Giorgino F, Logoluso F, Davalli A M, Napoli R, Laviola L, Hirshman M F, Horton E S, Weir G C, Smith R J
Istituto di Clinica Medica, Endocrinologia e Malattie Metaboliche, University of Bari School of Medicine, Italy.
Diabetes. 1999 Apr;48(4):801-12. doi: 10.2337/diabetes.48.4.801.
Insulin-dependent diabetes in rats is characterized by abnormalities of post-binding insulin signaling reactions that are not fully corrected by exogenous insulin therapy. The aim of this study was to investigate the effects of islet transplantation on insulin signaling in skeletal muscle and myocardium of streptozocin (STZ)-induced diabetic rats. Control rats, untreated diabetic rats, and diabetic rats transplanted with syngeneic islets under the kidney capsule were studied. Compared with controls, diabetic rats were characterized by multiple insulin signaling abnormalities in skeletal muscle, which included 1) increased insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrates IRS-1 and IRS-2, 2) increased substrate tyrosine phosphorylation in the basal state, 3) a decreased amount of IRS-1 protein, 4) markedly elevated basal and insulin-stimulated phosphatidylinositol (PI) 3-kinase activity in anti-IRS-1 immunoprecipitates from total tissue extracts, and 5) increased PI 3-kinase activity in low-density microsomes. A similar augmentation of insulin receptor and substrate tyrosine phosphorylation in response to STZ-diabetes was also found in myocardium, although with lower magnitude than that found in skeletal muscle. In addition, STZ-diabetes resulted in decreased IRS-1 and increased IRS-2 protein levels in myocardium. Islet transplantation fully corrected the diabetes-induced changes in protein tyrosine phosphorylation and PI 3-kinase activity and normalized IRS-1 and IRS-2 protein content in both skeletal muscle and myocardium. Thus, insulin delivered into the systemic circulation by pancreatic islets transplanted under the kidney capsule can adequately correct altered insulin signaling mechanisms in insulinopenic diabetes.
大鼠胰岛素依赖型糖尿病的特征是胰岛素结合后信号反应异常，外源性胰岛素治疗无法完全纠正这些异常。本研究的目的是调查胰岛移植对链脲佐菌素（STZ）诱导的糖尿病大鼠骨骼肌和心肌中胰岛素信号的影响。研究了对照大鼠、未经治疗的糖尿病大鼠以及在肾被膜下移植同基因胰岛的糖尿病大鼠。与对照组相比，糖尿病大鼠骨骼肌存在多种胰岛素信号异常，包括：1）胰岛素刺激的胰岛素受体β亚基、胰岛素受体底物IRS-1和IRS-2的酪氨酸磷酸化增加；2）基础状态下底物酪氨酸磷酸化增加；3）IRS-1蛋白量减少；4）从总组织提取物的抗IRS-1免疫沉淀中，基础和胰岛素刺激的磷脂酰肌醇（PI）3激酶活性显著升高；5）低密度微粒体中PI 3激酶活性增加。在心肌中也发现了类似的因STZ糖尿病导致的胰岛素受体和底物酪氨酸磷酸化增强，尽管程度低于骨骼肌。此外，STZ糖尿病导致心肌中IRS-1减少，IRS-2蛋白水平增加。胰岛移植完全纠正了糖尿病引起的蛋白质酪氨酸磷酸化和PI 3激酶活性变化，并使骨骼肌和心肌中的IRS-1和IRS-2蛋白含量恢复正常。因此，通过肾被膜下移植的胰岛释放到体循环中的胰岛素能够充分纠正胰岛素缺乏型糖尿病中改变的胰岛素信号机制。
