OBJECTIVE—In advanced β-cell failure, counterregulatory glucagon responses may be impaired due to a reduced decrement in insulin secretion during the development of hypoglycemia. The present studies were therefore undertaken to test the hypothesis that these may be improved by increasing this decrement in insulin secretion.

RESEARCH DESIGN AND METHODS—Twelve subjects with type 2 diabetes who have been insulin requiring were studied as a model of advanced β-cell failure. Glucagon responses were examined during a 90-min hypoglycemic clamp (∼2.8 mmol/l) on two separate occasions. On one occasion, tolbutamide was infused for 2 h before the clamp so that the decrement in insulin secretion during the induction of hypoglycemia would be increased. On the other occasion, normal saline was infused as a control.

RESULTS—Before the hypoglycemic clamp, infusion of tolbutamide increased insulin secretion ∼1.9-fold (P < 0.001). However, during hypoglycemia, insulin secretion decreased to similar rates on both occasions (P = 0.31) so that its decrement was approximately twofold greater following the tolbutamide infusion (1.63 ± 0.20 vs. 0.81 ± 0.17 pmol · kg⁻¹ · min⁻¹, P < 0.001). This was associated with more than twofold-greater glucagon responses (42 ± 11 vs. 19 ± 8 ng/l, P < 0.002) during the hypoglycemic clamp but unaltered glucagon responses to intravenous arginine immediately thereafter (449 ± 50 vs. 453 ± 50 ng/l, P = 0.78).

CONCLUSIONS—Increasing the decrement in insulin secretion during the development of hypoglycemia improves counterregulatory glucagon responses in advanced β-cell failure. These findings further support the concept that the impaired counterregulatory glucagon responses in advanced β-cell failure may at least partially be due to a reduced decrement in insulin secretion.