Kindlin-2调节胰岛β细胞质量及胰岛素表达与分泌的作用及其机制研究

β-Cell dysfunction and reduction in β-cell mass play an important role in the pathological process of diabetes mellitus. We have recently found that selective deletion of Kindlin-2 expression in pancreatic β-cells during mouse development results in multiple diabetic phenotypes, including low fasting blood insulin, high fasting blood glucose, severe glucose intolerance and impaired glucose-stimulated insulin secretion. Deletion of Kindlin-2 dramatically decreases, while overexpression of Kindlin-2 increases, the protein level of MafA, a major regulator of insulin expression. Kindlin-2 binds to and stabilizes MafA. Furthermore, Kindlin-2 inactivation reduces β-cell proliferation and increases β-cell apoptosis and thereby decreases β-cell mass probably by down-regulating, at least in part, β-catenin. Systemic administration of a β-catenin activator BIO partially restores the glucose intolerance in Kindlin-2 mutant mice. These results demonstrate that Kindlin-2 plays a critical role in regulation of the β-cell mass and function during pancreatic development. Based on our preliminary results, we hypothesize that Kindlin-2 regulates insulin expression and secretion and normal β-cell mass and, thereby, maintains normal glucose metabolism by up-regulating the protein levels of MafA and β-catenin in pancreatic β-cells. In this study, we will test our hypothesis by using a combination of sophisticated molecular and cellular approaches along with multiple novel mouse models and define the roles and mechanisms whereby Kindlin-2 modulates β-cell mass and functions in adult and aging animals. In addition, we will define microRNAs that suppresses Kindlin-2 expression in aging and diabetic states. Results from this study will help on identifying potential therapeutic targets for diabetes.

β细胞质量减少和功能障碍在糖尿病病理过程中起重要作用。我们发现删除β细胞Kindlin-2表达，导致严重糖尿病。Kindlin-2删除显著降低、Kindlin-2过表达明显提高MafA蛋白水平。Kindlin-2结合并稳定MafA蛋白。删除Kindlin-2降低β-catenin表达和β细胞质量。小鼠全身注射β-catenin激活剂BIO部分恢复Kindlin-2删除所致的糖耐量异常。我们假设：Kindlin-2通过上调MafA和β-catenin的蛋白水平，增加β细胞中胰岛素的表达和分泌及β细胞质量，从而维持正常的糖代谢。本课题将应用最新分子和细胞生物学手段及新型小鼠模型，深入系统研究Kindlin-2在成年和衰老过程中调节β细胞质量和功能的作用和机制，确定在衰老和糖尿病状态下抑制Kindlin-2表达的miRNA。这项研究的结果将为糖尿病的防治提供新的理论基础和新靶点。

糖尿病是一种世界性的流行性疾病，目前全球大约有十分之一的人口患有糖尿病。 但是目前为止，糖尿病的发病机制尚不完全清楚。在本研究中，我们发现肝脏和胰岛beta 细胞表达丰富的Kindlin-2，删除其表达可以影响糖尿病的发生发展。在胰岛beta细胞中，Kindlin-2通过其c端区域，结合并稳定MafA，激活胰岛素表达。Kindlin-2缺失通过激活GSK-3beta，下调beta-catenin，进而导致beta细胞增殖和质量降低。在胰腺早期发育过程中，我们发现Kindlin-2的缺失降低beta细胞的比例，增加beta细胞比例。beta-catenin在beta细胞中的遗传激活可以恢复由Kindlin-2缺失引起的糖尿病样表型。beta细胞Kindlin-2的诱导缺失导致成年小鼠的糖尿病表型。此外，我们发现肝细胞Kindlin-2单倍剂量不足可以在不影响小鼠的能量代谢的情况下，改善由高脂饮食（HFD）诱导的小鼠糖尿病表型。在肝细胞中，Kindlin-2可通过调节 FoxO1调节糖尿病的发生发展。综上来说，我们的研究证明了Kindlin-2在糖尿病发生发展中发挥重要作用，并为糖尿病的治疗提供了靶点。

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