GLUCOSE COUNTERREGULATION - PREVENTION AND CORRECTION OF HYPOGLYCEMIA IN HUMANS

The prevention or correction of hypoglycemia in humans is the result of both dissipation of insulin and activation of glucose counterregulatory (glucose-raising) systems. Whereas insulin is the dominant glucose-lowering factor, there are redundant glucose counterregulatory factors. Furthermore, there is a hierarchy among the glucoregulatory factors. The first defense against a decrement in plasma glucose is decreased insulin secretion; this occurs with glucose decrements within the physiological range at a glycemic threshold of 4.6 +/- 0.2 mmol/l. However, biological glucose recovery from hypoglycemia can occur despite mild (approximately 2-fold) peripheral hyperinsulinemia and can occur in the absence of portal hypoinsulinemia. Thus additional (glucose counterregulatory) factors must be involved. Critical glucose counterregulatory systems are activated at glycemic thresholds of approximately 3.8 mmol/l (the level at which brain glucose uptake is first (measurably reduced), well above the thresholds for symptoms of hypoglycemia approximately 3.0 mmol/l) and those for cognitive dysfunction resulting from neuroglycopenia (approximately 2.7 mmol/l). Among the glucose counterregulatory factors, glucagon plays a primary role. Indeed, it may be that hypoglycemia does not occur if the secretion and actions of both glucagon and insulin, among the glucoregulatory hormones, are normal. Epinephrine is not normally critical, but it becomes critical to glucose counterregulation when glucagon is deficient. Because hypoglycemia develops or progresses when both glucagon and epinephrine are deficient and insulin is present, these three hormones stand high in the hierarchy of redundant glucoregulatory factors. Other factors, such as growth hormone and cortisol in defense against prolonged hypoglycemia, are known to be involved, glucose autoregulation may be operative during severe hypoglycemia, and fatty acid elevations appear to mediate, in part, the effects of epinephrine. Other hormones, neurotransmitters, or other metabolic substrate effects may also be shown to be involved. Nonetheless, all of these latter factors must stand low in the hierarchy of redundant glucose counterregulatory factors since, despite their actions, hypoglycemia develops or progresses when both glucagon and epinephrine are deficient and insulin is present.