Antecedent hypoglycemia impairs autonomic cardiovascular function - implications for rigorous glycemic control

Objective: Glycemic control decreases the incidence and progression of diabetic complications, but increases the incidence of hypoglycemia. Hypoglycemia can impair hormonal and autonomic responses to subsequent hypoglycemia. Intensive glycemic control may increase mortality in individuals with type 2 diabetes at high risk for cardiovascular complications. We tested the hypothesis that prior exposure to hypoglycemia leads to impaired cardiovascular autonomic function. Research Design and Methods: Twenty healthy subjects (age 28±2 years; 10 males) participated in two 3-day in-patient visits, separated by 1-3 months. Autonomic testing was performed on days 1 and 3 to measure sympathetic, parasympathetic and baroreflex function. A 2 hour hyperinsulinemic [hypoglycemic (2.8 mmol/l) or euglycemic (5.0 mmol/l)] clamp was performed in both the morning and afternoon of day 2. Results: Comparison of the day 3 autonomic measurements demonstrated that antecedent hypoglycemia leads to: (1) reduced baroreflex sensitivity (16.7±1.8 vs. 13.8±1.4 ms/mmHg, P=0.03); (2) decreased muscle sympathetic nerve activity response to transient nitroprussideinduced hypotension (53.3±3.7 vs. 40.1±2.7 bursts/minute, P<0.01); and (3) reduced (P<0.001) plasma norepinephrine response to lower body negative pressure (3.0±0.3 vs. 2.0±0.2 nmol/l at 40 mmHg). Conclusions: Baroreflex sensitivity and the sympathetic response to hypotensive stress are attenuated following antecedent hypoglycemia. Because impaired autonomic function, including decreased cardiac vagal baroreflex sensitivity, may contribute directly to mortality in diabetes and cardiovascular disease, our findings raise new concerns regarding the consequences of hypoglycemia.