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Am J Physiol Endocrinol Metab 293: E1459-E1464, 2007. First published August 28, 2007; doi:10.1152/ajpendo.00375.2007
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INNOVATIVE METHODOLOGY

Measurement of pancreatic islet cell proliferation by heavy water labeling

¹KineMed, Inc., Emeryville; ²Department of Nutritional Sciences and Toxicology, University of California at Berkeley, Berkeley; and ³Division of Endocrinology and Metabolism, Department of Medicine, San Francisco General Hospital, University of California at San Francisco, San Francisco, California

Submitted 16 June 2007 ; accepted in final form 16 August 2007

We describe a sensitive technique for measuring long-term islet cell proliferation rates in vivo in rats. Pancreatic islets were isolated and the incorporation of deuterium (²H) from heavy water (²H₂O) into the deoxyribose moiety of DNA was measured by GC-MS. The results of heavy water labeling and BrdU staining were compared. The two methods were highly correlated (r = 0.9581, P < 0.001). Based on long-term heavy water labeling, 50% of islet cells divided in rats between 8 and 15 wk of age. Of interest, long-term BrdU administration suppressed proliferation of islet cells significantly, but not of bone marrow cells. Physiological evidence further supported the validity of the method: older animals (24 wk old) had 60% lower islet cell proliferation rates than younger rats (5 wk old), and partial (50%) pancreatectomy increased proliferation by 20%. In addition, cholecystokinin-8 treatment significantly stimulated proliferation in pancreatectomized rats only. In summary, heavy water labeling is a quantitative approach for measuring islet cell proliferation and testing therapeutic agents.

diabetes; -cell; 5-bromodeoxyuridine; sulfated cholecystokinin-8