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Diabetes 54:1528-1533, 2005
© 2005 by the American Diabetes Association, Inc.

Reduced Insulin and IGF-I Signaling, not Hyperglycemia, Underlies the Diabetes-Associated Depletion of Interstitial Cells of Cajal in the Murine Stomach

Viktor J. Horváth1, Harsha Vittal1,2, and Tamás Ördög1

1 Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, Nevada
2 Department of Internal Medicine, University of Nevada, Reno School of Medicine, Reno, Nevada

Damage to interstitial cells of Cajal (ICC), pacemakers, and mediators of neuromuscular neurotransmission in the gastrointestinal tract contributes to the pathogenesis of diabetic gastroenteropathy in both patients and animal models. ICC depletion in diabetes may result from chronic hyperglycemia or lost/ineffective insulin signaling. Because independent control of insulin and glucose concentrations is difficult in chronic in vivo studies, we used long-term organotypic cultures to address this problem. Murine gastric muscles were cultured in normoglycemic or hyperglycemic basal media with or without insulin or IGF-I for 1–3 months, the time required for gastroparesis and ICC damage to develop in diabetic mice. ICC were assessed by c-Kit immunohistochemistry and quantitative analysis of c-kit expression. Electrical pacemaking was studied by intracellular recording of slow waves. ICC survived for at least 34 days in unsupplemented normoglycemic media, but their networks, c-kit expression, and slow waves were profoundly reduced after 68 days. These changes could be entirely prevented by insulin or IGF-I supplementation. ICC networks were completely resistant to hyperglycemia for at least 72 days. Thus, hyperglycemia is unlikely to be responsible for the diabetes-associated depletion of ICC. In contrast, maintenance of ICC requires insulin or IGF-I, which are reduced or ineffective in diabetes.

Address correspondence and reprint requests to Tamás Ördög, MD, Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Anderson Bldg., Mail Stop 352, Reno, NV 89557. E-mail: tamas{at}unr.edu

Abbreviations: ICC, interstitial cells of Cajal


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2005 by the American Diabetes Association.