Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes

Abstract

A reduced sympathoadrenal response, induced by recent antecedent hypoglycemia, is the key feature of hypoglycemia-associated autonomic failure (HAAF) and, thus, the pathogenesis of iatrogenic hypoglycemia in diabetes. Understanding of the mechanism(s) of that reduced response awaits new insight into its basic molecular, cellular, organ, and whole-body physiology and pathophysiology in experimental models. In this issue of the JCI, McCrimmon and colleagues report that application of urocortin I (a corticotrophin-releasing factor receptor-2 agonist) to the ventromedial hypothalamus reduces the glucose counterregulatory response to hypoglycemia in rats (see the related article beginning on page 1723). Thus, hypothalamic urocortin I release during antecedent hypoglycemia is, among other possibilities, a potential mechanism of HAAF.

Figure 2. HAAF in T1DM and advanced T2DM.

Figure modified from the New England Journal of Medicine, with permission from the Massachusetts Medical Society (1).

Figure 1. Physiological and behavioral defenses against hypoglycemia.

Decrements in insulin and increments in glucagon are lost and increments in epinephrine and neurogenic symptoms are often attenuated in insulin-deficient — T1DM and advanced T2DM — diabetes. SNS, sympathetic nervous system; PNS, parasympathetic nervous system; NE, norepinephrine; ACh, acetylcholine; α cell, pancreatic islet α cells; β cell, pancreatic islet β cells.