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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 men) participated in two 3-day inpatient visits, separated by 1-3 months. Autonomic testing was performed on days 1 and 3 to measure sympathetic, parasympathetic, and baroreflex function. A 2-h hyperinsulinemic [hypoglycemic (2.8 mmol/l) or euglycemic (5.0 mmol/l)] clamp was performed in the morning and in the 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 nitroprusside-induced hypotension (53.3 ± 3.7 vs. 40.1 ± 2.7 bursts/min, 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/1 at -40 mmHg).
CONCLUSIONS-Baroreflex sensitivity and the sympathetic response to hypotensive stress are attenuated after 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. Diabetes 58:360-366, 2009
Control of blood glucose is the cornerstone of diabetes management because glycemic control decreases the incidence and progression of diabetic microvascular (1-4) and, in some studies, macrovascular complications (2,5). However, rigorous glycemic control leads to an increased incidence of hypoglycemia (1,6). Even a single episode of hypoglycemia may impair the counterregulatory metabolic and autonomic responses to subsequent hypoglycemia (7). Recently, evidence has emerged suggesting an association between hypoglycemia and increased mortality in critically ill patients receiving insulin therapy (8). An increase in mortality was also observed in the highly intensive treated limb (targeting AlC values of <6%) of a multicenter clinical trial of individuals with type 2 diabetes at high risk for cardiovascular disease events (9). The cause of the mortality in these studies could not be directly attributed to hypoglycemia.