title: Direct measure of insulin sensitivity with the hyperinsulinemic-euglycemic clamp and surrogate measures of insulin sensitivity with the oral glucose tolerance test: correlations with aberrant crypt foci promotion in rats.
abstract: The similarity in lifestyle risk factors for the development of colorectal cancer (CRC) and type 2 diabetes suggests that there are common underlying pathogenic mechanisms. High-risk lifestyle factors may lead to insulin resistance that, through increased circulating levels of energy substrates, insulin, and insulin-like growth factor-1, may promote the development of CRC. The objective was to determine the extent to which direct and surrogate measures of insulin resistance correlate with multiplicity of aberrant crypt foci, which are putative precursors of CRC. Rats were initiated with the carcinogen azoxymethane, then fed low, intermediate, or high saturated fat diets. Metabolic parameters were assessed at 50 days and ACF at 100 days after initiation. Results indicate that CRC promotion was most strongly correlated with direct measures of insulin sensitivity as assessed with the hyperinsulinemic-euglycemic clamp (r = -0.52, P < 0.009). Practical surrogate measures of insulin resistance such as insulin levels at 180 min after an oral glucose load were strongly correlated with direct measures of insulin sensitivity (r = -0.61, P < 0.001) and with CRC promotion (r = 0.42, P = 0.044) in this animal model. Fasting levels of glucose, insulin, total insulin-like growth factor-1, nonesterified fatty acids, and triglyceride, as well as body weight and insulin sensitivity indices (such as fasting insulin resistance index, quantitative insulin sensitivity check index, homeostasis model assessment formula, insulin sensitivity index of glycemia, oral glucose insulin sensitivity, and composite insulin sensitivity index for the hepatic and peripheral tissues) were all less strongly correlated with direct measures of insulin sensitivity and all poorly correlated with CRC promotion in this animal model. These correlations do not prove causality, however, they suggest possible mechanisms linking diet, insulin resistance with its related parameters, and promotion of CRC.
authors.affiliation: Department of Nutritional Sciences, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
authors.forename: Thien T
authors.initials: TT
authors.lastname: Tran
authors.forename: Neehar
authors.initials: N
authors.lastname: Gupta
authors.forename: Tracy
authors.initials: T
authors.lastname: Goh
authors.forename: Dinaz
authors.initials: D
authors.lastname: Naigamwalla
authors.forename: Marie C
authors.initials: MC
authors.lastname: Chia
authors.forename: Niloofar
authors.initials: N
authors.lastname: Koohestani
authors.forename: Shruti
authors.initials: S
authors.lastname: Mehrotra
authors.forename: Gail
authors.initials: G
authors.lastname: McKeown-Eyssen
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
authors.forename: W Robert
authors.initials: WR
authors.lastname: Bruce
mesh_terms: D000818:Animals; D001397:Azoxymethane; D015179:Colorectal Neoplasms / Q000097:blood* / Q000139:chemically induced; D004041:Dietary Fats / Q000008:administration & dosage; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006946:Hyperinsulinism / Q000097:blood; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D011230:Precancerous Conditions / Q000097:blood* / Q000139:chemically induced; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D004041:Dietary Fats; D007328:Insulin; D001397:Azoxymethane