HIERARCHY OF PHYSIOLOGICAL-RESPONSES TO HYPOGLYCEMIA - RELEVANCE TO CLINICAL HYPOGLYCEMIA IN TYPE-I (INSULIN-DEPENDENT) DIABETES-MELLITUS

Hypoglycemia elicits a characteristic sequence of responses in healthy humans. These responses (and their arterialized venous glycemic thres holds) include: 1) Decreased insulin secretion (similar to 4.5 mmol/L) . 2) Increased glucose counterregulatory hormone (glucagon, epinephrin e, growth hormone and cortisol) secretion (similar to 3.6-3.8 mmol/L). 3) Symptoms of hypoglycemia (similar to 3.0 mmol/L). 4) Cognitive dys function (similar to 2.6 mmol/L). Thus, insulin secretion decreases as plasma glucose levels fall within the physiological range, and counte rregulatory hormone secretion increases as plasma glucose levels fall just below the physiological range at substantially higher glucose lev els than those required to produce symptoms and impair cognitive funct ion. These data a re entirely consistent with the body of evidence tha t insulin, glucagon and epinephrine stand high in the hierarchy of red undant glucoregulatory factors that prevent, as well as correct, hypog lycemia. When the same methods are used, these thresholds are remarkab ly reproducible from laboratory to laboratory. Nonetheless, the glycem ic thresholds are dynamic rather than static. They vary in relation to recent antecedent glycemia. For example, lower plasma glucose concent rations are required to elicit autonomic, including epinephrine, and s ymptomatic responses in patients with well controlled IDDM, a phenomen on best attributed to recent antecedent iatrogenic hypoglycemia. This is the basis of the clinical syndrome of hypoglycemia unawareness, whi ch is now known to be reversible with scrupulous avoidance of iatrogen ic hypoglycemia. The latter also at least partially reverses reduced e pinephrine responses to hypoglycemia, a key component (in the setting of absent glucagon responses) of the syndrome of defective glucose cou nterregulation. While perhaps seemingly adaptive, these threshold shif ts appear to be maladaptive since both defective glucose counterregula tion and hypoglycemia unawareness are associated with substantially in creased rates of severe iatrogenic hypoglycemia in people with IDDM.