Hyperinsulinemia, But Not Other Factors Associated with Insulin Resistance, Acutely Enhances Colorectal Epithelial Proliferation in Vivo

Abstract

The similarity in risk factors for insulin resistance and colorectal cancer (CRC) led to the hypothesis that markers of insulin resistance, such as elevated circulating levels of insulin, glucose, fatty acids, and triglycerides, are energy sources and growth factors in the development of CRC. The objective was thus to examine the individual and combined effects of these circulating factors on colorectal epithelial proliferation in vivo. Rats were fasted overnight, randomized to six groups, infused iv with insulin, glucose, and/or Intralipid for 10 h, and assessed for 5-bromo-2-deoxyuridine labeling of replicating DNA in colorectal epithelial cells. Intravenous infusion of insulin, during a 10-h euglycemic clamp, increased colorectal epithelial proliferation in a dose-dependent manner. The addition of hyperglycemia to hyperinsulinemia did not further increase proliferation. Intralipid infusion alone did not affect proliferation; however, the combination of insulin, glucose, and Intralipid infusion resulted in greater hyperinsulinemia than the infusion of insulin alone and further increased proliferation. Insulin infusion during a 10-h euglycemic clamp decreased total IGF-I levels and did not affect insulin sensitivity. These results provide evidence for an acute role of insulin, at levels observed in insulin resistance, in the proliferation of colorectal epithelial cells in vivo.

Association Between Hyperglycemia and Survival in Patients With Newly Diagnosed Glioblastoma

“…31 In vivo studies have shown that high insulin levels enhance colorectal and breast cancer cell proliferation via receptors on the tumors. 32,33 Furthermore, treatment with metformin, which lowers insulin levels, decreases the incidence and size of mammary adenocarcinomas in tumor-prone transgenic mice. 34 Human glial tumors possess insulin receptors with binding activities and characteristics identical to peripheral insulin receptors, and insulin has been shown to stimulate glucose uptake in cultures of human GBM cells.…”

Insulin, Insulin-like Growth Factor-I, Endogenous Estradiol, and Risk of Colorectal Cancer in Postmenopausal Women

“…For example, insulin binding to the IR leads to activation of IR substrate molecules and the downstream activation of the mitogen-activated protein kinase pathway. Furthermore, animal models have found that high insulin levels promote the development of aberrant crypt foci in the colon, which are posited to be colorectal cancer precursors (4), and overexpression of the IR can induce cell transformation in vitro (5). x Multivariate model plus waist circumference, insulin, free IGF-I and HT/E2.…”

“…Insulin resistance and hyperinsulinemia are prevalent in obese patients and insulin, in addition to its metabolic effects, has promitotic and antiapoptotic activity that may be tumorigenic. In laboratory models, for example, high insulin levels have been shown to promote the development of aberrant crypt foci in the colon (which are posited to be colorectal cancer precursors), as well as the growth of colon cancer cells (4). Furthermore, overexpression of the insulin receptor (IR) can induce cell transformation in vitro (5), and human colorectal adenocarcinomas have been shown to express the IR at high levels, indicating that these cells may be sensitive to the growth effects of insulin (6).…”

Association of the TCF7L2 polymorphism with colorectal cancer and adenoma risk

“…Specifically, Grant et al (2006) demonstrated that a polymorphism in TCF7L2 is associated with increased risk of type II diabetes (T2D) [6][7][8][9][10][11][12] by impaired beta-cell function [7,9]. Epidemiologic studies have suggested that hyperinsulinemia may be related to the risk of colon adenoma and cancer [13][14][15][16]. Given its relevance to the etiology of colorectal cancer, we evaluated the association of the TCF7L2 (RS12255372) polymorphism with colorectal cancer and adenoma in the prospective Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS) cohorts.…”