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Contribution of Different Mechanisms to Pancreatic Beta-cell Hyper-secretion in Non-obese Diabetic (NOD) Mice during Pre-diabetes*

Kuo Liang,Wen Du,Wenzhen Zhu,Shuang Liu,Ye-qing Cui,Hai-chen Sun,Bin Luo,Yanhong Xue,Lu Yang,Liangyi Chen,Fei Li

Published 2011 in Journal of Biological Chemistry

ABSTRACT

Background: Pre-diabetic islet hyper-secretion is crucial to the development of the disease but the mechanisms remain unknown. Results: We reveal dynamic changes in beta-cell mass and function in non-obese diabetic (NOD) mice of different ages. Conclusion: Beta-cell mass increase and individual beta-cell secretory ability enhancement contribute to islet hyperactivity at different stages. Significance: This may provide insights into alteration of beta-cell function during the disease progression. The development of insulin-dependent diabetes mellitus (IDDM) results from the selective destruction of pancreatic beta-cells. Both humans and spontaneous models of IDDM, such as NOD mice, have an extended pre-diabetic stage. Dynamic changes in beta-cell mass and function during pre-diabetes, such as insulin hyper-secretion, remain largely unknown. In this paper, we evaluated pre-diabetic female NOD mice at different ages (6, 10, and 14 weeks old) to illustrate alterations in beta-cell mass and function as disease progressed. We found an increase in beta-cell mass in 6-week-old NOD mice that may account for improved glucose tolerance in these mice. As NOD mice aged, beta-cell mass progressively reduced with increasing insulitis. In parallel, secretory ability of individual beta-cells was enhanced due to an increase in the size of slowly releasable pool (SRP) of vesicles. Moreover, expression of both SERCA2 and SERCA3 genes were progressively down-regulated, which facilitated depolarization-evoked secretion by prolonging Ca2+ elevation upon glucose stimulation. In summary, we propose that different mechanisms contribute to the insulin hyper-secretion at different ages of pre-diabetic NOD mice, which may provide some new ideas concerning the progression and management of type I diabetes.

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