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Diabetes 55:1605-1613, 2006
DOI: 10.2337/db06-0016
© 2006 by the American Diabetes Association
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Peroxisome Proliferator–Activated Receptor {alpha} Improves Pancreatic Adaptation to Insulin Resistance in Obese Mice and Reduces Lipotoxicity in Human Islets

Fanny Lalloyer1,2,3, Brigitte Vandewalle4, Frédéric Percevault1,2,3, Gérard Torpier1,2,3, Julie Kerr-Conte4, Maaike Oosterveer5, Réjane Paumelle1,2,3, Jean-Charles Fruchart1,2,3, Folkert Kuipers5, François Pattou4, Catherine Fiévet1,2,3, and Bart Staels1,2,3

1 Institut Pasteur de Lille, Département d’Athérosclérose, Lille, France
2 Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 545, Lille, France
3 Faculté de Pharmacie, Université de Lille 2, Lille, France
4 Cell Therapy for Diabetes, Institut National de la Santé et de la Recherche Médicale/Université de Lille 2, Faculté de Médecine, Lille, France
5 Center for Liver, Digestive and Metabolic Diseases, Laboratory of Pediatrics, University Hospital, Groningen, the Netherlands

Address correspondence and reprint requests to Bart Staels, Unité 545 INSERM, Institut Pasteur de Lille, 1 rue du Professeur Calmette, 59019 Lille, France. E-mail: bart.staels{at}pasteur-lille.fr

Abbreviations: ELISA, enzyme-linked immunosorbent assay; FFA, free fatty acid; GIPR, gastrointestinal polypeptide receptor; GIR, glucose infusion rate; GLP1, glucagon-like peptide-1; GSIS, glucose-stimulated insulin secretion; IPGTT, intraperitoneal glucose tolerance test; OGTT, oral glucose tolerance test; PDX-1, pancreatic duodenal homeobox-1; PPAR, peroxisome proliferator–activated receptor

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


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