β-Cell-Mediated Signaling Predominates Over Direct α-Cell Signaling in the Regulation of Glucagon Secretion in Humans

OBJECTIVE - Given evidence of both indirect and direct signaling, we tested the hypothesis that increased beta-cell-mediated signaling of alpha-cells negates direct a-cell signaling in the regulation of glucagon secretion in humans. RESEARCH DESIGN AND METHODS - We measured plasma glucagon concentrations before and after ingestion of a formula mixed meal and, on a separate occasion, ingestion of the sulfonylurea glimepiride in 24 basal insulin-infused, demonstrably beta-cell-deficient patients With type I diabetes and 20 nondiabetic, demonstrably P-cell-sufficient individuals; the latter were infused with glucose to prevent hypoglycemia after glimepiride. RESULTS - After the mixed meal, plasma glucagon concentrations increased from 22 +/- 1 pmol/l (78 +/- 4 pg/ml) to 30 +/- 2 pmolA (103 +/- 7 pg/ml) in the patients with type 1 diabetes but were unchanged from 27 I pmol/l (93 - 3 pg/ml) to 26 - I pmolA (89 +/- 3 pg/ml) in the nondiabetic individuals (P < 0.0001). After glimepiride, plasma glucagon concentrations increased from 24 +/- 1. pmol/l (83 +/- 4 pg/ml) to 26 +/- 1 pmol/l (91 +/- 4 pg/ml) in the patients with type I diabetes and decreased from 28 +/- 1 pmol/l (97 +/- 5 pg/ml) to 24 +/- 1 pmol/l (82 +/- 4 pg/ml) in the nondiabetic individuals (P < 0.0001). Thus, in the presence of both beta-cell and alpha-cell secretory stimuli (increased amino acid and glucose levels, a sulfonylurea) glucagon secretion was prevented when beta-cell secretion was sufficient but not when beta-cell secretion was deficient. CONCLUSIONS - These data indicate that, among the array of signals, indirect reciprocal beta-cell-mediated signaling predominates over direct alpha-cell signaling in the regulation of glucagon secretion in humans.