Peroxisome proliferator-activated receptor alpha improves pancreatic adaptation to insulin resistance in obese mice and reduces lipotoxicity in human islets.

Peroxisome proliferator-activated receptor (PPAR) alpha is a transcription factor controlling lipid and glucose homeostasis. PPARalpha-deficient (-/-) mice are protected from high-fat diet-induced insulin resistance. However, the impact of PPARalpha in the pathophysiological setting of obesity-related insulin resistance is unknown. Therefore, PPARalpha(-/-) mice in an obese (ob/ob) background were generated. PPARalpha deficiency did not influence the growth curves of the obese mice but surprisingly resulted in a severe, age-dependent hyperglycemia. PPARalpha deficiency did not aggravate peripheral insulin resistance. By contrast, PPARalpha(-/-) ob/ob mice developed pancreatic beta-cell dysfunction characterized by reduced mean islet area and decreased insulin secretion in response to glucose in vitro and in vivo. In primary human pancreatic islets, PPARalpha agonist treatment prevented fatty acid-induced impairment of glucose-stimulated insulin secretion, apoptosis, and triglyceride accumulation. These results indicate that PPARalpha improves the adaptative response of the pancreatic beta-cell to pathological conditions. PPARalpha could thus represent a promising target in the prevention of type 2 diabetes.