EFFECTS OF GLYCEMIC CONTROL ON PROTECTIVE RESPONSES AGAINST HYPOGLYCEMIA IN TYPE-2 DIABETES

OBJECTIVE - To determine the effects of glycemic control on the counte rregulatory responses to hypoglycemia in type 2 diabetes. RESEARCH DES IGN AND METHODS - Seven poorly controlled type 2 diabetes patients (me an HbA(1c), 11.3 +/- 1.1%) were studied by stepped hyperinsulinemic hy poglycemic clamp (nadir, 2.4 mmol/l) before and after improving glycem ic control with insulin treatment. Counterregulatory hormones, symptom s, and four-choice reaction time were measured at each glucose plateau . RESULTS - In patients with poorly controlled type 2 diabetes, counte rregulatory hormone responses began at higher plasma glucose levels th an did those in healthy subjects (epinephrine, 4.4 +/- 0.2 vs. 3.7 +/- 0.2 mmol/l, P = 0.011). After significant improvement in glycemic con trol (mean HbA(1c), 8.1 +/- 0.9%, P < 0.001) was achieved without seve re hypoglycemia, hormonal responses started at much lower plasma gluco se levels (e.g., epinephrine, 3.5 +/- 0.3 mmol/l, P = 0.005) and were significantly reduced in magnitude (e.g., area under epinephrine respo nse curve, 306 +/- 93 vs. 690 +/- 107 nmol.min(-1).1(-1), P = 0.012). This was accompanied by a change in the plasma glucose threshold at wh ich hypoglycemic symptoms first developed from 3.6 +/- 0.2 to 3.0 +/- 0.2 mmol/l (P = 0.019). In contrast, the plasma glucose threshold at w hich four-choice reaction time deteriorated did not change significant ly (3.1 +/- 0.1 vs. 2.9 +/- 0.1 mmol/l, P = 0.125). CONCLUSIONS - Coun terregulatory responses begin at normoglycemia in poorly controlled ty pe 2 diabetes. Improving glycemic control with insulin therapy normali zes hormonal responses but lowers the plasma glucose levels at which h ypoglycemic symptoms develop to levels associated with impairment of f our-choice reaction time, a marker of cognitive function. This process potentially increases the risk of severe hypoglycemia, but to a lesse r extent than occurs in type 1 disease.