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c-Kit in Early Onset of Diabetes: A Morphological and Functional Analysis of Pancreatic β-Cells in c-Kit^W-v Mutant Mice

Children’s Health Research Institute (M.K., F.A., J.L., A.W.L., M.W., Y.W., R.W.), Departments of Pathology (M.K.), Physiology and Pharmacology (F.A., J.L., Y.W., R.W.), Medicine (R.W.), Biochemistry (S.-P.Y.), and Oncology (S.-P.Y.), University of Western Ontario, London, Ontario, Canada N6C 2V5

Address all correspondence and requests for reprints to: Dr. Rennian Wang, Victoria Laboratory Centre, Room A5-140, 800 Commissioners Road East, London, Ontario, Canada N6C 2V5. E-mail: rwang{at}uwo.ca.

c-Kit tyrosine receptor kinase, a well-established stem cell marker, is expressed in a variety of tissues including the pancreas. The involvement of c-Kit in fetal rat and human endocrine pancreatic development, survival, and function has been well characterized but primarily using in vitro experimental approaches. Therefore, the aim of the current study was to examine whether deficiency of a functional c-Kit receptor would have physiological and functional implications in vivo. We characterized the c-Kit mutant mouse, c-Kit^W-v/+, to evaluate the in vivo role of c-Kit in β-cell growth and function. Here we report that male c-Kit^W-v/+ mice, at 8 wk of age, showed high fasting blood glucose levels and impaired glucose tolerance, which was associated with low levels of insulin secretion after glucose stimulation in vivo and in isolated islets. Morphometric analysis revealed that β-cell mass was significantly reduced (50%) in male c-Kit^W-v/+ mice when compared with controls (c-Kit^+/+) (P < 0.05). In parallel, a reduction in pancreatic duodenal homeobox-1 and insulin gene expression in whole pancreas as well as isolated islets of c-Kit^W-v/+ male mice was noted along with a decrease in pancreatic insulin content. Furthermore, the reduction in β-cell mass in male c-Kit^W-v/+ mice was associated with a decrease in β-cell proliferation. Interestingly, these changes were not observed in female c-Kit^W-v/+ mice until 40 wk of age. Our results clearly demonstrate that the c-Kit receptor is involved in the regulation of glucose metabolism, likely through an important role in β-cell development and function.