Palmitate stimulation of glucagon secretion in mouse pancreatic alpha-cells results from activation of L-type calcium channels and elevation of cytoplasmic calcium.
We have investigated the short-term effects of the saturated free fatty acid (FFA) palmitate on pancreatic alpha-cells. Palmitate (0.5 or 1 mmol/l bound to fatty acid-free albumin) stimulated glucagon secretion from intact mouse islets 1.5- to 2-fold when added in the presence of 1-15 mmol/l glucose. Palmitate remained stimulatory in islets depolarized with 30 mmol/l extracellular K(+) or exposed to forskolin, but it did not remain stimulatory after treatment with isradipine or triacsin C. The stimulatory action of palmitate on secretion correlated with a 3.5-fold elevation of intracellular free Ca(2+) when applied in the presence of 15 mmol/l glucose, a 40% stimulation of exocytosis (measured as increases in cell capacitance), and a 25% increase in whole-cell Ca(2+) current. The latter effect was abolished by isradipine, suggesting that palmitate selectively modulates l-type Ca(2+) channels. The effect of palmitate on exocytosis was not mediated by palmitoyl-CoA, and intracellular application of this FFA metabolite decreased rather than enhanced Ca(2+)-induced exocytosis. The stimulatory effects of palmitate on glucagon secretion were paralleled by a approximately 50% inhibition of somatostatin release. We conclude that palmitate increases alpha-cell exocytosis principally by enhanced Ca(2+) entry via l-type Ca(2+) channels and, possibly, relief from paracrine inhibition by somatostatin released by neighboring delta-cells.
Olofsson
Charlotta S
CS
Department of Physiological Sciences, Lund University, Sweden. charlotta.olofsson@mphy.lu.se.
Salehi
Albert
A
Göpel
Sven O
SO
Holm
Cecilia
C
Rorsman
Patrik
P
D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D005934:Glucagon / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D017275:Isradipine / Q000494:pharmacology; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D019308:Palmitic Acid / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D014226:Triazenes / Q000494:pharmacology
D014226:Triazenes; D005576:Colforsin; D019308:Palmitic Acid; C034613:triacsin C; D005934:Glucagon; D003981:Diazoxide; D011188:Potassium; D017275:Isradipine