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

  1. Rasmus Pold1,
  2. Lasse S. Jensen1,
  3. Niels Jessen1,
  4. Esben S. Buhl1,
  5. Ole Schmitz12,
  6. Allan Flyvbjerg1,
  7. Nobuharu Fujii3,
  8. Laurie J. Goodyear3,
  9. Carsten F. Gotfredsen4,
  10. Christian L. Brand4 and
  11. Sten Lund1
  1. 1Medical Research Laboratory and Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, Aarhus, Denmark
  2. 2Department of Clinical Pharmacology, University of Aarhus, Aarhus, Denmark
  3. 3Research Division, Joslin Diabetes Center and Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  4. 4Department of Research and Development, Novo Nordisk, Bagsvaerd, Denmark
  1. 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.

Footnotes

    • Accepted January 1, 2005.
    • Received August 10, 2004.
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