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Reduced susceptibility of muscle-specific insulin receptor knockout mice to colon carcinogenesis
Kafi N Ealey1, Suying Lu, Dominic Lau
1Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Abstract:
Insulin resistance is a risk factor for colon cancer, but it is not clear which of its metabolic sequelae are involved. The objective of this study was to determine whether increased adiposity and elevated circulating lipids commonly seen in insulin resistance promote colon carcinogenesis independent of changes in insulin. We made use of muscle-specific insulin receptor knockout (MIRKO) mice that exhibit elevated serum triglycerides (TG), free fatty acids (FFA), and fat mass but have similar body weights, circulating glucose, and insulin and insulin sensitivity to their wild-type littermates used as controls. Seven-week-old male MIRKO mice and controls received four weekly intraperitoneal injections of either 5 mg/kg azoxymethane (AOM) to induce aberrant crypt foci (ACF) or 10 mg/kg AOM to induce tumors and were killed at 24 or 40 wk of age, respectively. The MIRKO mice displayed hyperinsulinemia at 7 wk of age and reduced insulin sensitivity at 16 wk of age compared with controls. The previously reported MIRKO phenotype developed between 16 and 24 wk of age. By 40 wk of age, however, MIRKO mice were again insulin resistant. ACF development did not differ between MIRKO mice and controls, but MIRKO mice developed significantly fewer colon tumors. Our results suggest that circulating TG and FFA are not promoters of colon tumor development. Indeed, we show that the cumulative effects of the metabolic changes that occur with knockout of the insulin receptor in muscle are associated with reduced susceptibility to colon tumorigenesis.
Insights
Insulin resistance is linked to colon cancer. This study found that elevated triglycerides and free fatty acids, common in insulin resistance, do not promote colon tumor growth. Muscle insulin receptor knockout mice showed reduced tumor development.
Area of Science:
- Metabolic research
- Cancer research
- Endocrinology
Background:
- Insulin resistance is a known risk factor for colon cancer.
- The specific metabolic factors driving this association remain unclear.
- Increased adiposity and elevated circulating lipids are common in insulin resistance.
Purpose of the Study:
- To investigate if increased adiposity and elevated circulating lipids promote colon carcinogenesis independently of insulin changes.
- To determine the role of metabolic sequelae of insulin resistance in colon cancer development.
Main Methods:
- Utilized muscle-specific insulin receptor knockout (MIRKO) mice exhibiting elevated triglycerides (TG), free fatty acids (FFA), and fat mass.
- Administered azoxymethane (AOM) to induce aberrant crypt foci (ACF) and tumors in MIRKO and control mice.
- Monitored metabolic parameters, insulin sensitivity, and tumor development over time.
Main Results:
- MIRKO mice showed hyperinsulinemia and reduced insulin sensitivity, developing the expected phenotype.
- No significant difference in ACF development was observed between MIRKO and control mice.
- MIRKO mice developed significantly fewer colon tumors compared to controls, suggesting a protective effect.
Conclusions:
- Circulating triglycerides and free fatty acids do not appear to promote colon tumor development.
- Metabolic changes resulting from muscle insulin receptor knockout are associated with reduced susceptibility to colon tumorigenesis.
- The study suggests a complex interplay between insulin signaling, metabolic alterations, and colon cancer risk.
