Protective effect of metformin in CD1 mice placed on a high carbohydrate–high fat diet

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Abstract

A high carbohydrate–high fat (HC–HF) diet-associated with hyperinsulinemia has been previously reported to induce accelerated growth of prostate cancer in a xenograft model. High energy supply and insulin/insulin growth factor-1 axis are two of the mechanisms proposed. We hypothesize that metformin may have a protective effect against prostate cancer progression by affecting metabolisms associated with high energy intake. In the present study, animals were randomized into five groups, receiving a HC–HF diet with 50, 100, or 250 mg/kg body weight (mg/kg) metformin in drinking water, a standard diet or HC–HF diet alone. Animals on the HC–HF diet developed obesity and insulin resistance. They had significantly higher body weight, fasting blood glucose at an upper level of normal range, higher insulin secretion and utilization, and fatty degeneration of the liver. Metformin at the doses employed significantly reduced food and water consumption; however, only a dose of 250 mg/kg showed a significant reduction in body weight gain and suppression of gluconeogenesis as well remarkably reduced insulin secretion. There was no observed metformin-related hepato-toxicity in any of the groups. In summary, metformin at various doses exhibits protective effects on the metabolic disorder caused by the HC–HF diet with the most effective protection at a dose of 250 mg/kg. These effects may explain its translational role relating to its anti-neoplastic potential.

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.

Section snippets

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.

References (22)

  • V. Venkateswaran et al.

    Association of diet-induced hyperinsulinemia with accelerated growth of prostate cancer (LNCaP) xenografts

    J. Natl. Cancer Inst.

    (2007)
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