Beta-cell-mediated signaling predominates over direct alpha-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 alpha-cell signaling in the regulation of glucagon secretion in humans.


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 1 diabetes and 20 nondiabetic, demonstrably beta-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 pmol/l (103 +/- 7 pg/ml) in the patients with type 1 diabetes but were unchanged from 27 +/- 1 pmol/l (93 +/- 3 pg/ml) to 26 +/- 1 pmol/l (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 1 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.
Cooperberg
Benjamin A
BA
Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, USA.
Cryer
Philip E
PE
D002096:C-Peptide / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy; D004435:Eating; D004837:Epinephrine / Q000097:blood; D005215:Fasting; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005934:Glucagon / Q000097:blood / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism* / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D012016:Reference Values; D015398:Signal Transduction; D013453:Sulfonylurea Compounds / Q000627:therapeutic use
D002096:C-Peptide; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; C057619:glimepiride; D005934:Glucagon; D004837:Epinephrine