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OBJECTIVE-The physiology of counterregulatory responses during hypoglycemia in intensively treated type 2 diabetic subjects is largely unknown. Therefore, the specific aims of the study tested the hypothesis that 1) 6 months of intensive therapy to lower AlC <7.0% would blunt autonomic nervous system (ANS) responses to hypoglycemia, and 2) antecedent hypoglycemia will result in counterregulatory failure during subsequent hypoglycemia in patients with suboptimal and good glycemic control.
RESEARCH DESIGN AND METHODS-Fifteen type 2 diabetic patients (8 men/7 women) underwent 6-month combination therapy of metformin, glipizide XL, and acarbose to lower AlC to 6.7% and 2-day repeated hypoglycemic clamp studies before and after intensive therapy. A control group of eight nondiabetic subjects participated in a single 2-day repeated hypoglycemic clamp study.
RESULTS-Six-month therapy reduced AlC from 10.2 ± 0.5 to 6.7 ± 0.3%. Rates of hypoglycemia increased to 3.2 episodes per patient/month by study end. Hypoglycemia (3.3 ±0.1 mmol/1) and insulinemia (1,722 i 198 pmol/1) were similar during all clamp studies. Intensive therapy reduced (P < 0.05) ANS and metabolic counterregulatory responses during hypoglycemia. Antecedent hypoglycemia produced widespread blunting (P < 0.05) of neuroendocrine, ANS, and metabolic counterregulatory responses during subsequent hypoglycemia before and after intensive therapy in type 2 diabetic patients and in nondiabetic control subjects.
CONCLUSIONS-Intensive oral combination therapy and antecedent hypoglycemia both blunt physiological defenses against subsequent hypoglycemia in type 2 diabetes. Prior hypoglycemia of only 3.3 ±0.1 mmol/1 can result in counterregulatory failure in type 2 diabetic patients with suboptimal control and can further impair physiological defenses against hypoglycemia in intensively treated type 2 diabetes. Diabetes 58:701-709, 2009
Large randomized controlled multicenter clinical trials have demonstrated the benefit of improved glycemic control on microvascular complications in both type 1 and type 2 diabetes (1,2). These compelling data have produced a paradigm shift in the treatment of diabetes (particularly type 2 diabetes) striving for AlC values <7.0% (3). The major drawbacks of tight metabolic control in patients with type 1 diabetes are well documented and include increased hypoglycemia and weight gain (4-8).
Recently, three large studies have investigated the effects of rigorous metabolic control (AlC <7.0%) on the prevalence of macrovascular disease in type 2 diabetes (9-11). The overall conclusion of these studies was that AlC values <7.0% did not produce a...