Protective effect of metformin in CD1 mice placed on a high carbohydrate–high fat diet
Introduction
High consumption of dietary carbohydrate and fat has been shown to have a direct impact on the promotion, progression and mortality of some solid tumors, including prostate cancer (PCa) [1], [2], [3]. Epidemiological and laboratory evidence suggests that high levels of serum insulin and IGF-1 [4], [5] as well as the additional energy substrates [6], [7], [8] provided to tumor cells are possible mechanisms. We have previously reported that a HC–HF diet induces hyperinsulinemia, stimulates the growth of xenograft tumors, and conditions the serum conferring an increased mitogenic potential in vitro[9]. A low-fat diet reduces the incidences of prostate cancer development in a genetically predisposed animal model [10].
Metformin, a biguanide, is used as a first line anti-diabetic drug and also prescribed to patients with insulin resistant status such as polycystic ovary syndrome. Emerging studies have shown that metformin exhibits some anti-neoplastic activities both in vitro[11], [12] and in vivo[11], [13], [14], [15] in several tumors. It may be a candidate medication for intervention in cancer patients who are obese and hyperinsulinemic since it may improve their metabolic status and inhibit tumor growth [16], [17].
The present study was designed to optimize the dose–response of metformin in CD1 animals placed on a HC–HF diet for a relative long period of treatment. We sought to investigate the role of metformin in the intervention of PCa progression in a xenograft model under the influence of a HC–HF diet.
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Animals and diets
Twenty-five 7-week-old male CD1 mice (Charles River Laboratories, Canada) were randomly and evenly divided into five groups, which were a standard diet group (Std Diet), a HC–HF diet group (HC–HF Diet), and three groups receiving the HC–HF diet and a respective dose of 50, 100, or 250 mg/kg of metformin (Met-50, Met-100 and Met-250). The standard diet consisted of 50.0% carbohydrate, 18.8% protein, 6.0% fat, which provided 3.3 kcal/g calories (2018 Teklad Global 18% Protein Rodent Diet, Harlan
The HC–HF diet developed obesity and insulin resistance
Animals placed on the HC–HF diet with or without metformin for a period of 12 weeks appeared to be obese with a greasy coating except for those receiving metformin at a dose of 250 mg/kg. This high energy diet induced a metabolic status of insulin resistance (see details in the following sections).
Metformin significantly altered food and water consumption
Compared to those on the standard diet, animals on the HC–HF diet consumed significantly higher amount of food and water (Fig. 1A and B). Administration of metformin caused a significant reduction in
Discussion
The present study was conducted in normal male CD1 mice placed on a HC–HF (high energy) diet ad libitum for continuous 12 weeks with and without the administration of metformin at varying doses. The results showed that feeding the animals with the HC–HF diet induced obesity and insulin resistance. This was manifested with higher body weight (Fig. 2), stimulation of insulin secretion (Fig. 3B) and higher percent insulin utilization (Fig. 3C) but more glucose left in blood (Fig. 3A), and
Conclusion
Our study has demonstrated that feeding the animals with a HC–HF diet induces obesity and insulin resistances and the simultaneous administration of metformin influences both the systemic and cellular metabolisms. Metformin, at sufficient doses, is able to offer protection from the unfavorable metabolic consequences of the HC–HF diet.
Acknowledgments
This work was supported by grants from the Prostate Cancer Canada to V.V. and NCIC to M.P. The authors would like to thank Latha Jacob and Ye Wang for their excellent technical assistance as well as to Michelle Martin and Denise Pantlin, Comparative Research Sunnybrook Health Science Centre for their excellent technical support.
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