Finegood D T, McArthur M D, Kojwang D, Thomas M J, Topp B G, Leonard T, Buckingham R E
Diabetes Research Laboratory, School of Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.
Diabetes. 2001 May;50(5):1021-9. doi: 10.2337/diabetes.50.5.1021.
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, beta-cell degranulation, and increased beta-cell death. It is unknown whether these changes precede or develop as a result of the increasing plasma glucose, or whether the increased beta-cell death can be prevented. Early intervention with thiazolidinediones prevents disruption of the islet architecture. To determine the specific effects of rosiglitazone (RSG) on beta-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 micromol. 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). beta-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 beta-cell mass was unchanged in obese RSG rats. At 10 weeks of treatment (age 16 weeks), beta-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 beta-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 approximately 0.3-0.5% in all groups by 6 weeks of treatment (age 12 weeks). After 10 weeks of treatment, beta-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 beta-cell turnover indicated that net beta-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 beta-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 beta-cell death. beta-cell proliferation compensates for the increased beta-cell loss at a time when plasma glucose is moderately elevated, but compensation ultimately fails and the plasma glucose levels increase beyond approximately 20 mmol/l. Treatment with rosiglitazone, previously shown to reduce insulin resistance, prevents the loss of beta-cell mass in obese ZDF rats by maintaining beta-cell proliferation and preventing increased net beta-cell death.
雄性瘦素受体缺陷（fa/fa）的Zucker糖尿病脂肪（ZDF）大鼠糖尿病的进展与正常胰岛结构破坏、β细胞脱颗粒以及β细胞死亡增加有关。尚不清楚这些变化是先于血糖升高出现还是血糖升高的结果，也不清楚增加的β细胞死亡是否可以预防。噻唑烷二酮类药物的早期干预可防止胰岛结构破坏。为了确定罗格列酮（RSG）对β细胞质量动态的具体影响，给6周龄的雄性fa/fa（肥胖）和+/fa或+/+（瘦）大鼠喂食普通饲料（对照组[CN]）或添加剂量为10 μmol·kg⁻¹体重·天⁻¹罗格列酮的普通饲料（RSG组）。在治疗0、2、4、6或10周后（即6、8、10、12或16周龄时）处死大鼠。肥胖CN组大鼠在治疗6周时血浆葡萄糖从0周时的8.9±0.4 mmol/L升至34.2±1.8 mmol/L（P = 0.0001），而肥胖RSG组大鼠血浆葡萄糖从8.0±0.3 mmol/L降至6.3±0.4 mmol/L（P = 0.02）。肥胖CN组大鼠在治疗2至6周（8 - 12周龄）时β细胞质量下降了51%（从6.9±0.9 mg降至3.4±0.5 mg；P < 0.05），而肥胖RSG组大鼠β细胞质量无变化。在治疗10周（16周龄）时，肥胖CN组大鼠的β细胞质量仅为肥胖RSG组大鼠的56%（分别为4.4±0.4 mg和7.8±0.3 mg；P = 0.0001）。β细胞复制率在瘦大鼠中从基线值0.95±0.12%和肥胖大鼠中从0.94±0.07%（0周时）在治疗6周（12周龄）时降至所有组的约0.3 - 0.5%。治疗10周后，肥胖RSG组大鼠的β细胞复制率高于CN组大鼠（分别为0.59±0.14%和0.28±0.05%；P < 0.02）。应用我们的β细胞更新质量平衡模型表明，治疗6周（12周龄）后，肥胖CN组大鼠的β细胞净死亡比RSG组大鼠高5倍。肥胖CN组大鼠在6周观察期内β细胞死亡的增加与血浆葡萄糖的增加密切相关（r² = 0.90，P < 0.0001）。这些结果表明，ZDF大鼠高血糖的发展与β细胞净死亡增加同时发生。在血浆葡萄糖适度升高时，β细胞增殖可补偿增加的β细胞损失，但最终补偿失败，血浆葡萄糖水平升至约20 mmol/L以上。先前已证明罗格列酮可降低胰岛素抵抗，通过维持β细胞增殖和防止β细胞净死亡增加来预防肥胖ZDF大鼠的β细胞质量损失。
