scholarly journals Association between Metformin Use and Clinical Outcomes Following Pancreaticoduodenectomy in Patients with Type 2 Diabetes and Pancreatic Ductal Adenocarcinoma

2020 ◽  
Vol 9 (6) ◽  
pp. 1953
Author(s):  
Daegwang Yoo ◽  
Nayoung Kim ◽  
Dae Wook Hwang ◽  
Ki Byung Song ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Overall Survival ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Clinical Outcomes ◽  
Ductal Adenocarcinoma ◽  
Time Varying ◽  
Start Date ◽  
Metformin Group ◽  
Time Varying Covariates

Retrospective studies on the association between metformin and clinical outcomes have mainly been performed on patients with non-resectable pancreatic ductal adenocarcinoma and may have been affected by time-related bias. To avoid this bias, recent studies have used time-varying analysis; however, they have only considered the start date of metformin use and not the stop date. We studied 283 patients with type 2 diabetes and pancreatic ductal adenocarcinoma following pancreaticoduodenectomy, and performed analysis using a Cox model with time-varying covariates, while considering both start and stop dates of metformin use. When start and stop dates were not considered, the metformin group showed significantly better survival. Compared with previous studies, adjusted analysis based on Cox models with time-varying covariates only considering the start date of postoperative metformin use showed no significant differences in survival. However, although adjusted analysis considering both start and stop dates showed no significant difference in recurrence-free survival, the overall survival was significantly better in the metformin group (Hazard ratio (HR), 0.747; 95% confidence interval (CI), 0.562–0.993; p = 0.045). Time-varying analysis incorporating both start and stop dates thus revealed that metformin use is associated with a higher overall survival following pancreaticoduodenectomy in patients with type 2 diabetes and pancreatic ductal adenocarcinoma.

scholarly journals A Pathway Analysis of Hereditary Hemochromatosis-related Genes and Pancreatic Ductal Adenocarcinoma Risk (FS11-05-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Sachelly Julián-Serrano ◽  
Kai Yu ◽  
Fangcheng Yuan ◽  
William Wheeler ◽  
Parisa Karimi ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Genetic Susceptibility ◽  
Pathway Analysis ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Ductal Adenocarcinoma ◽  
Cancer Case

Abstract Objectives Hereditary primary hemochromatosis is characterized by dysregulation of iron homeostasis and is caused by a genetic predisposition to absorb too much iron from foods. Hemochromatosis has been associated with some chronic diseases, including hepatocellular carcinoma and type 2 diabetes mellitus. Type 2 diabetes is an established risk factor and high red meat intake has been associated with pancreatic ductal adenocarcinoma (PDAC). We hypothesize that genetic susceptibility to hemochromatosis as determined by known hereditary hemochromatosis-related genes will be associated with PDAC. Methods We conducted a pathway analysis of genes known to contribute to hereditary hemochromatosis using the summary-based adaptive rank truncated product (sARTP) method on GWAS summary statistics derived from 9038 PDAC cases and 12,389 controls of European descent collected by the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PANC4).Our analysis included 7 hereditary hemochromatosis genes (HFE, BMP2, HJV, HAMP, TFR2, SLC40A1, and FTH1) and close genomic regions (20 kb upstream and 20 kb downstream) with a total of 176 single nucleotide polymorphisms (SNPs). The sARTP method combines SNP-level associations across SNPs in a gene or a pathway. Results The hereditary hemochromatosis pathway was significantly associated with PDAC (P-value = 0.011). HJV and TFR2 genes contributed the most to the association with PDAC risk (gene level P-values = 0.003 and 0.013, respectively). Conclusions This study supports the hypothesis that genetic susceptibility related to hereditary hemochromatosis genes are associated with PDAC. Further studies should evaluate the modifying effect of iron-rich foods and genetic susceptibility of hemochromatosis and PDAC risk. Funding Sources This work was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health.

scholarly journals Islet Inflammation: The Link between Type 2 Diabetes and Pancreatic Cancer

2021 ◽  
Author(s):  
Alpana Mukhuty
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Protein Protein Interactions ◽  
Proinflammatory Response ◽  
Islet Inflammation ◽  
Underlying Mechanisms ◽  
And Migration

The role of islet inflammation in type 2 diabetes (T2DM) and pancreatic ductal adenocarcinoma (PDAC) is complex. About 80% of pancreatic cancer patients have glucose intolerance or T2D. Chronic type 2 diabetes increases risk for pancreatic cancer, but the mechanisms are unknown. In this context two hypotheses exist: (i) pancreatic cancer causes diabetes and (ii) diabetes promotes the development of pancreatic cancer. Pancreatic ductal adenocarcinoma is the most common and deadly form of pancreatic cancer that is associated with diabetes. There are many possibilities by which obesity links to pancreatic cancer. These possibilities include insulin resistance, hyperinsulinemia and inflammation. Adipose tissue deposition near pancreas (peri-pancreatic depot) increase proinflammatory response to a high fat or high calorie containing diet. Inflammatory processes in the islets act as main mediators during the development and progression of pancreatic cancer. Recently, studies have been carried out to investigate the underlying mechanisms that contribute to tumorigenesis induced by inflammation. Tumor-elicited inflammation, secretion of pro-inflammatory cytokines and migration of immune cells play the key roles in initiation, promotion and progression of malignant metastasis in pancreatic cancer. Initiation and progression of islet inflammation in diabetes and pancreatic cancer occurs as a result of various protein–protein interactions and genetic events. The increase in pancreatic cancer cases may be attributed to the obesity endemic and obesity mediated Type 2 diabetes. The existence of link between islet inflammation in chronic diabetes and pancreatic cancer cannot be ignored, although the details about the underlying mechanisms are not clear, and must be studied in detail.

scholarly journals Metformin alters the duodenal microbiome and decreases the incidence of pancreatic ductal adenocarcinoma promoted by diet-induced obesity

2019 ◽  
Vol 317 (6) ◽  
pp. G763-G772 ◽  
Author(s):  
Tien S. Dong ◽  
Hui-Hua Chang ◽  
Meg Hauer ◽  
Venu Lagishetty ◽  
William Katzka ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Mouse Model ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Microbial Composition ◽  
Diet Induced Obesity ◽  
Potential Mediator

Pancreatic ductal adenocarcinoma (PDAC)’s growing incidence has been linked to the rise in obesity and type 2 diabetes mellitus. In previous work, we have shown that metformin can prevent the increased incidence of PDAC in a KrasG12D mouse model subjected to a diet high in fat and calories (HFCD). One potential way that metformin can affect the host is through alterations in the gut microbiome. Therefore, we investigated microbial associations with PDAC development and metformin use in the same mouse model. Lox-Stop-Lox Kras G12D/+ (LSL-Kras G12D/+); p48-Cre (KC) mice were given control diet, HFCD, or HFCD with 5 mg/mL metformin in drinking water for 3 mo. At the end of the 3 mo, 16S rRNA sequencing was performed to characterize microbiome composition of duodenal mucosal, duodenal luminal, and cecal luminal samples. KC mice on an HFCD demonstrated depletion of intact acini and formation of advanced pancreatic intraepithelial neoplasia. This effect was completely abrogated by metformin treatment. HFCD was associated with significant changes in microbial composition and diversity in the duodenal mucosa and lumen, much of which was prevented by metformin. In particular, Clostridium sensu stricto was negatively correlated with percent intact acini and seemed to be inhibited by the addition of metformin while on an HFCD. Administration of metformin eliminated PDAC formation in KC mice. This change was associated with significant microbial changes in both the mucosal and luminal microbiome of the duodenum. This suggests that the microbiome may be a potential mediator of the chemopreventive effects of metformin. NEW & NOTEWORTHY Pancreatic ductal adenocarcinoma (PDAC)’s growing incidence has been linked to the rise in obesity and type 2 diabetes mellitus. Administration of metformin eliminated PDAC formation in KC mice with diet-induced obesity. This change was associated with significant microbial changes in both the mucosal and luminal microbiome of the duodenum. This suggests that the microbiome may be a potential mediator of the chemopreventive effects of metformin.

Retrospective survival analysis in patients with metastatic pancreatic ductal adenocarcinoma with insulin-treated type 2 diabetes mellitus

2020 ◽  
pp. 030089162097694
Author(s):  
Andrea Pretta ◽  
Pina Ziranu ◽  
Marco Puzzoni ◽  
Eleonora Lai ◽  
Giulia Orsi ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Overall Survival ◽  
Validation Cohort ◽  
Medical Oncology ◽  
Univariate Analysis ◽  
University Hospital ◽  
Ductal Adenocarcinoma ◽  
Diabetic Patients

Introduction: The association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated and the role of antidiabetic medications such as metformin has also been investigated. The objective of this study was to examine the association between insulin use and overall survival (OS) in patients with advanced PDAC and DM2. Methods: We retrospectively collected data from 164 patients, including an exploratory cohort of 96 patients from Medical Oncology Unit, University Hospital and University of Cagliari, Italy, and a validation cohort of 68 patients from Medical Oncology of Modena University Hospital. Patients had metastatic disease and received a first-line gemcitabine-based chemotherapy and, subsequently, a second-line fluoropyrimidines-based chemotherapy. We performed univariate analysis to evaluate correlation between long-term diabetes and overall survival. Then we performed multivariate analysis, adjusting for sex, metastatic sites, Eastern Cooperative Oncology Group Performance Status, Ca19.9 levels, N/L ratio, and lactate dehydrogenase levels at diagnosis, to confirm the independence of the variable. Results: In the exploratory cohort, DM2 was significantly associated with higher median OS at univariate analysis (16 vs 10 months; p = 0.004). This result was confirmed by validation cohort (11 months vs 6 months; p = 0.01). In multivariate analysis, insulin-treated patients compared with non diabetic patients showed a significantly increased survival of 4.6 months ( p = 0.03). Conclusions: Patients with insulin-treated metastatic PDAC showed better OS than non diabetic patients, as demonstrated by both cohorts. The correlation between OS and insulin-treated DM2 should be investigated further through a prospective clinical trial.

scholarly journals EXPRESSION OF HIF-1α IN A PANCREATIC DUCTAL ADENOCARCINOMA IN A PATIENT WITH NEWLY DIAGNOSED TYPE 2 DIABETES

2018 ◽  
Vol 4 (3) ◽  
pp. e263-e266
Author(s):  
Jessica R. Weaver ◽  
Carolina M. Casellini ◽  
Henri K. Parson ◽  
Aaron I. Vinik
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Newly Diagnosed
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