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

Abstract

Background: Free 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.

Methods: Insulin 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.

Results: The 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.

Conclusions: The 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.

Keywords: Human pancreatic islets; Insulin secretion; Mitochondrial respiration; Monounsaturated fatty acids; Saturated fatty acids.

Fig. 1

Acute effects of free fatty acids on insulin secretion at 5.5 mmol/l glucose. Human islets were incubated at 5.5 mmol/l glucose in the presence or absence of 0.5 mM palmitate (PA), palmitoleate (PAO), stearate (SA), or oleate (OA) for 20 min. a Insulin secretion from statically incubated human islets was expressed as fold secretion at control. b Representative graph of dynamic insulin secretion from perifused islets is shown. Fatty acids were added as indicated. c-e Total, first-phase, and second-phase of fatty acid-stimulated insulin secretion during perifusion was expressed as fold control. Results are means ± SEM of 8 donors. *P < 0.05 vs Control, #P < 0.05 PA vs PAO or SA vs OA

Fig. 2

Effects of free fatty acids on metabolism at 5.5 mmol/l glucose. Human islets were incubated at 5.5 mmol/l glucose in the presence or absence of palmitate (PA), palmitoleate (PAO), stearate (SA), or oleate (OA) for 40 min. a Representative graph of oxygen consumption rate (OCR) is shown. Rotenone and antimycin A were added as indicated by arrow. b and c OCR and extracellular acidification rate (ECAR) during 40 min were expressed as fold control. Results are means ± SEM of 4 donors. *P < 0.05 vs Control, #P < 0.05 PA vs PAO or SA vs OA

Fig. 3

Effects of free fatty acids on metabolism in the absence of glucose. Human islets were incubated with or without palmitate (PA), palmitoleate (PAO), stearate (SA), or oleate (OA) for 40 min in the absence of glucose. a Extracellular acidification rate (ECAR) was expressed as fold control. b Representative graph of oxygen consumption rate (OCR) is shown. Rotenone and antimycin A were added as indicated by arrow. c OCR was expressed as fold control. Results are means ± SEM of 4 donors

Fig. 4

Acute effects of free fatty acids on insulin secretion in the absence of glucose. Human islets were incubated with or without palmitate (PA), palmitoleate (PAO), stearate (SA), or oleate (OA) for 20 min in the absence of glucose. a Insulin secretion from statically incubated human islets was expressed as fold secretion at control. b Representative graph of dynamic insulin secretion from perifused islets is shown. Fatty acids were added as indicated. c-e Total, first-phase, and second-phase of fatty acid-stimulated insulin secretion during perifusion was expressed as fold control. Results are means ± SEM of 8 donors. *P < 0.05 vs control, #P < 0.05 PA vs PAO or SA vs OA

Fig. 5

Contribution of the fatty acid metabolism and FFAR1/GPR40 signaling to FFA-induced insulin secretion in the absence of glucose. Human islets were incubated with or without palmitate (PA) (a-d) or oleate (OA) (e-h) for 20 min in the absence of glucose. a and e Representative graphs of dynamic insulin secretion from perifused islets is shown. Fatty acids were added as indicated. b, c, d, f, g and h) Total, first-phase and second-phase of FFA-stimulated insulin secretion during perifusion was expressed as fold control. Results are means ± SEM of 3 donors. *P < 0.05 vs control, #P < 0.05 vs fatty acid alone