Intensive Therapy Compromises Regulatory Response to Hypoglycemia in Diabetics

According to a recent study, both intensive oral combination therapy and antecedent hypoglycemia blunt the body’s physiological defenses against later hypoglycemia in people with Type 2 diabetes.

The study’s objective was to better understand the physiology of counterregulatory responses during hypoglycemia in patients whose Type 2 diabetes was intensively treated.

The study participants, 8 men and 7 women with Type 2 diabetes, underwent a 6-month course of intensive therapy with oral metformin, glipizide XL and acarbose. The goal was to tightly control their blood glucose and so keep their glycosylated hemoglobin (A1c) levels under 7.0%.

In addition, each diabetic participant underwent two in-hospital “hypoglycemic experiments:” one at the beginning and one at the end of the 6-month trial. In these experiments, after an overnight 10-hour fast, each participant was brought into three approximately 2-hour hypoglycemic periods, including a blood glucose nadir of 3.3 mmol/L, using a modified glucose clamp technique.

Extrapolating from studies published since 2005, the researchers, led by Dr. Stephen N. Davis, theorized that the intensive course of treatment, along with the hypoglycemic experiments, would impair the body’s homeostatic counterregulatory responses to hypoglycemia.

During the 6 months of intensive therapy, average A1c levels were reduced from 10.2% to 6.7%, with average body weight remaining stable.

Based on neuroendocrine responses, intermediary metabolism, muscle sympathetic nerve activity, hypoglycemia symptoms, cardiovascular responses and other factors, the researchers concluded that “intensive treatment with oral combination therapy substantially reduces” both autonomic nervous system and metabolic symptoms and cardiovascular responses to hypoglycemia.

More specifically, the counterregulatory hormone epinephrine was reduced by about 50% and muscle sympathetic nerve activity was reduced by about 66%. Overall, both central sensing of hypoglycemia and end-organ responses were reduced by the intensive therapy. By the end of the study, the near normalization of A1c levels resulted in an increased monthly frequency of hypoglycemic episodes among the participants.

In addition, the authors found that antecedent hypoglycemia is capable of producing “further widespread (i.e., neuroendocrine) reductions in the above physiological counterregulatory mechanisms in Type 2 diabetic patients both before and after intensive therapy.”

This finding “further reinforces,” the researchers wrote, “the therapeutic goal of achieving good glycemic control while minimizing the occurrence of any hypoglycemia.”

Diabetes March, 2009;58:701-709.