糖尿病治疗新途径的基因研究

24个月前重返列表：中介

2014年6月19日的一项新研究描述了一种糖尿病相关基因功能在影响胰岛素释放的生物学途径中的作用。这项研究的作者说，寻找药物作用于这一途径可能最终导致1型糖尿病患者的新的治疗方法。

“2007，我们的基因组学研究小组发现在全基因组搜索的第一个基因在1型糖尿病中发挥主要作用，但我们不知道它的功能，说：”共同研究领导者人Hakon Hakonarson博士，博士，美国在费城儿童医院应用基因组学中心主任（CHOP）。现在我们明白了这个基因在调节胰岛素代谢中起着关键的作用。

多丽丝·A·斯托福斯，医学博士，博士，研究所的糖尿病、肥胖和在宾夕法尼亚大学医学院的代谢，与共同高级作者Hakonarson，是这项研究的通讯作者，今天在网上出现细胞。

目前的结果是建立在2007的全基因组关联研究（GWAS）Hakonarson和同事在印章显示的变化kiaa0305基因，也被称为CLEC16A, correlate with higher risk of type 1 diabetes and other autoimmune diseases。

Hakonarson的集团随后开发的小鼠品系，其中CLEC16Agene was deactivated。 They then collaborated with Stoffers, an endocrinology expert, to breed a subset of the knockout mice in which only the pancreatic cells were affected。

科学家们表明CLEC16Agene acts upon a pathway crucial to insulin secretion。 CLEC16Anormally helps protect mitochondria, the tiny energy-producing components of cells。 When the CLEC16Agene is knocked out, damaged mitochondria are then digested, a process called mitophagy, and the resulting loss of energy output disrupts beta cells in the pancreas in their normal job of secreting insulin。 “The ultimate result of the deletion of CLEC16Ais an accumulation of unhealthy mitochondria, leading to less insulin being secreted by the beta cells,” said Stoffers。

In humans, inability to produce insulin is the hallmark of type 1 diabetes。 The study team showed that humans with single-base variants in CLEC16Ahave reduced beta cell function, although with less extreme effects than in the knockout mice。

The researchers showed that the CLEC16Abiological pathway has downstream effects on a protein called Parkin, already known to be a master regulator of mitophagy。 The current study is the first to link the CLEC16Apathway with regulation of Parkin-mediated mitophagy and to suggest how this process may affect diabetes by dysregulating insulin secretion。

If drugs can be developed to act on the CLEC16Apathway, they could provide a new, targeted therapy for patients with type 1 diabetes who harbor risk variants in the CLEC16Agene, said Hakonarson。

Hakonarson said that GWAS research has often been criticized for not identifying gene variants with major impacts on the risk of complex diseases, but that in this case, the GWAS seven years ago identified a previously uncharacterized gene that has proved to play a crucial role, not only in type 1 diabetes, but also, as his group subsequently helped discover, in multiple sclerosis, rheumatoid arthritis, Crohn’s disease and other autoimmune diseases。 He added that “more work needs to be done to identify additional causal gene variants in type 1 diabetes。”

The National Institutes of Health provided support for this study (grants DK089117, DK049210, and DK085708)。 Other funders were the Margaret Q。 Landenberger Foundation, the Juvenile Diabetes Research Foundation and the Charles H。 Humpton, Jr。 Endowment。

First author Scott A。 Soleimanpour, MD, a postdoctoral researcher in the Stoffers lab when the study was performed, is now at the Brehm Diabetes Research Center at the University of Michigan。 Other co-authors are from Lund University and Skane University Hospital in Sweden and Baylor College of Medicine in Houston。

“糖尿病易感基因CLEC16A调节线粒体自噬，”细胞, published online June 19, 2014。