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Epinephrine Secretion, Hypoglycemia Unawareness, and Diabetic Autonomic Neuropathy

Robert D. Hoeldtke, MD, PhD; and Guenther Boden, MD
[+] Article, Author, and Disclosure Information

From West Virginia University, Morgantown, West Virginia; Temple University, Philadelphia, Pennsylvania. Requests for Reprints: Robert D. Hoeldtke, MD, PhD: West Virginia University, Department of Medicine, P.O. Box 9159, Health Sciences Center North, Morgantown, WV 26506-9159. Grant Support: By grants R01-AG-07988 and R01-DK-32239 from the National Institutes of Health, grant RR-349 from the General Clinical Research Center, Temple University, a clinical research grant from the American Diabetes Association, and a grant from the CE Compton Nutrition Foundation.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1994;120(6):512-517. doi:10.7326/0003-4819-120-6-199403150-00011
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The pathophysiology of iatrogenic hypoglycemia in patients with insulin-dependent diabetes mellitus has been studied extensively during the past decade. It is now widely recognized that some patients with long-standing diabetes lose their ability to secrete the major counterregulatory hormones, glucagon and epinephrine, and fail to have hypoglycemia-related autonomic warning symptoms. Many investigators focused initially on the role of autonomic neuropathy, assuming that the latter might explain the diminished epinephrine response to hypoglycemia and the blunted adrenergic warning signs. Although these studies confirmed that patients with advanced diabetic autonomic neuropathy have attenuated counterregulatory hormonal responses to hypoglycemia, many patients with inadequate counterregulatory hormone secretion lack the typical signs, symptoms, or cardiovascular reflex abnormalities typical of diabetic autonomic neuropathy. These patients may have a new variant of diabetic autonomic failure that selectively affects the central and peripheral autonomic mechanisms, which initiate epinephrine secretion and the defense against hypoglycemia.

A potentially reversible cause for the failure of the counterregulatory hormone response to hypoglycemia has also been recently described.In this instance, the central nervous system fails to recognize hypoglycemia. The brain does not activate counterregulation, and the patient develops no symptoms of hypoglycemia. Decreased central recognition of hypoglycemia results from either strict antecedent control or from a recent hypoglycemic event.


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Figure 1.
Neuroendocrine and symptomatic responses to subsequent hypoglycemia after a 1-hour episode of hypoglycemia.PPPP[10]

Plasma glucose concentrations (mean ±SE), total symptom scores, and plasma epinephrine concentrations during hyperinsulinemic glucose clamps on mornings before and after interval afternoon (1400 to 1600 hours) euglycemia (approximately 3 mM) and mornings before and after afternoon hypoglycemia (approximately 3 mM) in nondiabetic patients. *  < 0.05, **  < 0.02, ***  < 0.01, and ****  < 0.001. Reproduced with permission of Heller and Cryer , Diabetes, and the American Diabetes Association, Inc.

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Figure 2.
Autonomic neuropathy and the secretion of counterregulatory hormones.closed circlesopen circlesdashed linedotted line[20]

Blood glucose and hormonal responses to insulin-induced hypoglycemia are shown for normal persons ( ), diabetic patients without autonomic neuropathy ( ), diabetic patients with parasympathetic neuropathy ( ), and diabetic patients with severe sympathetic neuropathy ( ). Reproduced with permission from Webb and Castaner and Clinical Physiology.

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Figure 3.
Effect of intensive insulin therapy on epinephrine responses to hypoglycemia.white boxesblack circleswhite circlesPP++P[34]Annals of Internal Medicine

Plasma levels of epinephrine during the basal state, euglycemic clamp, and hypoglycemic clamp in normal controls ( ) and in patients with type I diabetes before ( ) and after ( ) intensified insulin treatment. *  < 0.05 comparing values in patients with diabetes before pump treatment with values after pump treatment; **  < 0.01 comparing values in patients with diabetes before pump treatment with values after pump treatment; < 0.01 comparing values in controls with those in patients with diabetes after intensive therapy. Reproduced with permission of Simonson and colleagues and .

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