支链氨基酸代谢障碍致胰岛β细胞功能障碍及2型糖尿病的机制探究

胰岛β细胞功能损伤是2型糖尿病发病的重要诱因。我国2型糖尿病的发病率正在逐年升高，由此导致的死亡病例也随之增加。目前已知的是2型糖尿病患者血液中支链氨基酸(BCAA)显著升高，然而尚不清楚BCAA升高对β细胞功能的影响。我们发现β细胞中表达与BCAA分解代谢有关的酶，可将BCAA分解并产生BCKA等下游代谢物。然而，糖尿病小鼠胰岛中BCAA代谢减弱，PPM1K-BCKDH信号轴异常。高浓度BCKA诱导β细胞死亡和抑制胰岛素分泌。BCKDH激活剂促进β细胞中的BCAA代谢，减轻上述有害作用。反之，抑制PPM1K导致BCKDH失活，损害胰岛β细胞功能。因此，我们推测血液BCAA升高和β细胞BCAA代谢异常会损害β细胞功能，引发糖尿病。本项目拟进一步研究BCAA代谢如何影响β细胞功能，进而探索是否可以通过调节BCAA代谢从而改善β细胞功能，为将BCAA作为靶点治疗糖尿病提供科学依据。

Pancreatic β-cell dysfunction, characterized by reduced β-cell mass and defective glucose-stimulated insulin secretion (GSIS), drives the progression of type 2 diabetes mellitus (T2DM). This chronic metabolic disease is a leading cause of morbidity and mortality in China. Circulating levels of branched chain amino acid (valine, isoleucine and leucine-BCAA) is elevated in T2DM, perhaps due to defective BCAA catabolism in the peripheral tissues including adipose tissue and skeletal muscle. However, whether elevated circulating BCAA triggers β-cell dysfunction and/or defective BCAA catabolism in β-cells accelerates the progression of T2DM are vaguely known. .Our preliminary data demonstrate that pancreatic β-cells abundantly express key BCAA catabolic enzymes including branched-chain aminotransferase (BCATm), Protein Phosphatase, Mg2+/Mn2+ Dependent 1K (PPM1K) and branched-chain α-ketoacid dehydrogenase (BCKDH) complex. Importantly, treatment with BCAA provoked kinase activity of BCKDH complex, leading to degradation of BCAA into alpha-ketoacid and C3 and C5 acylcarnitine in pancreatic β-cells. However, this catabolic pathway was abolished in islets isolated from db/db diabetic mice, which is accompanied with aberrant PPM1K-BCKDH axis. Treatment with α-ketoacids induced demise and defective GSIS in pancreatic β-cells. Such detrimental effects were alleviated by promoting BCAA catabolism using the pharmacological activator 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid (BT2). On the contrary, inactivation of BCKDH complex via knocking down PPM1K impairs insulin secretion induced by glucose/leucine and induces β-cell death. .Based on our preliminary data and above background, we propose that elevated circulating BCAA and/or its metabolites triggers β-cell dysfunction in T2DM. Furthermore, defective BCAA catabolism in β-cells worsens β-cell dysfunction by accumulating cytotoxic α-ketoacids. In this proposal, we will address 1) whether BCCA catabolism is disrupted in pancreatic β-cells under diabetic condition using metabolomics analysis; 2) whether and how catabolic defect of BCAA triggers β-cell dysfunction; 3) whether manipulation of BCAA catabolism by genetic or pharmacological approach is able to regulate pancreatic function. The findings can allow us to further understand the pathogenesis of β-cell dysfunction in T2DM, and help to design new therapeutic approach for this incurable and deadly disease.