Endocrine Abstracts

Activation of PPARalpha pharmacologically by WY14,643 enhances insulin sensitivity in insulin-resistant high-fat-fed rats. PPARalpha is expressed in pancreatic islets, where it affects genes involved in lipid metabolism. We investigated effects of PPARalpha activation by WY14,643 on glucose-stimulated insulin secretion (GSIS) in a rat model of high-fat feeding in which insulin resistance is observed in conjunction with compensatory insulin hypersecretion. To identify persistent effects, GSIS studies were conducted using isolated islets subjected to stepwise glucose perifusion (glucose concentrations of 6-8 mM and 14-15 mM, each for 16 min). After this, perifusate glucose concentration returned to basal (2 mM). Insulin release by control (CON) islets at 6-8 mM glucose was not increased above basal. Raising perifusate glucose to 14-15 mM increased GSIS to peak rates 13.8 fold above basal (P<0.01). Basal insulin release by perifused islets from high-fat-fed (HIFAT) rats was significantly higher (52%; P<0.05) than CON. On raising perifusate glucose to 6-8 mM, GSIS remained higher (63-79%; P<0.05) than CON. Raising perfusate glucose to 14-15 mM resulted in more rapid increases in and 2.7-4.3-fold (P<0.05) higher rates of GSIS, compared with CON. Peak GSIS by perifused HIFAT islets was 1.5-fold higher (P<0.01) than peak GSIS by CON islets. WY14,643 treatment of CON rats did not affect basal or glucose-stimulated insulin release. While WY14,643 treatment of HIFAT rats did not affect insulin release at low glucose, it reduced (48-63%; P<0.05) GSIS at high glucose. Insulin release by islets from WY14,643-treated HIFAT rats did not differ significantly from those of WY14,643-treated CON rats. Our data demonstrate that compensatory GSIS induced by high-fat feeding is retained ex vivo, eliminating acute influences of circulating factors, and show that PPARalpha activation in vivo for 24 h reverses the effects of long-term high-fat feeding to enhance GSIS by perifused islets ex vivo.