Diabetes Promotes DMH-Induced Colorectal Cancer by Increasing the Activity of Glycolytic Enzymes in Rats

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Abstract

The objective of the present study was to investigate the association between diabetes mellitus and colorectal carcinogenesis as well as the possible mechanism involved in this interaction. Diabetes rat models were induced with a low dose of STZ followed by a low dose of DMH to induce colorectal cancer. The formation of ACF in the colon and the incidence, number and size of tumors were measured. The activity of glycolytic enzymes in colonic tissues was also measured. The results demonstrated that both the total number of ACF and the number of foci that contain a different number of crypts were increased in diabetic rats. At the end of the experimental treatment, the incidence, number and size of tumors were also increased in diabetic rats. Overall, these data indicated that diabetes increased the risk of colorectal cancer. The activity of HK and PK in colonic tissues was increased in diabetic rats, whereas the activity of PDH was decreased. In addition, the activities of these enzymes in intratumor were higher than that of in peritumor. These data indicated that the high rate of glycolysis may play a role in colorectal carcinogenesis in diabetic rats.

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Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening.

K. SRINIVASAN, B Viswanad, Lydia Asrat … (2005)

The objective of the present study was to develop a rat model that replicates the natural history and metabolic characteristics of human type 2 diabetes and is also suitable for pharmacological screening. Male Sprague-Dawley rats (160-180 g) were divided into two groups and fed with commercially available normal pellet diet (NPD) (12% calories as fat) or in-house prepared high-fat diet (HFD) (58% calories as fat), respectively, for a period of 2 weeks. The HFD-fed rats exhibited significant increase in body weight, basal plasma glucose (PGL), insulin (PI), triglycerides (PTG) and total cholesterol (PTC) levels as compared to NPD-fed control rats. Besides, the HFD rats showed significant reduction in glucose disappearance rate (K-value) on intravenous insulin glucose tolerance test (IVIGTT). Hyperinsulinemia together with reduced glucose disappearance rate (K-value) suggested that the feeding of HFD-induced insulin resistance in rats. After 2 weeks of dietary manipulation, a subset of the rats from both groups was injected intraperitoneally with low dose of streptozotocin (STZ) (35 mg kg(-1)). Insulin-resistant HFD-fed rats developed frank hyperglycemia upon STZ injection that, however, caused only mild elevation in PGL in NPD-fed rats. Though there was significant reduction in PI level after STZ injection in HFD rats, the reduction observed was only to a level that was comparable with NPD-fed control rats. In addition, the levels of PTG and PTC were further accentuated after STZ treatment in HFD-fed rats. In contrast, STZ (35 mg kg(-1), i.p.) failed to significantly alter PI, PTG and PTC levels in NPD-fed rats. Thus, these fat-fed/STZ-treated rats simulate natural disease progression and metabolic characteristics typical of individuals at increased risk of developing type 2 diabetes because of insulin resistance and obesity. Further, the fat-fed/STZ-treated rats were found to be sensitive for glucose lowering effects of insulin sensitizing (pioglitazone) as well as insulinotropic (glipizide) agents. Besides, the effect of pioglitazone and glipizide on the plasma lipid parameters (PTG and PTC) was shown in these diabetic rats. The present study represents that the combination of HFD-fed and low-dose STZ-treated rat serves as an alternative animal model for type 2 diabetes simulating the human syndrome that is also suitable for testing anti-diabetic agents for the treatment of type 2 diabetes.

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Insulin, insulin-like growth factors and colon cancer: a review of the evidence.

E Giovannucci (2001)

Insulin and insulin-like growth factor (IGF) axes are major determinants of proliferation and apoptosis and thus may influence carcinogenesis. In various animal models, modulation of insulin and IGF-1 levels through various means, including direct infusion, energy excess or restriction, genetically induced obesity, dietary quality including fatty acid and sucrose content, inhibition of normal insulin secretion and pharmacologic inhibition of IGF-1, influences colonic carcinogenesis. Human evidence also associates high levels of insulin and IGF-1 with increased risk of colon cancer. Clinical conditions associated with high levels of insulin (noninsulin-dependent diabetes mellitus and hypertriglyceridemia) and IGF-1 (acromegaly) are related to increased risk of colon cancer, and increased circulating concentrations of insulin and IGF-1 are related to a higher risk of colonic neoplasia. Determinants and markers of hyperinsulinemia (physical inactivity, high body mass index, central adiposity) and high IGF-1 levels (tall stature) are also related to higher risk. Many studies indicate that dietary patterns that stimulate insulin resistance or secretion, including high consumption of sucrose, various sources of starch, a high glycemic index and high saturated fatty acid intake, are associated with a higher risk of colon cancer. Although additional environmental and genetic factors affect colon cancer, the incidence of this malignancy was invariably low before the technological advances that rendered sedentary lifestyles and obesity common, and increased availability of highly processed carbohydrates and saturated fatty acids. Efforts to counter these patterns are likely to have the most potential to reduce colon cancer incidence, as well as cardiovascular disease and diabetes mellitus.

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Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings.

R P Bird (1987)

In the present study a methodological approach is taken which quantitates aberrant dysplastic crypts in the unsectioned murine colon. C57BL/6J or CF1 female mice (7-8 weeks old) were injected (i.p.) with azoxymethane (5 mg/kg body wt./week) for 4 weeks. Their colons were excised, cut open on the median axis and fixed flat in buffered formalin. Unsectioned colons were stained with methylene blue. The mucosal side was examined under a light microscope. The aberrant crypts, which are larger and have a thicker epithelial lining, were easily visualized using X 4 or X 10 objectives. CF1 mice, which are more sensitive to developing colon tumors, had a higher number of aberrant crypts/colon than their less sensitive counterparts, C57BL/6J mice (5.0 +/- 0.7 vs. 2.4 +/- 0.7). The usefulness of this observation as a possible measure of neoplastic events is discussed in the animal and human situation.

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Author and article information

Contributors

Daotai Nie: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 17 October 2014

Volume: 9

Issue: 10

Electronic Location Identifier: e110455

Affiliations

[1 ]Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, China

[2 ]Department of Gastroenterology, 456 Hospital of PLA, Jinan, Shandong, China

[3 ]Department of Pathology, 456 Hospital of PLA, Jinan, Shandong, China

Southern Illinois University School of Medicine, United States of America

Author notes

* E-mail: tiankeli@ 123456sdu.edu.cn

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: YJ GX KT. Performed the experiments: YJ GX WZ ZW. Analyzed the data: YJ GX KT. Contributed reagents/materials/analysis tools: YJ WZ ZW LM SZ XX HY. Contributed to the writing of the manuscript: YJ KT.

¶ YJ and GX are co-authors on this work.

Article

Publisher ID: PONE-D-14-22412

DOI: 10.1371/journal.pone.0110455

PMC ID: 4201553

PubMed ID: 25329503

SO-VID: 1fade7fa-4ad7-4cdc-8efa-cc2badd7e1bb

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 4 June 2014

Date accepted : 12 September 2014

Page count

Pages: 9

Funding

This work was supported by The Natural Science Foundation of Shandong Province (2009ZRB01346). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Diabetes Promotes DMH-Induced Colorectal Cancer by Increasing the Activity of Glycolytic Enzymes in Rats

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Most cited references 28

Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening.

Insulin, insulin-like growth factors and colon cancer: a review of the evidence.

Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings.

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