Glucagon-like peptide 1 stimulates lipolysis in clonal pancreatic beta-cells (HIT).
Glucagon-like peptide 1 (GLP-1) is the most potent physiological incretin for insulin secretion from the pancreatic beta-cell, but its mechanism of action has not been established. It interacts with specific cell-surface receptors, generates cAMP, and thereby activates protein kinase A (PKA). Many changes in pancreatic beta-cell function have been attributed to PKA activation, but the contribution of each one to the secretory response is unknown. We show here for the first time that GLP-1 rapidly released free fatty acids (FFAs) from cellular stores, thereby lowering intracellular pH (pHi) and stimulating FFA oxidation in clonal beta-cells (HIT). Similar changes were observed with forskolin, suggesting that stimulation of lipolysis was a function of PKA activation in beta-cells. Triacsin C, which inhibits the conversion of FFAs to long-chain acyl CoA (LC-CoA), enhanced basal FFA efflux as well as GLP-1-induced acidification and efflux of FFAs from the cell. Increasing the concentration of the lipase inhibitor orlistat progressively and largely diminished the increment in secretion caused by forskolin. However, glucose-stimulated secretion was less inhibited by orlistat and only at the highest concentration tested. Because the acute addition of FFAs also increases glucose-stimulated insulin secretion, these data suggest that the incretin function of GLP-1 may involve a major role for lipolysis in cAMP-mediated potentiation of secretion.
Yaney
G C
GC
Evans Department of Medicine, Boston Medical Center, Massachusetts 02118, USA.
Civelek
V N
VN
Richard
A M
AM
Dillon
J S
JS
Deeney
J T
JT
Hamilton
J A
JA
Korchak
H M
HM
Tornheim
K
K
Corkey
B E
BE
Boyd
A E
AE
D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides; D006863:Hydrogen-Ion Concentration; D007425:Intracellular Membranes / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D007783:Lactones / Q000494:pharmacology; D008049:Lipase / Q000037:antagonists & inhibitors; D008066:Lipolysis / Q000187:drug effects*; D000077403:Orlistat; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011498:Protein Precursors / Q000494:pharmacology*; D002787:Sterol Esterase / Q000378:metabolism
D004791:Enzyme Inhibitors; D007783:Lactones; D010446:Peptide Fragments; D011498:Protein Precursors; C055453:glucagon-like peptide 1 (7-36)amide; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077403:Orlistat; D002787:Sterol Esterase; D008049:Lipase; D002118:Calcium