The Relationship Between Type 2 Diabetes And Pancreatic Cancer And The Impact Of Metformin On Pancreatic Cancer Cell Growth

ObjectiveThe relationship between pancreatic cancer and diabetes mellitus is close and complex.To better understand the relationship and impact within each other,we intend to identify the clinical characteristics of pancreatic cancer(PC)with diabetes mellitus(DM)and to analyze impact of different factors on the onset age of PC.Recent evidences have demonstrated the potential role of metformin in anti-tumor growth and progression.To explore impact of metformin on pancreatic cancer in different doses of glucose,and to better understand the mechanism of metformin's anti-cancer effects.MethodsWe collected patients with PC and DM and analyzed basic information of the patients.The patients were divided into two subgroups according to the duration of DM:new-onset DM(?2years)and long term DM(>2years).We analyzed clinical characteristics,cancer features of the two subgroups,and the association between the onset age of PC and various factors including sex,life style,family history,past history and medications.In the second part,the PANC-1 pancreatic cancer cell lines were exposed to DMEM medium with high(25mM)or normal(5mM)glucose and treated with different doses of metformin(0/10/20mM).Cell proliferation,apoptosis,migration and cell cycle were assessed to explore the impact of metformin in different doses of glucose on pancreatic cancer growth.ResultsCompared with patients with long-term DM,the new-onset DM patients were younger at onset of PC(60.6±9.5years vs.64.4±9.0years,P<0.001),with a higher proportion of negative family history of DM(86.2%vs.75.7%,P=0.016),more loss of weight(9.0±7.0kg vs.5.0±5.0kg,P=0.003).The onset age of PC were younger in patients who were male?smoker?drinker.In vitro study showed that the proliferation of PANC-1 cells were almost totally inhibited when added with metformin(10mM?20mM)in 5mM glucose(29.25±4.33%to 0.00±0.00%,P<0.001),and the apoptosis proportion increased significantly(7.27±1.5%to 83.35±4.63%?95.85±4.85%,respectively,P<0.001).When treated with metformin(10mM?20mM)in 25mM glucose,PANC-1 cell proliferation was significantly reduced(30.48±2.76%to 16.02±3.26%?7.46±.57%,respectively,P<0.001),the apoptosis ratio increased significantly(22.19±3.85%to 44.13±9.47%?52.32±14.98%respectively,P<0.001).20mM metformin significantly inhibited cell migration in 5mM glucose(3.20±0.65%to 0.81±0.23%,P=0.004),whereas had no effect on cell migration when cultured in 25mM glucose.Metformin decreased G1 phase cell ratio(P<0.001)and increased S phase cell ratio(P<0.001).ConclusionsPatients newly diagnosed with DM might be at high risk to develop PC if they have no family history of DM,experienced obvious weight loss,or are drinkers or smokers,thus demanding further investigation for PC.Metformin can significantly decrease the proliferation and enhance the apoptosis of pancreatic cancer in vitro in a dose dependent way,which is more obvious in 5mM glucose than in 25mM glucose.High dose of metformin(20mM)can inhibit cell migration in normal glucose(5mM).Metformin can promote PANC-1 cel]cycle progression from phase G1 to phase S.