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Diabetes 50:1021-1029, 2001
© 2001 by the American Diabetes Association, Inc.

ß-Cell Mass Dynamics in Zucker Diabetic Fatty Rats

Rosiglitazone Prevents the Rise in Net Cell Death

Diane T. Finegood1, M. Dawn McArthur1, David Kojwang1, Marion J. Thomas1, Brian G. Topp1, Thomas Leonard2, and Robin E. Buckingham3

1 Diabetes Research Laboratory, School of Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada; and SmithKline Beecham Pharmaceuticals
2 Collegeville, Pennsylvania and
3 Harlow, U.K.

The evolution of diabetes in the male leptin receptor-deficient (fa/fa) Zucker diabetic fatty (ZDF) rat is associated with disruption of normal islet architecture, ß-cell degranulation, and increased ß-cell death. It is unknown whether these changes precede or develop as a result of the increasing plasma glucose, or whether the increased ß-cell death can be prevented. Early intervention with thiazolidinediones prevents disruption of the islet architecture. To determine the specific effects of rosiglitazone (RSG) on ß-cell mass dynamics, male fa/fa (obese) and +/fa or +/+ (lean) rats age 6 weeks were fed either chow (control group [CN]) or chow mixed with rosiglitazone (RSG group) at a dosage of 10 µmol · kg-1 body wt · day-1. Rats were killed after 0, 2, 4, 6, or 10 weeks of treatment (at age 6, 8, 10, 12, or 16 weeks). Plasma glucose increased from 8.9 ± 0.4 mmol/l at 0 weeks to 34.2 ± 1.8 mmol/l (P = 0.0001) at 6 weeks of treatment in obese CN rats and fell from 8.0 ± 0.3 to 6.3 ± 0.4 mmol/l in obese RSG rats (P = 0.02). ß-cell mass fell by 51% from 2 to 6 weeks of treatment (ages 8–12 weeks) in obese CN rats (6.9 ± 0.9 to 3.4 ± 0.5 mg; P < 0.05), whereas ß-cell mass was unchanged in obese RSG rats. At 10 weeks of treatment (age 16 weeks), ß-cell mass in obese CN rats was only 56% of that of obese RSG rats (4.4 ± 0.4 vs. 7.8 ± 0.3 mg, respectively; P = 0.0001). The ß-cell replication rate fell from a baseline value of 0.95 ± 0.12% in lean rats and 0.94 ± 0.07% in obese rats (at 0 weeks) to ~0.3–0.5% in all groups by 6 weeks of treatment (age 12 weeks). After 10 weeks of treatment, ß-cell replication was higher in obese RSG rats than in CN rats (0.59 ± 0.14 vs. 0.28 ± 0.05%, respectively; P < 0.02). Application of our mass balance model of ß-cell turnover indicated that net ß-cell death was fivefold higher in obese CN rats as compared with RSG rats after 6 weeks of treatment (age 12 weeks). The increase in ß-cell death in obese CN rats during the 6-week observation period was well correlated with the increase in plasma glucose (r2 = 0.90, P < 0.0001). These results suggest that the development of hyperglycemia in ZDF rats is concomitant with increasing net ß-cell death. ß-cell proliferation compensates for the increased ß-cell loss at a time when plasma glucose is moderately elevated, but compensation ultimately fails and the plasma glucose levels increase beyond ~20 mmol/l. Treatment with rosiglitazone, previously shown to reduce insulin resistance, prevents the loss of ß-cell mass in obese ZDF rats by maintaining ß-cell proliferation and preventing increased net ß-cell death.


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