Question: 

Free fatty acids (FFAs) are known to enhance glucose-induced insulin secretion (GIIS). The insulinotropic effect of FFAs depends on the activation of free fatty acid receptor 1 (FFA1/GPR40), a Gq-coupled receptor which activates phospholipase C. We aimed to investigate effects of FFA1 activation on the cytosolic Ca²⁺ concentration ([Ca²⁺]_c) as an important parameter in stimulus-secretion coupling.

Methods: 

Insulin secretion was measured by radioimmunoassay and [Ca²⁺]_c by the fura-2 technique.

Results: 

The synthetic FFA1-agonist TUG-469 stimulated insulin secretion from human islets and enhanced GIIS in INS1E-cells. Surprisingly, stimulation of secretion by TUG-469 was neither inhibited by ryanodine nor by xestospongin which inhibit mobilization of Ca²⁺ from ryanodine-sensitive and IP₃-sensitive intracellular Ca²⁺ stores, respectively. TUG-469 (100nM) augmented [Ca²⁺]_c in mouse beta-cells at a stimulatory glucose concentration (n=20). This effect too was not owing to Ca²⁺-release since the glucose and TUG-induced increase in [Ca²⁺]_c was abolished by nifedipine (10mM) whereas activation of muscarinic receptors by carbachol (10mM) still transiently increased [Ca²⁺]_c (n=8). The effect of TUG-469 on [Ca²⁺]_c was absent in beta-cells of FFA1- knock-out mice (n=18). Similar to TUG-469, conjugated linoleic acids (CLAs), widely used as dietary supplements, stimulate insulin secretion through FFA1. The increase in [Ca²⁺]_c induced by both isomers, CLA9c,11t (n=31) and CLA10t,12c (n=32) (100mM), was, however, only partly reduced in beta-cells of FFA1 knock-out mice (n=31 and n=46).

Conclusions: 

The data show that FFA1-induced IP₃-dependent Ca²⁺-release does not explain TUG-469 and CLA-induced changes in [Ca²⁺]_c. The specific activation of FFA1 augments GIIS which makes FFA1 attractive as target for oral antidiabetic drugs.