2. Hypoglycemia Detection.

Abstract

Insulin-induced hypoglycemia is a life-threatening iatrogenic phenomenon that activates multiple neural and humoral corrective systems. When blood glucose levels begin to fall below 80 mg/dL, a sequential series of events occurs. Insulin secretion ceases; secretion of glucagon, epinephrine (E), corticosterone, and growth hormone is initiated, and neurogenic systems trigger food intake. All of these responses are recruited when glucose decreases to approximately 60 mg/dL. Together, these corrective responses (counter-regulatory responses or CRR) rapidly restore euglycemia. Unfortunately, however, the magnitude of the CRR decreases with recurring hypoglycemic episodes, leading to a syndrome known as hypoglycemia-associated autonomic failure (HAAF). During HAAF, glucose levels can fall dangerously low without eliciting the behavioral signs that usually accompany hypoglycemia. HAAF is the major limiting factor of the intensive insulin therapy needed to control the deleterious effects of diabetic hyperglycemia (1, 2). In order to understand and develop therapies for HAAF, it is critical to understand the mechanisms underlying hypoglycemia detection and initiation of the CRR. For many decades, it has been clear that there are glucose sensors located throughout the body and the central nervous system (CNS) (3–8). The goal of this chapter is to describe glucose sensing by central and peripheral glucose sensors and evidence that supports their roles in hypoglycemia detection and HAAF. The authors will focus on 3 glucose-sensing systems that contribute importantly to glucose counterregulation: the ventrome-dial hypothalamic nucleus (VMN) (9, 10), the hindbrain catecholamine neurons (11), and the portal-mesenteric vein (PMV) (12).