β-Cell Mass Dynamics in Zucker Diabetic Fatty Rats

Abstract

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, ␤-cell degranulation, and increased ␤-cell death. It is unknown whether these changes precede or develop as a result of the increasing plasma glucose, or whether the increased ␤-cell death can be prevented. Early intervention with thiazolidinediones prevents disruption of the islet architecture. To determine the specific effects of rosiglitazone (RSG) on ␤-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 mol ⅐ kg ؊1 body wt ⅐ 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). ␤-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 ␤-cell mass was unchanged in obese RSG rats. At 10 weeks of treatment (age 16 weeks), ␤-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 ␤-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 ϳ0.3-0.5% in all groups by 6 weeks of treatment (age 12 weeks). After 10 weeks of treatment, ␤-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 ␤-cell turnover indicated that net ␤-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 ␤-cell death in obese CN rats during the 6-week observation period was well correlated with the increase in plasma glucose (r 2 ‫؍‬ 0.90, P < 0.0001). These results suggest that the development of hyperglycemia in ZDF rats is concomitant with increasing net ␤-cell death. ␤-cell proliferation compensates for the increased ␤-cell loss at a time when plasma glucose is moderately elevated, but compensation ultimately fails and the plasma glucose levels increase beyond ϳ20 mmol/l. Treatment with rosiglitazone, previously shown to reduce insulin resistance, prevents the loss of ␤-cell mass in obese ZDF rats by maintaining ␤-cell proliferation and preventing increased net ␤-cell death.

Effect of Type 2 Diabetes Mellitus and Diabetic Nephropathy on IgG Pharmacokinetics and Subcutaneous Bioavailability in the Rat

“…Animals were weighted and blood (through saphenous vein) and urine samples were collected throughout the studies to characterize the hyperglycemia and renal function of the animals. The disposition of hIgG was studied at the age of 12-13 weeks (phase A; the observed age for the development of diabetes in the ZDF obese diabetic model) and then at the age of 29-30 weeks (phase B; when the ZDF diabetic rats demonstrated nephropathy with progressive albuminuria and rising urinary albumin to creatinine ratios (ACR)) (15,17). Animals were dosed with 1 mg/kg of hIgG IV (dissolved in 0.9% saline) through the jugular cannula or penile vein or SC (in the flank region).…”

Treatment of Type 2 Diabetes With Combined Therapy

“…Various studies have demonstrated the positive effects of glitazones on ␤-cell function (32)(33)(34)(35). In addition, glitazones ameliorate sensitivity of skeletal muscle, adipose tissue, and hepatocytes to circulating insulin.…”

Automated recognition and quantification of pancreatic islets in Zucker diabetic fatty rats treated with exendin-4

“…Several reports have demonstrated an increase in pancreatic insulin-positive b-cells by exendin-4 treatment in animal models of type 2 diabetes (Xu et al 1999, Stoffers et al 2000, Tourrel et al 2001, Wang & Brubaker 2002, Li et al 2003. Here, we have investigated beneficial effects of chronic exendin-4 treatment on glycemic control and pancreatic islet histology in Zucker diabetic fatty (ZDF) rats, which has not been sufficiently investigated (Finegood et al 2001).…”