OBJECTIVE To determine the effects of glycemic control on the counterregulatory responses to hypoglycemia in type 2 diabetes.

RESEARCH DESIGN AND METHODS Seven poorly controlled type 2 diabetes patients (mean HbA_1c, 11.3 ± 1.1%) were studied by stepped hyperinsulinemic hypoglycemic clamp (nadir, 2.4 mmol/1) before and after improving glycemic control with insulin treatment. Counterregulatory hormones, symptoms, and four-choice reaction time were measured at each glucose plateau.

RESULTS In patients with poorly controlled type 2 diabetes, counterregulatory hormone responses began at higher plasma glucose levels than did those in healthy subjects (epinephrine, 4.4 ± 0.2 vs. 3.7 ± 0.2 mmol/1, P = 0.011). After significant improvement in glycemic control (mean HbA_1c, 8.1 ± 0.9%, P < 0.001) was achieved without severe hypoglycemia, hormonal responses started at much lower plasma glucose levels (e.g., epinephrine, 3.5 ± 0.3 mmol/1, P = 0.005) and were significantly reduced in magnitude (e.g., area under epinephrine response curve, 306 ± 93 vs. 690 ± 107 nmol · min⁻¹ · l⁻¹, P = 0.012). This was accompanied by a change in the plasma glucose threshold at which hypoglycemic symptoms first developed from 3.6 ± 0.2 to 3.0 ± 0.2 mmol/1 (P = 0.019). In contrast, the plasma glucose threshold at which four-choice reaction time deteriorated did not change significantly (3.1 ±0.1 vs. 2.9 ± 0.1 mmol/1, P = 0.125).

CONCLUSIONS Counterregulatory responses begin at normoglycemia in poorly controlled type 2 diabetes. Improving glycemic control with insulin therapy normalizes hormonal responses but lowers the plasma glucose levels at which hypoglycemic symptoms develop to levels associated with impairment of four-choice reaction time, a marker of cognitive function. This process potentially increases the risk of severe hypoglycemia, but to a lesser extent than occurs in type 1 disease.