.
- Banarer S, Cryer PE. Sleep-related hypoglycemia-associated autonomic failure in type 1 diabetes: reduced awakening from sleep during hypoglycemia. Diabetes 2003; 52:1195.
- Tordjman KM, Havlin CE, Levandoski LA, et al. Failure of nocturnal hypoglycemia to cause fasting hyperglycemia in patients with insulin-dependent diabetes mellitus. N Engl J Med 1987; 317:1552.
- Hirsch IB, Smith LJ, Havlin CE, et al. Failure of nocturnal hypoglycemia to cause daytime hyperglycemia in patients with IDDM. Diabetes Care 1990; 13:133.
- Campbell PJ, Bolli GB, Cryer PE, Gerich JE. Pathogenesis of the dawn phenomenon in patients with insulin-dependent diabetes mellitus. Accelerated glucose production and impaired glucose utilization due to nocturnal surges in growth hormone secretion. N Engl J Med 1985; 312:1473.
- REGULATION OF GLUCOSE HOMEOSTASIS
- RESPONSE TO HYPOGLYCEMIA IN NORMAL SUBJECTS
- Counterregulatory hormones
- - Relation between insulin and glucagon
- Behavioral defenses
- RESPONSE TO HYPOGLYCEMIA IN DIABETES
- Impairment of behavioral and counterregulatory responses
- - Insulin
- - Glucagon
- - Epinephrine
- Hypoglycemia-associated autonomic failure
- - Mechanism
- - Type 1 versus type 2
- Nocturnal hypoglycemia