β-cell mass dynamics in Zucker diabetic fatty rats -: Rosiglitazone prevents the rise in net cell death
β-cell mass dynamics in Zucker diabetic fatty rats -: Rosiglitazone prevents the rise in net cell death
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DOI：
10.2337/diabetes.50.5.1021
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发表时间：
2001-05-01
期刊：
影响因子：
7.7
通讯作者：
Buckingham, RE
中科院分区：
文献类型：
--
作者：
Finegood, DT;McArthur, MD;Buckingham, RE
在雄性瘦素受体缺陷(FA/FA)Zucker糖尿病肥胖(ZDF)大鼠中，糖尿病的演变与正常胰岛结构的破坏、β细胞脱颗粒和β细胞死亡增加有关。目前尚不清楚这些变化是在血糖升高之前还是由于血糖升高而发生的，也不清楚是否可以防止β细胞死亡的增加。早期使用噻唑烷二酮类药物干预可防止胰岛结构的破坏。为探讨罗格列酮(RSG)对6周龄雄性FA/FA(肥胖)和+/FA(+/+)或+/+(瘦)大鼠胰岛β细胞质量动力学的影响，将6周龄雄性FA/FA(肥胖)和+/FA或+/+(瘦)大鼠按10mU·mol·kg~(-1)体重·d(-1)的剂量分别饲喂饲料(对照组)和饲料与罗格列酮混合饲料(RSG组)。在治疗0、2、4、6或10周(6、8、10、12或16周)后处死大鼠。治疗6周后，正常对照组大鼠血糖由治疗前的8.9±-0.4 mm o l/L升至治疗6周的34.2±1.8 m o l/L(P=0.0 2)，正常对照组由治疗前的8.0±-0.3降至治疗后的6周的6.3±0.4 m ol/L(P=0.0 2)。从治疗2周到6周(8-12周)，肥胖CN大鼠的β细胞质量下降了51%(6.9+/-0.9到3.4+/-0.5 mg；P<；0.05)，而肥胖RSG大鼠的β细胞质量没有变化。治疗10周(16周龄)，肥胖CN大鼠的β细胞质量仅为肥胖RSG大鼠的56%(分别为4.4+/-0.4vs.7.8+/-0.3 mg；P=0.0001)。经过6周的治疗(12周龄)，β细胞复制率从瘦大鼠的0.95+/-0.12%和肥胖大鼠的0.94a-0.07%的基准值下降到与所有组的0.3-0.5%相似。治疗10周后，肥胖RSG大鼠的β细胞复制高于CN大鼠(分别为0.59+/-0.14和0.28+/-0.05%，P<；0.02)。应用我们的β细胞周转的质量平衡模型表明，肥胖的CN大鼠在治疗6周(12周)后，与RSG大鼠相比，肥胖的CN大鼠的净β细胞死亡率高出5倍。在8周的观察期内，肥胖CN大鼠胰岛β细胞死亡率的增加与血糖的升高有很好的相关性(r(2)=0.9，P<；0.0001)。这些结果表明，ZDF大鼠高血糖的发展伴随着阿尔法细胞净死亡的增加。当血糖适度升高时，β细胞增殖可以补偿增加的β细胞损失，但补偿最终失败，血糖水平上升到接近20 mmoL/L的水平。罗格列酮治疗之前被证明可以减少胰岛素抵抗，通过维持β细胞增殖和防止增加的β细胞净死亡来防止肥胖ZDF大鼠的β细胞质量损失。
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 mu mol 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 a 0.07% in obese rats (at 0 weeks) to similar to0.3-0.5% 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 8-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 alpha -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 similar to 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.