Expression patterns and roles of the insulin receptor in the intestinal epithelium Public Deposited

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  • March 19, 2019
Creator
  • Andres, Sarah
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • Hyperinsulinemia predicts increased risk of precancerous colon adenoma. Obesity, hyperinsulinemia, and insulin resistance are also associated with aberrant lipid handling by the small intestine. Despite these effects of elevated insulin, little is known about the expression or roles of the insulin receptor (IR) within intestinal epithelial cells (IEC). Two IR isoforms, IR-A and IR-B are linked to growth or metabolic actions on insulin, respectively. This dissertation tested the following hypotheses: 1) IR-A and IR-B are differentially expressed in highly proliferative intestinal epithelial stem cells (IESC), progenitors or colorectal cancer (CRC) cells versus post-mitotic or differentiated IEC/CRC and 2) genetic deletion of both IR isoforms in all IEC subtypes promotes IESC hyper-proliferation and impacts whole body glucose tolerance or insulin status in the basal state or during high fat diet (HFD)-induced obesity and hyperinsulinemia. Results: There is a gradient of IR-A and IR-B expression along the crypt villus axis. IR-A predominates in the proliferative IESC and progenitors and IR-B predominates in post-mitotic, differentiated lineages. IR-B is decreased in early precancerous adenomas in mice, and in aggressively growing human CRC cell lines. Lentivirus-mediated IR-B expression reduced proliferation of both Caco-2 and aggressively growing SW480 CRC cells and accelerated differentiation and barrier function in Caco-2 cells. Altered expression of pre-mRNA splicing factors muscleblind-like 2 (MBNL2) or CUG-triplet repeat RNA binding protein 1(CUGBP1) accompanied IR isoform switching in adenomas or CRC cell lines. Genetic deletion of both IR isoforms in IEC did not affect intestinal development, intestinal growth parameters, or glucose tolerance in lean, adult mice fed normal chow. During HFD, mice with IEC-specific IR deletion exhibited delayed weight gain and were protected from HFD-induced hyperinsulinemia and increases in mRNAs encoding the cholesterol transporter Scarb1 and Paneth cell-derived antimicrobial mRNAs. We conclude that IR-B, typically considered the metabolic IR, has functional and beneficial roles to limit proliferation and promote differentiation of CRC, and restrict IESC proliferation during chronic HFD feeding. Conversely, loss of IR protects against several potentially adverse metabolic consequences of chronic HFD feeding, suggesting that intestinal IR normally contributes to metabolic dysfunction during HFD
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  • In Copyright
Advisor
  • Lund, Pauline Kay
Degree
  • Doctor of Philosophy
Graduation year
  • 2014
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