Fatty acids stimulate insulin secretion from human pancreatic islets at fasting glucose concentrations via mitochondria-dependent and -independent mechanisms

Abstract

BackgroundFree fatty acids (FFAs) acutely stimulate insulin secretion from pancreatic islets. Conflicting results have been presented regarding this effect at non-stimulatory glucose concentration, however. The aim of our study was to investigate how long-chain FFAs affect insulin secretion from isolated human pancreatic islets in the presence of physiologically fasting glucose concentrations and to explore the contribution of mitochondria to the effects on secretion.MethodsInsulin secretion from human pancreatic islets was measured from short-term static incubation or perfusion system at fasting glucose concentration (5.5 mM) with or without 4 different FFAs (palmitate, palmitoleate, stearate, and oleate). The contribution of mitochondrial metabolism to the effects of fatty acid-stimulated insulin secretion was explored.ResultsThe average increase in insulin secretion, measured from statically incubated and dynamically perifused human islets, was about 2-fold for saturated free fatty acids (SFAs) (palmitate and stearate) and 3-fold for mono-unsaturated free fatty acids (MUFAs) (palmitoleate and oleate) compared with 5.5 mmol/l glucose alone. Accordingly, MUFAs induced 50 % and SFAs 20 % higher levels of oxygen consumption compared with islets exposed to 5.5 mmol/l glucose alone. The effect was due to increased glycolysis. When glucose was omitted from the medium, addition of the FFAs did not affect oxygen consumption. However, the FFAs still stimulated insulin secretion from the islets although secretion was more than halved. The mitochondria-independent action was via fatty acid metabolism and FFAR1/GPR40 signaling.ConclusionsThe findings suggest that long-chain FFAs acutely induce insulin secretion from human islets at physiologically fasting glucose concentrations, with MUFAs being more potent than SFAs, and that this effect is associated with increased glycolytic flux and mitochondrial respiration.

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

“…7,8 While both the chain length and saturation of FA affect the potency of the stimulation, palmitic acids (16:0, PA) and oleic acids (18:1, OA), two FA abundant in the circulation and cells, are both potent stimulators of GSIS. 9,10 The augmentation of GSIS by FA is partially mediated by the activation of the cell surface FFA1/GPR40 receptor (FFAR1). 6 In addition, intracellular metabolism of FA in beta cells is considered to generate metabolic coupling factors (MCF) that contribute to insulin secretion.…”

“…Although the concept of lipotoxicity was originally proposed over 20 years ago, a sequence of events that initiates beta cell dysfunction and drives progressive doi: 10.1111/nyas.14037 beta cell failure in human T2D remains poorly defined. We discuss recent advances in the understanding of molecular mechanisms by which FA support insulin secretion through receptor-and cell-mediated pathways.…”

Mechanisms of beneficial effects of metformin on fatty acid-treated human islets

“…OCR of isolated human islets was determined by Extracellular Flux Analyzer XF e 96 (Seahorse Bioscience, MA, USA) as previously reported (Cen et al 2016). Ten hand-picked human islets were placed into the wells of the XF e 96 cell culture microplate pre-coated with 3% ECM gel (Sigma-Aldrich) and 5 μg/mL fibronectin (Sigma-Aldrich).…”

Adiposity and fat metabolism during combined fasting and lactation in elephant seals

“…Circulating fatty acids stimulate β-cell insulin secretion on an acute time frame (Cen et al, 2016). Although some studies support the idea that chronically elevated NEFA impairs β cell insulin secretion, effects can vary by species, current metabolic state and genetic background (Rebelos et al, 2015;Carpentier et al, 2000;Yaney and Corkey, 2003).…”