Attenuated Sympathoadrenal Responses, but Not Severe Hypoglycemia, During Aggressive Glycemic Therapy of Early Type 2 Diabetes

Iatrogenic hypoglycemia is a major limiting factor in the strict glycemic management of diabetes (1,2). Hypoglycemia can cause recurrent morbidity in many people with type 1 diabetes and also in some with advanced type 2 diabetes (2,3). Rarely fatal, fear of hypoglycemia precludes maintenance of euglycemia over a lifetime with diabetes and full realization of the vascular benefits of glycemic control. Hypoglycemic events compromise defenses against subsequent falling plasma glucose concentrations and thus cause a vicious cycle of recurrent hypoglycemia.

Hypoglycemia in diabetes is fundamentally the result of episodes of therapeutic hyperinsulinemia caused by treatment with an insulin secretagogue or insulin. In general, the incidence of iatrogenic hypoglycemia is a function of the degree of β-cell failure (1,2,4), and risk is predicted by the absence of evidence of endogenous insulin secretion (C-peptide) (5). Incidence of hypoglycemia is lower in people with type 2 diabetes, who are not usually completely insulin deficient, than in those with type 1 diabetes, and this is especially true early in the course of type 2 diabetes. However, the incidence of hypoglycemia increases progressively over time (6), ultimately approximating that in those with type 1 diabetes (7,8), as type 2 diabetic individuals approach the insulin-deficient end of the spectrum. Because type 2 diabetes is ∼20-fold more prevalent than type 1 diabetes and many people with type 2 diabetes ultimately require treatment with insulin, most episodes of iatrogenic hypoglycemia, including severe hypoglycemia, occur in those with type 2 diabetes (1–3,9).

The key physiological defenses against falling plasma glucose concentrations are 1) a decrease in insulin secretion; 2) an increase in glucagon secretion; and, in the absence of the latter, 3 …