Insulin Resistance in Colon of Diabetic Rats: Mechanism for Carcinogenesis?

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 303-321-Cancer in Endocrine Tissues
Bench to Bedside
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-309
Swathi A.N. Rao*1, Hope Lao Torregosa1 and Betty Cheng Villafuerte2
1University of Louisville, Louisville, KY, 2Univ of Louisville Schl of Med, Louisville, KY
Epidemiologic studies suggest that type 2 diabetics with colon cancer have a higher recurrence rate and worse prognosis, but the mechanism relating insulin resistance to tumor promotion have not been established.  To test the hypothesis that insulin resistance in the metabolic pathway occurs in both insulin-sensitive tissue like the liver and in non-target tissue such as colon, leading to divergence of insulin signaling pathway towards the mitogenic pathway that leads to carcinogenesis, we compared insulin-induced signaling in the colonic mucosa of lean and diabetic Zucker rats.  Our studies showed that the phospho-Erk level was higher in the colon of diabetic compared to normal rats, but the insulin receptor, Akt and phospho-Akt levels were much lower in the colon of diabetic compared to normal rats, suggesting that hyperinsulinemia in diabetes led to down-regulation of insulin receptor expression, and a selective defect in the PI3-Akt signaling pathway in the colon.  This is similar to the signaling defect in the metabolic pathway observed in insulin-target tissue like the liver.  At the nuclear level, we have identified previously that the insulin-response element binding protein-1 (IRE-BP1) is a transcription factor that binds to insulin response elements (IREs) of multiple genes.  Expression of IRE-BP1 in diabetic liver reverses hyperglycemia by stimulating the metabolic actions of insulin.  IRE-BP1 appears to be a target of insulin signaling downstream of both PI3K-Akt and Erk pathways, and phosphorylation of IRE-BP1 by Akt enhances its transactivation function, while phosphorylation by Erk is inhibitory.  In the liver, IRE-BP1 is localized to the nucleus in lean rats but is sequestered to the cytoplasm in obese and diabetic rats, suggesting that nuclear localization is critical to induce the metabolic effects of insulin.  By contrast, nuclear localization of IRE-BP1 is enhanced in the colonic mucosa of diabetic compared to normal rats.  Since Akt signaling is impaired in diabetic colon, IRE-BP1 may be predominantly phosphorylated by Erk, leading to decreased IRE-BP1-mediated metabolic actions of insulin in the colon.  This is coupled to divergence of insulin signaling towards the mitogenic pathway of Erk stimulation.  In conclusion, resistance to metabolic actions of insulin may contribute to carcinogenesis in the colon in diabetes.  Whether this is related to expression of specific metabolic substrate or metabolic pathway, or whether similar mechanism occurs in the development of other type of tumors remain to be investigated.

Nothing to Disclose: SANR, HLT, BCV

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Sources of Research Support: University of Louisville CTRSP grant