The Effects of Intensive Therapy and Antecedent Hypoglycemia on Counterregulatory Responses to Hypoglycemia in Type 2 Diabetes

Abstract

Objective: The physiology of counterregulatory responses during hypoglycemia in intensively treated Type 2 DM subjects is largely unknown. Therefore, the specific aims of the study tested the hypothesis that 1) 6 months of intensive therapy to lower HBA_1C below 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 DM (8M/7F) underwent 6 month combination therapy of metformin, glipizide XL and acarbose to lower HBA_1C to 6.7% and 2-day repeated hypoglycemic clamp studies before and after intensive therapy. A control group of eight non-diabetic subjects participated in a single 2-day repeated hypoglycemic clamp study.

Results: Six months therapy reduced HBA_1C 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/L) and insulinemia (1722±198 pmol/L) 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 DM patients and in non-diabetic controls.

Conclusion: Intensive oral combination therapy and antecedent hypoglycemia both blunt physiologic defenses against subsequent hypoglycemia in Type 2 DM. Prior hypoglycemia of only 3.3±0.1 mmol/L can result in counterregulatory failure in Type 2 DM patients with suboptimal control and can further impair physiologic defenses against hypoglycemia in intensively treated Type 2 DM.