Journal
ISLETS
Volume 11, Issue 4, Pages 77-88Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/19382014.2019.1566683
Keywords
Octanoic acid; insulin secretion; islets; volume-sensitive anion channels
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Funding
- NIDDK NIH HHS [R37 DK056268, R01 DK098517, P30 DK019525] Funding Source: Medline
- NIGMS NIH HHS [R01 GM121375] Funding Source: Medline
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A potentiating effect of medium-chain triglycerides on glucose-stimulated insulin secretion (GSIS) has been observed since the 1960s. Subsequent observations identified octanoic acid (OA), the main component of medium-chain triglyceride, as the potentiator of GSIS, but the mechanism was unclear. We used wild-type (WT), short-chain 3-hydroxyacyl-CoA dehydrogenase knockout (Hadh(-/-)), and sulfonylurea receptor 1 knockout (Sur1(-/-)) mouse islets to define the mechanism of OA potentiation of insulin secretion. Application of OA alone induced a 2- to 3- fold increase of insulin secretion with an apparent threshold of 3 mM in WT mouse islets, suggesting that OA itself is a weak insulin secretagogue. However, OA at 1 mM strongly potentiated fuel-stimulated insulin secretion, especially GSIS. The potentiating effect on fuel-stimulated insulin secretion by OA did not require fatty acid beta-oxidation because OA also potentiated amino acid-stimulated insulin secretion in islets isolated from Hadh(-/-) mice, which cannot fully oxidize OA. Measurements using Sur1(-/-) islets indicated that the potentiating effect of OA on fuel-stimulated insulin secretion is Ca2+ dependent and is often accompanied by beta-cell membrane potential depolarization, and may also involve the Ca2+/calmodulin complex. Experiments using DCPIB, an ethacrynic acid derivative, to inhibit volume-sensitive anion channels (VSACs) in Sur1(-/-) islets demonstrated that the potentiation effects of OA on insulin secretion are in part medicated by activation of VSAC. In addition, inhibition of IP3 receptor also abolishes the OA-induced intracellular Ca2+ increase in Sur1(-/-) islets.
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