Increasing evidence from both model systems and epidemiologic studies support that insulin resistance resulting from long-term energy imbalance plays an important role in colon carcinogenesis. The fact that the incidences of obesity, insulin resistance syndrome, and type 2 diabetes are escalating at epidemic pace worldwide makes the exploration of the insulin resistance-colon neoplasia hypothesis a subject of pressing priority. We hypothesize that candidate genes and associated biomarkers in the insulin-growth hormone-insulin-like growth factor (IGF)-insulin receptor substrate 1 (IRS-1) axis, adipogenesis pathway (adiponectin, and peroxisome proliferator-activated receptor-gamma), and dietary factors may work jointly to drive the development of insulin resistance syndrome, and subsequently, the development of colon adenomatous polyps, established precursors of colon cancer. We propose a screening colonoscopy-based incident case-control study to address the insulin resistance syndrome-colon polyp hypothesis by prospectively recruiting 750 incident colon polyp cases and 750 frequency-matched controls. We will determine the candidate gene variants and haplotypes, associated biomarkers, and insulin resistance syndrome related serum markers using blood samples, and collect dietary and lifestyle risk factor information using questionnaires. We will analyze the resulting information using novel statistical models to gain comprehensive understanding of the link between insulin resistance syndrome and colon polyps. Specifically, we will 1) to investigate the impact of insulin resistance syndrome as an integral entity on colon polyps; 2) to examine the impact of candidate genes and associated biomarkers in the insulin-GH-IGF-IRS axis and adipogenesis pathway on colon polyps; 3) to evaluate the association of dietary patterns, glycemic index and glycemic load with colon polyps; and 4) to synthesize the information on candidate genes, biomarkers, and diet by looking at their joint effects on colon polyps, and to comprehensively evaluate these factors' potential direct as well as indirect (mediated by insulin resistance syndrome) impact on colon polyps. Our study will contribute to our understanding of how insulin resistance syndrome pathway-related candidate genes and dietary factors might work in concert in the etiology of colon adenomatous polyps. Our study may have profound implication for public health prevention/intervention strategies targeting at the early stages of the colon adenoma-cancer continuum.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZCA1)
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Case Western Reserve University
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