Inhibition of lipase activity and lipolysis in rat islets reduces insulin secretion.
Lipids may serve as coupling factors in K(ATP)-independent glucose sensing in beta-cells. We have previously demonstrated that beta-cells harbor lipase activities, one of which is the hormone-sensitive lipase. Whether beta-cell lipases are critical for glucose-stimulated insulin secretion (GSIS) by providing lipid-derived signals from endogenous lipids is unknown. Therefore, using a lipase inhibitor (orlistat), we examined whether lipase inhibition reduces insulin secretion. Islet lipolysis stimulated by glucose and diglyceride lipase activity was abolished by orlistat. Incubation of rat islets with orlistat dose dependently inhibited GSIS; this inhibition was reversed by 1 mmol/l palmitate, suggesting that orlistat acts via impaired formation of an acylglyceride-derived coupling signal. Orlistat inhibited the potentiating effect of forskolin on GSIS, an effect proposed to be due to activation of a lipase. In perifused islets, orlistat attenuated mainly the second phase of insulin secretion. Because the rise in islet ATP/ADP levels in response to glucose and oxidation of the sugar were unaffected by orlistat whereas the second phase of insulin secretion was reduced, it seems likely that a lipid coupling factor involved in K(ATP)-independent glucose sensing has been perturbed. Thus, beta-cell lipase activity is involved in GSIS, emphasizing the important role of beta-cell lipid metabolism for insulin secretion.
Mulder
Hindrik
H
Department of Cell and Molecular Biology, Lund University, Lund, Sweden. hindrik.muldur@medkem.lu.se
Yang
Shumin
S
Winzell
Maria Sörhede
MS
Holm
Cecilia
C
Ahrén
Bo
B
D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D007700:Kinetics; D007783:Lactones / Q000494:pharmacology; D008049:Lipase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008066:Lipolysis / Q000502:physiology*; D008071:Lipoprotein Lipase / Q000378:metabolism; D000077403:Orlistat; D010477:Perfusion; D051381:Rats
D007328:Insulin; D007783:Lactones; D005576:Colforsin; D000077403:Orlistat; D008049:Lipase; D008071:Lipoprotein Lipase