Role of the decrement in intraislet insulin for the glucagon response to hypoglycemia in humans

OBJECTIVE - Animal and in vitro studies indicate that a decrease in [I-cell insulin secretion, and thus a decrease in ionic alpha-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 stilt 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 -60 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 (similar to 2.6 mmol/l) and insulin levels (similar to 570 pmol/l) were comparable in both Sets of experiments (both P > 0.4). In the saline experiments, insulin secretion remained unchanged from baseline (-90 to -60 min) before insulin infusion and decreased from 1.20 +/- 0.12 to 0.16 +/- 0.04 pmol (.) kg(-1) (.) min(-1) during insulin infusion (P < 0.001). However, in the somatostatin experiments, insulin secretion decreased from 1.18 +/- 012 pmol (.) kg(-1) (.) min(-1) at baseline to 0.25 +/- 0.09 pmol (.) kg(-1) (.) min(-1) before insulin infusion so that it did not decrease further during insulin infusion (-0.12 +/- 0.10 pmol (.) k(-1) (.) 0.26) indicating the Complete lack of a decrement in intraislet insulin during hypoglycemia. This was associated with similar to 30% lower plasma glucagon concentrations (109 +/- 7 vs 136 +/- 9 pg/ml, P < 0.006) and increments in plasma glucagon above baseline (41 +/- 8 vs. 67 +/- 11 pg/ml, P < 0.008) during the last 15 min of the hypoglycemic clamp. In contrast, increases in plasma growth hormone were -70% greater during hypoglycernia alter somaLostatin infusion (P < 0.007), suggesting that to some extent the increases in plasma gfucagon 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 inLraislet insulin accounts for the glucagon responses to hypoglycernia remains to be established.