OBJECTIVE -Animal and in vitro studies indicate that a decrease in -cell insulin secretion, and thus a decrease in tonic ␣-cell inhibition by intraislet insulin, may be an important factor for the increase in glucagon secretion during hypoglycemia. However, in humans this role of decreased intraislet insulin is still unclear.
RESEARCH DESIGN AND METHODS-We studied glucagon responses to hypoglycemia in 14 nondiabetic subjects on two separate occasions. On both occasions, insulin was infused from 0 to 120 min to induce hypoglycemia. On one occasion, somatostatin was infused from Ϫ60 to 60 min to suppress insulin secretion, so that the decrement in intraislet insulin during the final 60 min of hypoglycemia would be reduced. On the other occasion, subjects received an infusion of normal saline instead of the somatostatin.RESULTS -During the 2nd h of the insulin infusion, when somatostatin or saline was no longer being infused, plasma glucose (ϳ2.6 mmol/l) and insulin levels (ϳ570 pmol/l) were comparable in both sets of experiments (both P Ͼ 0.4). In the saline experiments, insulin secretion remained unchanged from baseline (Ϫ90 to Ϫ60 min) before insulin infusion and decreased from 1.20 Ϯ 0.12 to 0.16 Ϯ 0.04 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 during insulin infusion (P Ͻ 0.001). However, in the somatostatin experiments, insulin secretion decreased from 1.18 Ϯ 0.12 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 at baseline to 0.25 Ϯ 0.09 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 before insulin infusion so that it did not decrease further during insulin infusion (Ϫ0.12 Ϯ 0.10 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 , P ϭ 0.26) indicating the complete lack of a decrement in intraislet insulin during hypoglycemia. This was associated with ϳ30% lower plasma glucagon concentrations (109 Ϯ 7 vs. 136 Ϯ 9 pg/ml, P Ͻ 0.006) and increments in plasma glucagon above baseline (41 Ϯ 8 vs. 67 Ϯ 11 pg/ml, P Ͻ 0.008) during the last 15 min of the hypoglycemic clamp. In contrast, increases in plasma growth hormone were ϳ70% greater during hypoglycemia after somatostatin infusion (P Ͻ 0.007), suggesting that to some extent the increases in plasma glucagon might have reflected a rebound in glucagon secretion.CONCLUSIONS -These results provide direct support for the intraislet insulin hypothesis in humans. However, the exact extent to which a decrement in intraislet insulin accounts for the glucagon responses to hypoglycemia remains to be established.
Diabetes Care 28:1124 -1131, 2005D efense against hypoglycemia normally involves inhibition of endogenous insulin secretion and increased release of several counterregulatory hormones, of which glucagon is considered to be most important (1,2). Epinephrine responses, although normally not critical for the defense against hypoglycemia, become critical when glucagon secretion is deficient (1,2). In type 1 diabetes, glucagon responses to hypoglycemia are universally lost early in the course of the disease (3). This abnormality therefore plays a key role in the development of defective glucose counterregulation when patients subsequently develop reduced epinephrine re...