Insulin Resistance, Apoptosis, and Colorectal Adenoma Risk

Abstract

Compelling evidence from epidemiologic studies indicates that elevated circulating insulin-like growth factor (IGF)-I, insulin resistance, and associated complications, such as elevated fasting plasma insulin, glucose and free fatty acids, glucose intolerance, increased body mass index, and visceral adiposity, are linked with increased risk of colorectal cancer. However, the role of insulin and markers of glucose control in the development of adenomas, precursors to colorectal cancer, has not been fully explored. We evaluated the relationship between plasma insulin, glucose, IGF-I, IGF-II, IGF-binding protein-3 (IGFBP-3), apoptosis, and colorectal adenomas in a case-control study. Participants were drawn from consenting patients undergoing colonoscopy at the University of North Carolina hospitals (Chapel Hill, NC). Participants were classified as cases or controls based on whether they had one or more colorectal adenomatous polyps. Fasting plasma insulin, IGF-I, IGF-II, and IGFBP-3 levels were assessed by ELISA. Glucose was measured by glucose hexokinase assay. Apoptosis was assessed by morphology on H&E-stained sections. Dietary and lifestyle information were obtained by telephone interview. Logistic regression was used to examine the association between adenoma status and insulin-IGF markers. Adenoma cases (n = 239) and adenoma-free controls (n = 517) provided rectal biopsies and/or blood samples and interview data. Consistent with prior findings, cases were more likely to be males, older, have higher waist-to-hip ratio, lower calcium intake, lower apoptosis, and less likely to report nonsteroidal anti-inflammatory drug use. Those in the highest quartile of insulin (adjusted odds ratio, 2.2; 95% confidence interval, 1.1-4.2) and glucose (adjusted odds ratio, 1.8; 95% confidence interval, 0.9-3.6) were more likely to have an adenoma compared with the lowest quartile. Similarly, subjects in the highest two quartiles of insulin were more likely to be in the lowest two quartiles of apoptosis. Overall, there were no significant differences between mean circulating levels of glucose, IGF-I, IGF-II, and IGFBP-3 among cases and controls and no association between these variables and apoptosis. The results provide novel evidence that elevated insulin and glucose are associated with increased adenoma risk and decreased apoptosis in normal rectal mucosa. These findings suggest that insulin may act early in the adenoma-carcinoma sequence to promote the development of colorectal adenoma by decreasing apoptosis in the normal mucosa. (Cancer Epidemiol Biomarkers Prev 2005;14(9):2076 -81)

Gender difference in the association of insulin and the insulin-like growth factor axis with colorectal neoplasia

“…The association of insulin and the IGF axis with colorectal adenoma has been investigated in at least 10 studies to date. 10,[16][17][18][19][20][21][22][23][24] Nevertheless, all were conducted in only three countries, the United States, the United Kingdom and Japan, and significant associations were mainly reported in the former two countries. This discrepancy is probably best explained as the sum of several differences in demographic characteristics between Japan and the other two countries including genetic predisposition.…”

“…In fact, there are only two studies of colorectal neoplasia in which circulating levels of these biomarkers were investigated for men and women separately in the same study settings, albeit both studies did not find any association in either men or women. 9,10 Further, no meta-analysis has been conducted for men and women separately to date.…”

“…However, epidemiological evidence for this possible gender difference is limited to date, and few previous studies have examined the association of insulin and the IGF axis with colorectal neoplasia for men and women separately in the same study settings. 9,10 Here, we measured plasma concentrations of C-peptide, a biomarker of pancreatic insulin secretion, IGF-I, IGFBP-1 and IGFBP-3 among middle-aged and elderly Japanese, and compared the association of these biomarkers with colorectal adenoma between men and women.…”

Increased rectal microbial richness is associated with the presence of colorectal adenomas in humans

“…Exclusion criteria included colitis (either ulcerative, Crohn's, radiation or infectious colitis, chronic inflammatory illnesses), previous colonic or small bowel resection, previous colon adenomas or colon cancer, sigmoidoscopy or incomplete colonoscopies, familial polyposis syndrome. The enrollment procedure as well as colonoscopy and biopsy procedures are similar to previously described protocols (Keku et al, 2005;Shen et al, 2010).…”

Insulin Resistance Reduces Sensitivity to Cis-Platinum and Promotes Adhesion, Migration and Invasion in HepG2 Cells

“…IR is an established risk factor for patients with hepatocellular carcinoma (HCC) due to the hypoxic and ischemic conditions encountered during tumor progression. Several studies revealed that IR was a prognostic factor for the postoperative recurrence of HCC (Yoshikawa et al, 2001;Keku et al, 2005;Soliman et al, 2006;Turati et al, 2013). However, the specific mechanism of IR and its relationship with multidrug resistance are unclear.…”