Regulation and impact of changes in PPARalpha expression on glucose-stimulated insulin secretion by pancreatic islets
MC Sugden, DX Augustine, K Bulmer, HS Lall & MJ Holness
Peroxisome proliferator-activated receptor (PPAR) alpha is one of three PPARs (alpha, beta (delta) and gamma), which are distinguished by distinct lipid and eicosanoid ligands. All three PPARs are present in pancreatic islets. PPARalpha expression and/or activity is important in the regulation of tissue triacylglycerol (TAG) content and fatty acid oxidation (FAO). PPARalpha binds the hypolipidaemic fibrates and promotes FA-mediated up-regulation of FAO. Surplus FA normally up-regulate PPARalpha and the FAO machinery, preventing the accumulation of excess lipids which is deleterious to islet function. We investigated whether prolonged exposure (24 h) to the PPARalpha agonist WY 14,643 (50 mg/kg body wt., i.p.) in vivo mimics the effect of FA to up-regulate islet PPARalpha expression and examined the effect of PPARalpha up-regulation on glucose-stimulated insulin secretion (GSIS). Islets were incubated with 20-mM glucose in the absence or presence of exogenous triglyceride (triolein, 1 mM). GSIS was only modestly impaired (by 28%; P<0.05) in islets from control fed rats on incubation with triolein. This suggests that incoming FAs are predominantly esterified rather than oxidised in the fed state, and that the resultant intracellular TAG accumulation suppresses GSIS. WY14,643 administration in vivo up-regulated islet PPARalpha protein expression by 1.6-fold (P<0.001), but had little effect on GSIS either in the absence (2% decrease) or presence (9% increase) of triolein. Starvation impaired GSIS (by 57%; P<0.001), an effect partially reversed by triolein addition (64% increase; P<0.05). We concluded that, in the fed state, islet FAO is suppressed proximal to beta-oxidation and therefore that up-regulation of PPARalpha-linked functions has a minimal impact on GSIS. The data also indicate that in the WY14,643-treated group, unlike the starved group, there is adequate 'glucose sensing' and metabolism to permit normal GSIS in the absence of triolein.