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

• Published in: Scientific reports 2018-04, Vol.8 (1), p.5899-10, Article 5899
• Main Authors: Chang, Hui-Hua, Moro, Aune, Chou, Caroline Ei Ne, Dawson, David W., French, Samuel, Schmidt, Andrea I., Sinnett-Smith, James, Hao, Fang, Hines, O. Joe, Eibl, Guido, Rozengurt, Enrique
• Format: Article
• Language: English
• Subjects: 631/67/1504; 631/67/2195; 64; 64/60; Adenocarcinoma; Administration, Oral; Animals; Antidiabetics; Body weight gain; Calories; Carcinogenesis - drug effects; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogenesis - pathology; Carcinoma, Pancreatic Ductal - etiology; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Carcinoma, Pancreatic Ductal - prevention & control; Chemoprevention - methods; Chronic illnesses; Diabetes mellitus; Diet; Diet, High-Fat - adverse effects; Disease Models, Animal; Drinking Water; Fatty liver; Fatty Liver - etiology; Fatty Liver - genetics; Fatty Liver - pathology; Fatty Liver - prevention & control; Female; Gene Expression Regulation; Histopathology; Humanities and Social Sciences; Humans; Hyperinsulinemia; Hyperinsulinism - etiology; Hyperinsulinism - genetics; Hyperinsulinism - pathology; Hyperinsulinism - prevention & control; Male; Mechanistic Target of Rapamycin Complex 1 - genetics; Mechanistic Target of Rapamycin Complex 1 - metabolism; Metformin; Metformin - pharmacology; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; multidisciplinary; Obesity; Obesity - etiology; Obesity - genetics; Obesity - pathology; Obesity - prevention & control; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - etiology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - prevention & control; Proto-Oncogene Proteins p21(ras) - deficiency; Proto-Oncogene Proteins p21(ras) - genetics; Risk factors; Rodents; Science; Science (multidisciplinary); Steatosis; Transcription Factors - genetics; Transcription Factors - metabolism; Weight Gain - drug effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-24337-8

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 Kras G12D mouse model subjected to a diet high in fats and calories (HFCD). LSL-Kras G12D /+ ; 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