Elimination of Hypoglycemia From the Lives of People Affected by Diabetes

  1. Philip E. Cryer
  1. From the Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri.
  1. Corresponding author: Philip E. Cryer, pcryer{at}

Iatrogenic hypoglycemia is a problem for people affected by diabetes (1). It causes recurrent morbidity in most people with type 1 diabetes and many with advanced type 2 diabetes, and it is sometimes fatal. It generally precludes maintenance of euglycemia over a lifetime of diabetes and thus full realization of the vascular benefits of glycemic control. And, it compromises defenses against subsequent falling plasma glucose concentrations and therefore causes a vicious cycle of recurrent hypoglycemia.

Hypoglycemia in diabetes is fundamentally iatrogenic, the result of therapeutic hyperinsulinemia caused by treatment with a sulfonylurea, a glinide, or insulin. But because of the effectiveness of the normal glucose counterregulatory mechanisms, hypoglycemia is typically the result of the interplay of therapeutic hyperinsulinemia and compromised physiological and behavioral defenses against falling plasma glucose concentrations in people with diabetes (1).

The compromised physiological defenses include loss of the normal decrements in insulin, increments in glucagon, and increments in epinephrine as glucose levels fall in absolute endogenous insulin deficient diabetes (1). Loss of decrements in insulin and of increments in glucagon develop early in people with type 1 diabetes but only later in people with type 2 diabetes. In view of increasing evidence that β-cell insulin secretion normally restrains α-cell glucagon secretion (2) and that a decrease in insulin normally signals an increase in glucagon secretion during hypoglycemia (3), loss of both the insulin and the glucagon responses is plausibly attributable to β-cell failure (1). That construct fits nicely with the fact that iatrogenic hypoglycemia becomes a major problem early in people with type 1 diabetes but only later in people with type 2 diabetes (1). Given the evidence that insulin also acts on the hypothalamus to restrain glucagon secretion, there may also be a central nervous system component to the loss of the glucagon response …

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