||5R01CA088007-03 Interpret this number
||University Of Colorado Denver
||Insulin Resistance and Adenomas of the Colorectum
There is considerable evidence that insulin and/or insulin-like
growth factors (IGFs) can increase risk of colorectal neoplasia. Epidemiologic
risk factors for colorectal neoplasia are similar to those for insulin
resistance syndromes, and prospective studies have shown both diabetes and
higher levels of IGF-1 to be associated with colorectal cancer risk. No
previous studies have included direct measures of insulin resistance, nor have
any included complete ascertainment of colorectal neoplasia by direct
examination of the entire colorectum. This study will assess the relationship
between insulin resistance and colorectal neoplasia by taking advantage of a
unique opportunity to examine a multi-ethnic cohort on whom prior measures of
insulin sensitivity have been made. The Insulin Resistance and Atherosclerosis
Study (IRAS) is a cohort study supported by the National Heart Lung and Blood
Institute. IRAS examined 1628 people of average age 55 in 1991-1994 for
atherosclerosis risk factors. The cohort, assembled in four clinical centers
(Alamosa, Co., Los Angeles, Oakland, and San Antonio) was established to be
multi-ethnic (34 percent Hispanic, 28 percent African American, and 38 percent
non-Hispanic white), bi-gender, and varied in diabetes risk. In 1998-1 999 over
85 percent of the surviving cohort was re-examined. Both of the examinations
have included measures of self-reported risk factors for atherosclerosis (diet,
physical activity, tobacco use, family history) as well as anthropometry and,
most importantly, oral glucose tolerance testing and frequently-sampled
intravenous glucose tolerance tests (FSIGT). The FSIGT is a sensitive and
specific measure of insulin resistance. All surviving cohort members (estimated
1518) will be invited to have a screening colonoscopy. Feasibility data
indicate that 1000 will agree to have a colonoscopic exam, among whom we
estimate 240 (range 206-274) will have adenomas. Mucosal biopsies will be taken
from the cecum and rectum of all subjects, and all adenomas will be removed and
examined for histologic features, Ki-ras mutations, proliferation, and
apoptosis. Serum samples will be assayed for insulin, IGF-1, IGFBPI, and IGFBP3
levels for all cohort members at both the time of colonoscopy, as well as at
the time of two earlier examinations (199 1-4 and 1998-9) using stored serum
samples. This study offers the advantage of the availability of prospective
measures of glucose tolerance, insulin resistance, measurements of most
colorectal neoplasia risk factors, and the availability of stored blood samples
from a multi-ethnic and bi-gender cohort. Complete colorectal visualization of
this entire cohort will enable unbiased estimates of colorectal neoplasia risk
related to these factors. This study therefore offers a time-efficient and a
cost-efficient method to test the hypothesis that colorectal neoplasia risk is
increased substantially by factors related to insulin resistance, and to
examine the biologic mechanisms whereby that risk is increased.
Nuclear accumulation of beta-catenin occurs commonly in the epithelial cells of juvenile polyps.
, Hoffenberg E.J.
, Carethers J.M.
, Doctolero R.
, Tajima A.
, Sugano K.
, Franklin W.A.
, Ahnen D.J.
Pediatric Research, 2005 Jan; 57(1), p. 4-9; discussion 1-3.