Metformin Decreases the Incidence of Pancreatic Ductal Adenocarcinoma Promoted by Diet-induced Obesity in the Conditional KrasG12D Mouse Model

Hui-Hua Chang,Fang Hao,Andrea I Schmidt,Guido Eibl,Caroline Ei Ne Chou,James Sinnett-Smith,Samuel French,Aune Moro,Enrique Rozengurt,O Joe Hines,David W Dawson

doi:10.1038/s41598-018-24337-8

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a particularly deadly disease. Chronic conditions, including obesity and type-2 diabetes are risk factors, thus making PDAC amenable to preventive strategies. We aimed to characterize the chemo-preventive effects of metformin, a widely used anti-diabetic drug, on PDAC development using the KrasG12D mouse model subjected to a diet high in fats and calories (HFCD). LSL-KrasG12D/+;p48-Cre (KC) mice were given control diet (CD), HFCD, or HFCD with 5 mg/ml metformin in drinking water for 3 or 9 months. After 3 months, metformin prevented HFCD-induced weight gain, hepatic steatosis, depletion of intact acini, formation of advanced PanIN lesions, and stimulation of ERK and mTORC1 in pancreas. In addition to reversing hepatic and pancreatic histopathology, metformin normalized HFCD-induced hyperinsulinemia and hyperleptinemia among the 9-month cohort. Importantly, the HFCD-increased PDAC incidence was completely abrogated by metformin (p < 0.01). The obesogenic diet also induced a marked increase in the expression of TAZ in pancreas, an effect abrogated by metformin. In conclusion, administration of metformin improved the metabolic profile and eliminated the promoting effects of diet-induced obesity on PDAC formation in KC mice. Given the established safety profile of metformin, our findings have a strong translational potential for novel chemo-preventive strategies for PDAC.

Highlights

We demonstrated that metformin potently stimulates AMP–activated protein kinase (AMPK) activation in Pancreatic ductal adenocarcinoma (PDAC) cells cultured in physiological glucose[15,16] and inhibited the mammalian target of rapamycin 1 and extracellular signal-regulated kinase (ERK) via AMPK at low concentrations[15,16,17]
To examine the effects of metformin on PDAC promoted by diet-induced obesity, we used a mouse model, in which an obesogenic diet markedly accelerated the development of PDAC in KC mice[11,12]
We demonstrate that orally administered metformin significantly prevents the development of PDAC in a relevant mouse model characterized by obesity and insulin resistance

Summary

Introduction

The insulin-lowering effects of metformin may contribute to its anti-cancer activity since insulin is a known mitogenic factor and hyperinsulinemia is one of the proposed mechanisms through which obesity promotes cancer. We used this animal model to characterize the chemo-preventive effects of metformin on obesity-related PDAC development. Oral administration of metformin attenuated or even reversed the pathologic results of DIO in this model, including metabolic disturbances and increased PDAC incidence. These results suggest that metformin offers a potentially novel approach for prevention/interception of obesity-associated PDAC

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