Mechanisms of octanoic acid potentiation of insulin secretion in isolated islets

Abstract

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 β-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 Ca 2+ dependent and is often accompanied by β-cell membrane potential depolarization, and may also involve the Ca 2+ /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 Ca 2+ increase in Sur1-/islets.

Dietary medium-chain fatty acids reduce food intake via the GDF15-GFRAL axis in mice

“…Notably, we observed an acute glucose-lowering effect of MCTs accompanied by increased insulin levels. Unraveling the mechanism behind MCFA-induced insulin secretion is a subject of future interest, which may involve direct effects on pancreatic cells [ 49 , 50 ] or indirect effects via gut-derived incretins in the portal vein.…”

Changes in the gut microbiota of NOD mice in response to an oral Salmonella-based vaccine against type 1 diabetes

“…Herein, we found that vaccinated mice had decreased succinic acid (butanedioic acid). Medium and long chain unsaturated fatty acids such as azelaic, linoleic, oleic, octanoic, and pentadecanoic acid promote insulin secretion [67][68][69][70]. Also, these SFAs (succinic, palmitic, oleic, linoleic acids) were indirectly regulated by MYC (S6C Fig) . Of note, inhibiting the medium and long chain fatty acid β-cell receptor (GPR40) impaired insulin secretion [71].…”