Long-Term AICAR Administration and Exercise Prevents Diabetes in ZDF Rats

Long-Term AICAR Administration and Exercise Prevents Diabetes in ZDF Rats Rasmus Pold 1 , Lasse S. Jensen 1 , Niels Jessen 1 , Esben S. Buhl 1 , Ole Schmitz 1 2 , Allan Flyvbjerg 1 , Nobuharu Fujii 3 , Laurie J. Goodyear 3 , Carsten F. Gotfredsen 4 , Christian L. Brand 4 and Sten Lund 1 1 Medical Research Laboratory and Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, Aarhus, Denmark 2 Department of Clinical Pharmacology, University of Aarhus, Aarhus, Denmark 3 Research Division, Joslin Diabetes Center and Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 4 Department of Research and Development, Novo Nordisk, Bagsvaerd, Denmark Address correspondence and reprint requests to Sten Lund, MD, DMSc, Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, Aarhus Sygehus, DK-8000 Aarhus C, Denmark. E-mail: sl{at}dadlnet.dk Abstract Lifestyle interventions including exercise programs are cornerstones in the prevention of obesity-related diabetes. The AMP-activated protein kinase (AMPK) has been proposed to be responsible for many of the beneficial effects of exercise on glucose and lipid metabolism. The effects of long-term exercise training or 5-aminoimidazole-4-carboxamide-1-β- d -riboruranoside (AICAR) treatment, both known AMPK activators, on the development of diabetes in male Zucker diabetic fatty (ZDF) rats were examined. Five-week-old, pre-diabetic ZDF rats underwent daily treadmill running or AICAR treatment over an 8-week period and were compared with an untreated group. In contrast to the untreated, both the exercised and AICAR-treated rats did not develop hyperglycemia during the intervention period. Whole-body insulin sensitivity, as assessed by a hyperinsulinemic-euglycemic clamp at the end of the intervention period, was markedly increased in the exercised and AICAR-treated animals compared with the untreated ZDF rats ( P < 0.01). In addition, pancreatic β-cell morphology was almost normal in the exercised and AICAR-treated animals, indicating that chronic AMPK activation in vivo might preserve β-cell function. Our results suggest that activation of AMPK may represent a therapeutic approach to improve insulin action and prevent a decrease in β-cell function associated with type 2 diabetes. AICAR, 5-aminoimidazole-4-carboxamide-1-β-d-riboruranoside AMPK, AMP-activated protein kinase ZMP, 5-amino-4-imidazole carboxamide riboside 5′-monophosphate