George Stella, Rochford Justin J, Wolfrum Christian, Gray Sarah L, Schinner Sven, Wilson Jenny C, Soos Maria A, Murgatroyd Peter R, Williams Rachel M, Acerini Carlo L, Dunger David B, Barford David, Umpleby A Margot, Wareham Nicholas J, Davies Huw Alban, Schafer Alan J, Stoffel Markus, O'Rahilly Stephen, Barroso Inês
Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
Science. 2004 May 28;304(5675):1325-8. doi: 10.1126/science.1096706.
Inherited defects in signaling pathways downstream of the insulin receptor have long been suggested to contribute to human type 2 diabetes mellitus. Here we describe a mutation in the gene encoding the protein kinase AKT2/PKBbeta in a family that shows autosomal dominant inheritance of severe insulin resistance and diabetes mellitus. Expression of the mutant kinase in cultured cells disrupted insulin signaling to metabolic end points and inhibited the function of coexpressed, wild-type AKT. These findings demonstrate the central importance of AKT signaling to insulin sensitivity in humans.
长期以来，人们一直认为胰岛素受体下游信号通路的遗传性缺陷与人类2型糖尿病有关。在此，我们描述了一个家族中编码蛋白激酶AKT2/PKBβ的基因发生的突变，该家族呈现出严重胰岛素抵抗和糖尿病的常染色体显性遗传。在培养细胞中表达突变激酶会破坏胰岛素向代谢终点的信号传导，并抑制共表达的野生型AKT的功能。这些发现证明了AKT信号传导对人类胰岛素敏感性至关重要。
