title: Deficiency of a beta-arrestin-2 signal complex contributes to insulin resistance.
abstract: Insulin resistance, a hallmark of type 2 diabetes, is a defect of insulin in stimulating insulin receptor signalling, which has become one of the most serious public health threats. Upon stimulation by insulin, insulin receptor recruits and phosphorylates insulin receptor substrate proteins, leading to activation of the phosphatidylinositol-3-OH kinase (PI(3)K)-Akt pathway. Activated Akt phosphorylates downstream kinases and transcription factors, thus mediating most of the metabolic actions of insulin. Beta-arrestins mediate biological functions of G-protein-coupled receptors by linking activated receptors with distinct sets of accessory and effecter proteins, thereby determining the specificity, efficiency and capacity of signals. Here we show that in diabetic mouse models, beta-arrestin-2 is severely downregulated. Knockdown of beta-arrestin-2 exacerbates insulin resistance, whereas administration of beta-arrestin-2 restores insulin sensitivity in mice. Further investigation reveals that insulin stimulates the formation of a new beta-arrestin-2 signal complex, in which beta-arrestin-2 scaffolds Akt and Src to insulin receptor. Loss or dysfunction of beta-arrestin-2 results in deficiency of this signal complex and disturbance of insulin signalling in vivo, thereby contributing to the development of insulin resistance and progression of type 2 diabetes. Our findings provide new insight into the molecular pathogenesis of insulin resistance, and implicate new preventive and therapeutic strategies against insulin resistance and type 2 diabetes.
authors.affiliation: Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, and Graduate School of the Chinese Academy of Sciences.
authors.forename: Bing
authors.initials: B
authors.lastname: Luan
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.forename: Haiya
authors.initials: H
authors.lastname: Wu
authors.forename: Baoyu
authors.initials: B
authors.lastname: Duan
authors.forename: Guangwen
authors.initials: G
authors.lastname: Shu
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
authors.forename: Dangsheng
authors.initials: D
authors.lastname: Li
authors.forename: Weiping
authors.initials: W
authors.lastname: Jia
authors.forename: Jiuhong
authors.initials: J
authors.lastname: Kang
authors.forename: Gang
authors.initials: G
authors.lastname: Pei
mesh_terms: D000818:Animals; D019390:Arrestins / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D007328:Insulin; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D011972:Receptor, Insulin; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt