Long‐term in vitro treatment of INS‐1 rat pancreatic β‐cells by unsaturated free fatty acids protects cells against gluco‐ and lipotoxicities via activation of GPR40 receptors

Abstract

G-protein coupled receptor 40 (GPR40) is a membrane-bound G-protein-coupled receptor with high binding affinity to medium- and long-chain free fatty acids (FFAs). Acute activation of GPR40 on pancreatic β-cells causes insulin secretion, whereas prolonged activation may contribute to a deterioration of the effect of saturated FFAs on β-cells. It has been documented that different types of FFAs produce various effects on insulin secretion; however, little information is available regarding the expression of GPR40 and its function after long-term exposure of β-cells to unsaturated FFAs. In the present study, GPR40 expression and function were assessed in INS-1 β-cells after 48 h exposure to different types of unsaturated FFAs. The mRNA and protein expression of GPR40 was increased significantly by long-term exposure of cells to polyunsaturated α-linolenic acid, but not to either oleic acid or linoleic acid. Immunocytochemistry revealed a reduction in the number of insulin-containing granules in cells treated with α-linolenic acid, which was correlated with an increase in cellular expression of GPR40. Basal and glucose-stimulated insulin secretion were markedly suppressed by 48 h treatment of cells with saturated palmitic acid, but not unsaturated α-linolenic acid. By testing various FFAs, it was found that FFA-induced suppression of basal and glucose-stimulated insulin secretion was attenuated by an increase in the degree of unsaturation of the FFAs and GPR40 expression in response to FFA treatment in INS-1 cells. The results of the present study indicate that long-term in vitro treatment of INS-1 rat pancreatic β-cells by unsaturated FFAs protects the cells against from gluco- and lipotoxicities and that this coincides with an increase in GPR40 expression.

Lipotoxicity in the Pancreatic Beta Cell: Not Just Survival and Function, but Proliferation as Well?

“…In one study hyperglycemia decreased, but hyperlipidemia increased, FFAR1 expression [29]. In INS-1 cells, saturated fatty acids decreased FFAR1 expression, whereas unsaturated fatty acids increased FFAR1 expression and protected against lipotoxicity [30]. Supporting a role for endogenous FFAR1 in insulin secretion, a single nucleotide polymorphism at the FFAR1 locus correlated with insulin secretory function in people; genotyping this locus may allow clinical prediction of which patients will respond to FFAR1 agonists [31].…”

Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells

“…However, some observations suggest that prolonged exposure to high levels of some unsaturated free fatty acids could protect beta-cell function and increase GSIS (Tuo et al, 2012). It was suggested that the medium-and long-chain free fatty acid receptor GPCR40 could mediate this effect by activation of the Gaq protein, Ca 21 release from the endoplasmic reticulum, and influx via L-type Ca 21 channels (Fujiwara et al, 2005).…”

Zsírsavtúltengés – inzulinrezisztencia és β-sejt-halál

“…Ilyenkor ugyanis dominánssá válnak a negatív hatások, amelyek a már részletezett oxidatív és ER-stressz közvetítésével érvényesülnek. A telítetlen zsírsavak protektív szerepe itt is tetten érhető, ugyanis hatásukra nő, míg telített zsírsavak hatására csökken az előnyös effektusokat közvetítő FFAR-1/GPR-40 expressziója [31].…”