Hypoglycemia: From the Laboratory to the Clinic

Hypoglycemia is the major, and most feared, complication of the pharmacological therapies for diabetes. In health, hypoglycemia sufficient to cause clinically relevant impairment of cognitive function or cardiac rhythm is prevented by highly efficient counterregulatory mechanisms that culminate in restoration of circulating glucose concentrations. In the accompanying article, McCrimmon (1) has summarized our current understanding of how these mechanisms may be initiated and coordinated by central glucose sensing, described the possible molecular mechanisms of neuronal glucose sensing, and alluded to the defective performance of these mechanisms in insulin-treated diabetes.

The principle clinical correlate of defective brain glucose sensing in diabetes is the change in the patient's awareness of the plasma glucose concentration. The clinical phenomenon of loss of awareness of hypoglycemia, and its associated increase in risk of severe hypoglycemia, is accompanied by measurable defects in the counterregulatory stress responses attributed at least in part to failure of central glucose sensing. As McCrimmon explains, the main determinant of the plasma glucose concentrations at which the brain responds actively to hypoglycemia appears to be the recent antecedent glucose exposure. Thus, people accustomed to chronic hyperglycemia may activate symptomatic stress responses as the glucose concentration falls within the physiological range—a barrier for some to tighten glucose control effectively. More extensively explored is the phenomenon of hypoglycemia unawareness, in which the body only mounts a protective counterregulatory response to falling blood glucose at glucose concentrations well below the physiologic norm. Added to the failure of glucagon responses to hypoglycemia that occurs early in type 1 diabetes, such additional counterregulatory failure may leave the patient symptom free and defenseless until plasma glucose concentrations are insufficient to support normal higher brain function. Confusion becomes the first sign of the hypoglycemia, and severe episodes (those in which the person is rendered incapable of self-treatment) ensue. In …