CAJ | 학술논문

II型糖尿病现已成为世界上影响范围最广、危害最大的疾病之一,其典型特征是外周组织的胰岛素耐受.胰岛素耐受的形成原因主要是血液中循环的胰岛素不能刺激激活脂肪、肝脏、肌肉中的胰岛素信号通路,但其形成的具体机制还不是很清楚.我们发现在II型糖尿病模型小鼠肝脏样品中β-arrestin2的表达水平显著下调,暗示了其在II型糖尿病中的潜在作用.我们进一步的研究发现β-arrestin2基因敲除可导致严重的胰岛素耐受,而过表达β-arrestin2则能显著提高胰岛素敏感性.我们发现β-arrestin2介导了胰岛素信号通路中新的信号复合物的形成,这一复合物包含IR/Akt/β-arrestin2/Src,并对胰岛素信号的传递以及胰岛素代谢功能的行使起到了至关重要的作用.β-arrestin2在这个复合物中起到了支架蛋白的作用,它将Akt、Src与IR联系在一起,β-arrestin2的缺失或功能异常直接导致复合物的解聚、胰岛素信号的阻滞并最终导致胰岛素耐受.我们的研究工作不仅发现了胰岛素信号途径中一个全新的由β-arrestin2介导的信号复合物,这个信号复合物对于胰岛素信号传递以及胰岛素敏感性的确立起着重要的作用,而且为II型糖尿病的防治和治疗提供了一个新的理论指导和研究靶点.
II형당뇨병현이성위세계상영향범위최엄、위해최대적질병지일,기전형특정시외주조직적이도소내수.이도소내수적형성원인주요시혈액중순배적이도소불능자격격활지방、간장、기육중적이도소신호통로,단기형성적구체궤제환불시흔청초.아문발현재II형당뇨병모형소서간장양품중β-arrestin2적표체수평현저하조,암시료기재II형당뇨병중적잠재작용.아문진일보적연구발현β-arrestin2기인고제가도치엄중적이도소내수,이과표체β-arrestin2칙능현저제고이도소민감성.아문발현β-arrestin2개도료이도소신호통로중신적신호복합물적형성,저일복합물포함IR/Akt/β-arrestin2/Src,병대이도소신호적전체이급이도소대사공능적행사기도료지관중요적작용.β-arrestin2재저개복합물중기도료지가단백적작용,타장Akt、Src여IR련계재일기,β-arrestin2적결실혹공능이상직접도치복합물적해취、이도소신호적조체병최종도치이도소내수.아문적연구공작불부발현료이도소신호도경중일개전신적유β-arrestin2개도적신호복합물,저개신호복합물대우이도소신호전체이급이도소민감성적학립기착중요적작용,이차위II형당뇨병적방치화치료제공료일개신적이론지도화연구파점.
Insulin resistance, a hallmark of type 2 diabetes, is a defect of insulin to stimulate insulin receptor (IR) signaling, and has become one of the most serious public health threats. We found that in diabetic mouse models,β-arrestin2 is severely downregulated. Knockdown of β-arrestin2 exacerbates insulin resistance, whereas administration of β-arrestin2 restores insulin sensitivity in mice. Further investigation reveals that insulin stimulates the formation of a novel β-arrestin2 signal complex, in which β-arrestin2 scaffolds Akt and Src to IR. Loss or dysfunction of β-arrestin2 results in deficiency of this signal complex and disturbs insulin signaling, thereby contributes to insulin resistance in vivo, demonstrating this complex is critical for mediating insulin signaling and downstream metabolic actions. Thus, our findings provide novel insight into the molecular pathogenesis of insulin resistance, and implicate new preventative and therapeutic strategies against insulin resistance and type 2 diabetes.