CAP/SORBS1 Gene and Diabetes
Background: Diabetes Mellitus (DM) is one of the leading causes of death in the United States (Bassett). The molecular defects underlying the development of most human Type 2 DM are not yet clear. But we know a combination of insulin resistance and islet cell failure brings on Type 2 DM. Insulin actions are mediated through insulin receptor. Recent transgenic studies have shown that defects in insulin receptor signaling may lead to both insulin resistance and islet cell dysfunction in experimental animals. However, the majority of the genetic defects in these transgenic models have not yet been implicated in the development of human diabetes.
Peroxisome proliferator-activated receptor gamma (PPAR?) is a ligand-dependent transcription factor that belongs to the nuclear receptor family that plays a critical role in adipocyte differentiation and lipid metabolism and are intimately connected to the cellular metabolism (carbohydrate, lipid and protein) and cell differentiation. When stimulated, PPAR induces the expression of genes that mediate fatty acid uptake, metabolism, and storage. PPAR activation also induces adipocyte differentiation and sensitivity to insulin.
Cbl-associated protein (CAP) is an insulin receptor signaling protein that has been implicated in the development of human diabetes. Alternative splicing of the gene SORBS1 results in multiple isoforms of CAP protein. CAP is upregulated by PPAR? agonists and is an adapter protein in the insulin receptor signaling network. Technology: CAP, also designated as SH3P12 or Ponsin by different laboratories, may play a role in human diabetes (Lin W et al). The human homolog for mouse CAP is SORBS1 (SH3-domain-containing 1) (Lin W et al). The expression of CAP/SORBS1 is dramatically up-regulated by PPAR? agonists thiazolidinediones, such as Pioglitazone (Bogacka et al; Ribon et al; Lin W et al.). In human, the A-allele of the T228A polymorphism in exon 7 of SORBS1 gene has a protective role against Type 2 diabetes (Relative Risk: 0.668, 95%CI 0.265-0.821) (Lin W et al). These data suggested that CAP/SORBS1 may play a role in human diabetes.
To study the function of CAP on glucose homeostasis, a CAP knockout mouse was generated. Application: A CAP knockout mouse has been generated and characterized genotypically and phenotypically. The CAP knockout mouse is an important tool for the study of glucose homeostasis, diabetes pathophysiology, obesity pathophysiology, and treatment and for the evaluation of the efficacy of insulin-sensitizing drugs and obesity drugs
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