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Sameni F, Elkhichi PA, Dadashi A, Sadeghi M, Goudarzi M, Eshkalak MP, Dadashi M. Global prevalence of Fusobacterium nucleatum and Bacteroides fragilis in patients with colorectal cancer: an overview of case reports/case series and meta-analysis of prevalence studies. BMC Gastroenterol 2025; 25:71. [PMID: 39930345 PMCID: PMC11808969 DOI: 10.1186/s12876-025-03664-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 01/31/2025] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the second deadliest carcinoma across the globe and has been known as a multi-factor induced-disease. Emerging research have demonstrated that bacterial colonization may contribute to the initiation and promotion of the CRC. The presence of Fusobacterium nucleatum (F. nucleatum) and Bacteroides fragilis (B. fragilis) in the gut is associated with the development of CRC. In this study, the prevalence of F. nucleatum and B. fragilis among CRC patients has been assessed worldwide through a systematic review and meta-analysis. METHODS The extensive search was performed using "Fusobacterium nucleatum", "Bacteroides fragilis", "Colorectal cancer" and all relevant keywords. Then, a systematic paper screening was done following a comprehensive search in Embase, Web of Science, and PubMed databases while the time range was limited between the years 2000 and 2024. Afterwards, statistical analysis was performed utilizing the comprehensive meta-analysis (CMA) software (version 2.0, Biostat, USA). RESULTS According to the meta-analysis of prevalence studies, the prevalence of F. nucleatum among 19 countries and B. fragilis among 10 countries were indicated to be 38.9% (95% CI 33.7-44.3%) and 42.5% (95% CI 34.4-51.1%), respectively, among the CRC patients. It was then revealed that Asia had the highest prevalence of F. nucleatum while most of the B. fragilis isolates in CRC cases were reported in European countries. Moreover, the data suggested that the most common comorbidity observed among the CRC cases was diabetes. CONCLUSION Our results emphasized the high prevalence of F. nucleatum and B. fragilis in CRC patients. Based on this meta-analysis review, regulating the gut microbiota in CRC patients seemed to be a promising approach to improving the efficacy of CRC therapy.
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Affiliation(s)
- Fatemeh Sameni
- Department of Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
- Molecular Microbiology Research Center, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Parisa Abedi Elkhichi
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Dadashi
- School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK
| | - Mohammad Sadeghi
- EA7375-EC2M3: Early, Detection of Colonic Cancer by Using Microbial & Molecular Markers,, Paris East Créteil University (UPEC), Créteil, 94010, France
| | - Mehdi Goudarzi
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Masoud Dadashi
- Department of Microbiology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.
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Liu P, Xiao J, Xiao J, Zhou J. Metformin and the risk of malignant tumors of digestive system: a mendelian randomization study. Diabetol Metab Syndr 2025; 17:6. [PMID: 39773528 PMCID: PMC11705776 DOI: 10.1186/s13098-024-01573-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 12/28/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Observational studies suggest that metformin may reduce the risk of malignant tumors of the digestive system (MTDS), but these findings are often confounded by bias and unmeasured variables. Recent meta-analyses have questioned these associations, emphasizing the need for robust causal inference. METHODS Mendelian randomization (MR) was used to evaluate the causal relationship between metformin and MTDS. Genetic variants associated with metformin's molecular targets were selected from GTEx, eQTLGen, and UK Biobank and validated using genetic colocalization to ensure instrument validity. GWAS summary statistics for MTDS, encompassing up to 314,193 controls and 6,847 colorectal cancer cases, were obtained from FinnGen and EBI. The primary analysis employed the inverse-variance weighted (IVW) method, supplemented by MR-Egger, weighted median, and weighted mode analyses. Bonferroni correction was applied to adjust for multiple testing across 14 cancer types. RESULTS Genetically proxied metformin use was associated with an increased risk of colorectal cancer (OR = 2.38, 95%CI = 1.38-4.09, P = 0.0018) and related subtypes. No causal relationship was found for hepatocellular carcinoma, gastric cancer, pancreatic cancer, or other digestive system cancers. The robustness of these findings was supported by sensitivity analyses, which indicated no significant pleiotropy, and leave-one-out tests. CONCLUSION This study provides robust genetic evidence that metformin use increases the risk of colorectal cancer, challenging its role as a preventive agent for digestive cancers. These findings emphasize the need for clinicians to carefully evaluate the risks and benefits of metformin, particularly in populations at higher risk for colorectal cancer. Future research should focus on delineating the mechanisms underlying this association to optimize the use of metformin in clinical practice.
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Affiliation(s)
- Ping Liu
- Department of Radiation Oncology and Hunan Key Laboratory of Translational Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, HunanCancer Hospital, Changsha, China
| | - Junqi Xiao
- Cancer center, The Second Affiliated Hospital, Hengyang Medical School, University of South China, No.35 of Jiefang Avenue, Hengyang City, P. R. China
| | - Jinghuang Xiao
- Department of Radiation Oncology and Hunan Key Laboratory of Translational Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, HunanCancer Hospital, Changsha, China
| | - Jumei Zhou
- Department of Radiation Oncology and Hunan Key Laboratory of Translational Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, HunanCancer Hospital, Changsha, China.
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Chen D, Ma Y, Li J, Wen L, Zhang G, Huang C, Yao X. Causality between insulin use and malignant tumors of the digestive system: a two-sample mendelian randomized study. BMC Cancer 2025; 25:31. [PMID: 39773128 PMCID: PMC11708065 DOI: 10.1186/s12885-025-13452-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 01/03/2025] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Existing cohort studies show no association between insulin use and cancers of the digestive system, while numerous meta-analyses suggest that insulin use increases the risk of digestive system tumours. This study uses two-sample Mendelian randomization (MR) to further investigate the causal relationship between the two. METHODS We selected single nucleotide polymorphisms (SNPs) strongly associated with insulin use as instrumental variables and used aggregated statistics on digestive system neoplasms as the outcome event. The primary method of analysis was inverse variance weighting (IVW), supplemented by weighted median, MR-Egger regression, weighted mode and simple mode methods. The reliability of the study was assessed by heterogeneity testing, pleiotropy analysis and sensitivity analysis. RESULT A total of 8 SNPs associated with insulin use were included as instrumental variables. Random-effects IVW analysis showed an association between insulin use and increased risk of colorectal cancer (OR = 1.1037, 95%CI = 1.0183-1.1962, P = 0.016). No statistically significant association was found between insulin use and the development of other digestive system tumours. The results were unaffected by pleiotropy and heterogeneity, and the reliability of the findings was confirmed by sensitivity analysis. CONCLUSION Our Mendelian randomization study suggests an association between insulin use and an increased risk of CRC, with no clear association observed for other digestive system tumours. However, further MR studies with larger sample sizes from genome-wide association study (GWAS) data are needed to verify this association.
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Affiliation(s)
- DengZhuo Chen
- Gannan Medical University, Ganzhou, China
- Ganzhou Hospital of Guangdong Provincial People's Hospital, Ganzhou Municipal Hospital, Ganzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
| | - YongLi Ma
- Ganzhou Hospital of Guangdong Provincial People's Hospital, Ganzhou Municipal Hospital, Ganzhou, China
| | - JingHui Li
- Gannan Medical University, Ganzhou, China
- Ganzhou Hospital of Guangdong Provincial People's Hospital, Ganzhou Municipal Hospital, Ganzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
| | - Liang Wen
- Gannan Medical University, Ganzhou, China
- Ganzhou Hospital of Guangdong Provincial People's Hospital, Ganzhou Municipal Hospital, Ganzhou, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
| | - GuoSheng Zhang
- Ganzhou Hospital of Guangdong Provincial People's Hospital, Ganzhou Municipal Hospital, Ganzhou, China
| | - ChengZhi Huang
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
| | - XueQing Yao
- Gannan Medical University, Ganzhou, China.
- Ganzhou Hospital of Guangdong Provincial People's Hospital, Ganzhou Municipal Hospital, Ganzhou, China.
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
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Luo Y, Yang L, Wu H, Xu H, Peng J, Wang Y, Zhou F. Exploring the Molecular Mechanism of Comorbidity of Type 2 Diabetes Mellitus and Colorectal Cancer: Insights from Bulk Omics and Single-Cell Sequencing Validation. Biomolecules 2024; 14:693. [PMID: 38927096 PMCID: PMC11201668 DOI: 10.3390/biom14060693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 06/06/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024] Open
Abstract
The relationship between type 2 diabetes mellitus (T2DM) and colorectal cancer (CRC) has long been extensively recognized, but their crosstalk mechanisms based on gene regulation remain elusive. In our study, for the first time, bulk RNA-seq and single-cell RNA-seq data were used to explore the shared molecular mechanisms between T2DM and CRC. Moreover, Connectivity Map and molecular docking were employed to determine potential drugs targeting the candidate targets. Eight genes (EVPL, TACSTD2, SOX4, ETV4, LY6E, MLXIPL, ENTPD3, UGP2) were identified as characteristic comorbidity genes for T2DM and CRC, with EVPL and ENTPD3 further identified as core comorbidity genes. Our results demonstrated that upregulation of EVPL and downregulation of ENTPD3 were intrinsic molecular features throughout T2DM and CRC and were significantly associated with immune responses, immune processes, and abnormal immune landscapes in both diseases. Single-cell analysis highlighted a cancer-associated fibroblast (CAF) subset that specifically expressed ENTPD3 in CRC, which exhibited high heterogeneity and unique tumor-suppressive features that were completely different from classical cancer-promoting CAFs. Furthermore, ENTPD3+ CAFs could notably predict immunotherapy response in CRC, holding promise to be an immunotherapy biomarker at the single-cell level. Finally, we identified that droperidol may be a novel drug simultaneously targeting EVPL and ENTPD3. In conclusion, previous studies have often focused solely on metabolic alterations common to T2DM and CRC. Our study establishes EVPL and ENTPD3 as characteristic molecules and immune biomarkers of comorbidity in T2DM and CRC patients, and emphasizes the importance of considering immunological mechanisms in the co-development of T2DM and CRC.
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Affiliation(s)
- Yongge Luo
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China
| | - Lei Yang
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China
- Hubei Provincial Clinical Research Center for Cancer, Wuhan 430071, China
| | - Han Wu
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China
- Hubei Provincial Clinical Research Center for Cancer, Wuhan 430071, China
| | - Hui Xu
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China
- Hubei Provincial Clinical Research Center for Cancer, Wuhan 430071, China
| | - Jin Peng
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China
- Hubei Provincial Clinical Research Center for Cancer, Wuhan 430071, China
| | - You Wang
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China
- Hubei Provincial Clinical Research Center for Cancer, Wuhan 430071, China
| | - Fuxiang Zhou
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China
- Hubei Provincial Clinical Research Center for Cancer, Wuhan 430071, China
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Kawakita E, Kanasaki K. Cancer biology in diabetes update: Focusing on antidiabetic drugs. J Diabetes Investig 2024; 15:525-540. [PMID: 38456597 PMCID: PMC11060166 DOI: 10.1111/jdi.14152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/25/2023] [Accepted: 01/08/2024] [Indexed: 03/09/2024] Open
Abstract
The association of type 2 diabetes with certain cancer risk has been of great interest for years. However, the effect of diabetic medications on cancer development is not fully understood. Prospective clinical trials have not elucidated the long-term influence of hypoglycemic drugs on cancer incidence and the safety for cancer-bearing patients with diabetes, whereas numerous preclinical studies have shown that antidiabetic drugs could have an impact on carcinogenesis processes beyond the glycemic control effect. Because there is no evidence of the safety profile of antidiabetic agents on cancer biology, careful consideration would be required when prescribing any medicines to patients with diabetes and existing tumor. In this review, we discuss the potential influence of each diabetes therapy in cancer 'initiation', 'promotion' and 'progression'.
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Affiliation(s)
- Emi Kawakita
- Department of Internal Medicine 1, Faculty of MedicineShimane UniversityIzumoJapan
| | - Keizo Kanasaki
- Department of Internal Medicine 1, Faculty of MedicineShimane UniversityIzumoJapan
- The Center for Integrated Kidney Research and Advance, Faculty of MedicineShimane UniversityIzumoJapan
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Lam R, Hwang WT, Chennareddy S, Boursi B, Yang YX. Exogenous Insulin Therapy Is Associated with the Risk of Advanced Colorectal Adenoma in Patients with Diabetes Mellitus. Dig Dis Sci 2024; 69:1834-1843. [PMID: 38517561 DOI: 10.1007/s10620-024-08350-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 02/09/2024] [Indexed: 03/24/2024]
Abstract
BACKGROUND/AIMS Exogenous insulin therapy increases systemic exposure to insulin which may promote the development of colorectal neoplasia. We sought to evaluate the association between exogenous insulin therapy and the incidence of advanced adenoma in type 2 diabetes mellitus. METHODS A retrospective cohort study was conducted from January 1, 2007, to January 1, 2018, in a regional health system serving the United States Philadelphia metropolitan area, Central New Jersey, and South Central Pennsylvania. Study patients consisted of a random sample of patients with type 2 diabetes mellitus aged 40-80 years who had undergone two rounds of colonoscopy examinations. The exposure was cumulative duration of insulin therapy (i.e., no use, 1-365 days and > 365 days). The outcome was time to incident advanced adenoma. RESULTS Of the 975 eligible patients, 184 patients accumulated > 365 days of insulin therapy before the follow-up colonoscopy. The mean (standard deviation) duration between the two rounds of colonoscopy examination was 5.1 (2.9) years among the insulin users and 5.3 (3.9) years among non-users. Compared to no insulin exposure, receiving > 365 days of insulin therapy was associated with an increased incidence of advanced adenoma (adjusted hazard ratio [aHR] 4.84, 95% confidence interval [CI] 2.82-8.30), right-sided advanced adenoma (aHR 5.48, 95% CI 2.90-10.35), and 3 or more adenomas (aHR 2.61, 95% CI 1.46-4.69) at the follow-up colonoscopy examination. CONCLUSION Insulin therapy is associated with an increased risk of advanced adenoma and may serve as a novel risk-stratification factor to enhance the efficiency of existing colorectal cancer screening and surveillance programs.
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Affiliation(s)
- Robert Lam
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Wei-Ting Hwang
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, 19104, USA
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | | | - Ben Boursi
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Tel-Aviv University, Tel-Aviv, Israel
- Department of Oncology, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
| | - Yu-Xiao Yang
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, 19104, USA.
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
- Gastrointestinal Section, Medicine Services, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, USA.
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Canha MI, Ramos G, Prata R, Lages Martins P, Viúla Ramos M, Coimbra J. Is Metformin Associated with a Lower Prevalence of Polyps, Adenomas, and Colorectal Carcinoma in Patients with Diabetes Mellitus? J Gastrointest Cancer 2024; 55:435-443. [PMID: 37987968 DOI: 10.1007/s12029-023-00989-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/13/2023] [Indexed: 11/22/2023]
Abstract
PURPOSE Recent studies suggested a protective role of metformin in the development of colorectal cancer (CRC) and its precursors. We aimed to investigate if metformin was associated with a lower prevalence and number of colorectal polyps in diabetic patients and also adenomas, high-risk adenomas, and CRC. METHODS Retrospective study on adult patients with diabetes mellitus followed in our hospital with a total colonoscopy between 2015 and 2019, treated with either metformin for > 5 years or other antidiabetic agent (control group). We assessed the number, size, and histopathology examination of proliferative lesions detected on colonoscopy. RESULTS We included 401 patients aged 69 ± 9 years, 57% males, divided into two groups: treated with metformin (n = 260) and without (n = 141). The number of polyps detected was significantly lower in patients under metformin (p = 0.014). There was a nonsignificant trend towards lower polyp detection rates in the metformin compared to the control group both in unadjusted analysis (50% vs 60%, p = 0.058) and multivariable adjusted analysis (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.43-1.09, p = 0.111). In the latter, we identified male gender (OR 2.24, 95%CI 1.44-3.49, p < 0.001), age (OR 1.35 for every 10 years, 95%CI 1.07-1.71, p = 0.012), glycated hemoglobin value (OR 1.20 for every 1% increase, 95%CI 1.06-1.37, p = 0.005), and hypertension (OR 1.76, 95%CI 1.01-3.08, p = 0.046) as factors associated with a higher prevalence of polyps. We saw no statistically significant differences regarding adenoma (p = 0.231), high-risk adenoma (p = 0.810), and CRC (p = 0.705) diagnoses between groups. CONCLUSION In our study, metformin was associated with less colorectal polyps in diabetic patients compared to other treatment modalities. We observed a nonsignificant trend towards lower polyp detection rates in the metformin group both in unadjusted and adjusted analyses.
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Affiliation(s)
- Maria Inês Canha
- Gastroenterology Department of Centro Hospitalar Universitário de Lisboa Central, EPE, Lisbon, Portugal.
- NOVA Medical School, Lisbon, Portugal.
| | - Gonçalo Ramos
- Gastroenterology Department of Centro Hospitalar Universitário de Lisboa Central, EPE, Lisbon, Portugal
- NOVA Medical School, Lisbon, Portugal
| | - Rita Prata
- Gastroenterology Department of Centro Hospitalar Universitário de Lisboa Central, EPE, Lisbon, Portugal
| | - Pedro Lages Martins
- Gastroenterology Department of Centro Hospitalar Universitário de Lisboa Central, EPE, Lisbon, Portugal
- NOVA Medical School, Lisbon, Portugal
| | - Marta Viúla Ramos
- Gastroenterology Department of Centro Hospitalar Universitário de Lisboa Central, EPE, Lisbon, Portugal
| | - João Coimbra
- Gastroenterology Department of Centro Hospitalar Universitário de Lisboa Central, EPE, Lisbon, Portugal
- NOVA Medical School, Lisbon, Portugal
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Li X, Liao M, Wang B, Zan X, Huo Y, Liu Y, Bao Z, Xu P, Liu W. A drug repurposing method based on inhibition effect on gene regulatory network. Comput Struct Biotechnol J 2023; 21:4446-4455. [PMID: 37731599 PMCID: PMC10507583 DOI: 10.1016/j.csbj.2023.09.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 09/05/2023] [Accepted: 09/07/2023] [Indexed: 09/22/2023] Open
Abstract
Numerous computational drug repurposing methods have emerged as efficient alternatives to costly and time-consuming traditional drug discovery approaches. Some of these methods are based on the assumption that the candidate drug should have a reversal effect on disease-associated genes. However, such methods are not applicable in the case that there is limited overlap between disease-related genes and drug-perturbed genes. In this study, we proposed a novel Drug Repurposing method based on the Inhibition Effect on gene regulatory network (DRIE) to identify potential drugs for cancer treatment. DRIE integrated gene expression profile and gene regulatory network to calculate inhibition score by using the shortest path in the disease-specific network. The results on eleven datasets indicated the superior performance of DRIE when compared to other state-of-the-art methods. Case studies showed that our method effectively discovered novel drug-disease associations. Our findings demonstrated that the top-ranked drug candidates had been already validated by CTD database. Additionally, it clearly identified potential agents for three cancers (colorectal, breast, and lung cancer), which was beneficial when annotating drug-disease relationships in the CTD. This study proposed a novel framework for drug repurposing, which would be helpful for drug discovery and development.
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Affiliation(s)
- Xianbin Li
- Institute of Computational Science and Technology, Guangzhou University, Guangzhou, China
- School of Computer Science of Information Technology, Qiannan Normal University for Nationalities, Duyun, China
| | - Minzhen Liao
- Institute of Computational Science and Technology, Guangzhou University, Guangzhou, China
| | - Bing Wang
- School of Medicine, Southeast University, Nanjing, China
| | - Xiangzhen Zan
- Institute of Computational Science and Technology, Guangzhou University, Guangzhou, China
| | - Yanhao Huo
- Institute of Computational Science and Technology, Guangzhou University, Guangzhou, China
| | - Yue Liu
- Institute of Computational Science and Technology, Guangzhou University, Guangzhou, China
| | - Zhenshen Bao
- Institute of Computational Science and Technology, Guangzhou University, Guangzhou, China
- School of Computer Science of Information Technology, Qiannan Normal University for Nationalities, Duyun, China
| | - Peng Xu
- Institute of Computational Science and Technology, Guangzhou University, Guangzhou, China
- School of Computer Science of Information Technology, Qiannan Normal University for Nationalities, Duyun, China
| | - Wenbin Liu
- Institute of Computational Science and Technology, Guangzhou University, Guangzhou, China
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de Andrade Mesquita L, Wayerbacher LF, Schwartsmann G, Gerchman F. Obesity, diabetes, and cancer: epidemiology, pathophysiology, and potential interventions. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2023; 67:e000647. [PMID: 37364149 PMCID: PMC10660996 DOI: 10.20945/2359-3997000000647] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 02/22/2023] [Indexed: 06/28/2023]
Abstract
The proportion of deaths attributable to cancer is rising, and malignant neoplasms have become the leading cause of death in high-income countries. Obesity and diabetes are now recognized as risk factors for several types of malignancies, especially endometrial, colorectal, and postmenopausal breast cancers. Mechanisms implicated include disturbances in lipid-derived hormone secretion, sex steroids biosynthesis, hyperinsulinemia, and chronic inflammation. Intentional weight loss is associated with a mitigation of risk for obesity-related cancers, a phenomenon observed specially with bariatric surgery. The impact of pharmacological interventions for obesity and diabetes is not uniform: while metformin seems to protect against cancer, other agents such as lorcaserin may increase the risk of malignancies. However, these interpretations must be carefully considered, since most data stem from bias-prone observational studies, and high-quality randomized controlled trials with appropriate sample size and duration are needed to achieve definite conclusions. In this review, we outline epidemiological and pathophysiological aspects of the relationship between obesity, diabetes, and malignancies. We also highlight pieces of evidence regarding treatment effects on cancer incidence in these populations.
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Affiliation(s)
- Leonardo de Andrade Mesquita
- Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
- Hospital de Clínicas de Porto Alegre, Porto Alegre, Brasil, Porto Alegre, RS, Brasil
| | - Laura Fink Wayerbacher
- Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Gilberto Schwartsmann
- Hospital de Clínicas de Porto Alegre, Porto Alegre, Brasil, Porto Alegre, RS, Brasil
- Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - Fernando Gerchman
- Programa de Pós-graduação em Ciências Médicas: Endocrinologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
- Hospital de Clínicas de Porto Alegre, Porto Alegre, Brasil, Porto Alegre, RS, Brasil,
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Tonry CL, Evans RM, Ruddock MW, Duggan B, McCloskey O, Maxwell AP, O’Rourke D, Boyd RE, Watt J, Reid CN, Curry DJ, Stevenson M, Young MK, Jamison CS, Gallagher J, Fitzgerald SP, Lamont J, Watson CJ. Clinical features and predictive biomarkers for bladder cancer in patients with type 2 diabetes presenting with haematuria. Diabetes Metab Res Rev 2022; 38:e3546. [PMID: 35578575 PMCID: PMC9542076 DOI: 10.1002/dmrr.3546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 05/10/2022] [Indexed: 11/10/2022]
Abstract
AIMS To identify clinical features and protein biomarkers associated with bladder cancer (BC) in individuals with type 2 diabetes mellitus presenting with haematuria. MATERIALS AND METHODS Data collected from the Haematuria Biomarker (HaBio) study was used in this analysis. A matched sub-cohort of patients with type 2 diabetes and patients without diabetes was created based on age, sex, and BC diagnosis, using approximately a 1:2 fixed ratio. Randox Biochip Array Technology and ELISA were applied for measurement of 66 candidate serum and urine protein biomarkers. Hazard ratios and 95% confidence intervals were estimated by chi-squared and Wilcoxon rank sum test for clinical features and candidate protein biomarkers. Diagnostic protein biomarker models were identified using Lasso-based binominal regression analysis. RESULTS There was no difference in BC grade, stage, and severity between individuals with type 2 diabetes and matched controls. Incidence of chronic kidney disease (CKD) was significantly higher in patients with type 2 diabetes (p = 0.008), and CKD was significantly associated with BC in patients with type 2 diabetes (p = 0.032). A biomarker model, incorporating two serum (monocyte chemoattractant protein 1 and vascular endothelial growth factor) and three urine (interleukin 6, cytokeratin 18, and cytokeratin 8) proteins, predicted incidence of BC with an Area Under the Curve (AUC) of 0.84 in individuals with type 2 diabetes. In people without diabetes, the AUC was 0.66. CONCLUSIONS We demonstrate the potential clinical utility of a biomarker panel, which includes proteins related to BC pathogenesis and type 2 diabetes, for monitoring risk of BC in patients with type 2 diabetes. Earlier urology referral of patients with type 2 diabetes will improve outcomes for these patients. TRIAL REGISTRATION http://www.isrctn.com/ISRCTN25823942.
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Affiliation(s)
- Claire L. Tonry
- Wellcome Wolfson Institute for Experimental MedicineQueen's University BelfastBelfastUK
| | | | - Mark W. Ruddock
- Randox Laboratories LtdCrumlin, Co. Antrim BT29 4QYCrumlinUK
| | - Brian Duggan
- Department of UrologySouth Eastern Health and Social Care TrustDundonaldUK
| | | | | | - Declan O’Rourke
- Consultant Histopathologist BHSCT and Clinical Lecturer QUBBelfastUK
| | - Ruth E. Boyd
- Northern Ireland Clinical Trials NetworkBelfastUK
| | - Joanne Watt
- Randox Laboratories LtdCrumlin, Co. Antrim BT29 4QYCrumlinUK
| | - Cherith N. Reid
- Randox Laboratories LtdCrumlin, Co. Antrim BT29 4QYCrumlinUK
| | | | | | - Margaret K. Young
- School of MedicineDentistry and Biomedical SciencesQueens University BelfastBelfastUK
| | - Catherine S. Jamison
- School of MedicineDentistry and Biomedical SciencesQueens University BelfastBelfastUK
| | - Joe Gallagher
- Irish College of General PractitionersLincoln PlaceDublin 2Ireland
| | | | - John Lamont
- Randox Laboratories LtdCrumlin, Co. Antrim BT29 4QYCrumlinUK
| | - Chris J. Watson
- Wellcome Wolfson Institute for Experimental MedicineQueen's University BelfastBelfastUK
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11
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Sun H, Qi X. The role of insulin and incretin-based drugs in biliary tract cancer: epidemiological and experimental evidence. Discov Oncol 2022; 13:70. [PMID: 35933633 PMCID: PMC9357599 DOI: 10.1007/s12672-022-00536-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 07/26/2022] [Indexed: 11/29/2022] Open
Abstract
Insulin and incretin-based drugs are important antidiabetic agents with complex effects on cell growth and metabolism. Emerging evidence shows that insulin and incretin-based drugs are associated with altered risk of biliary tract cancer (BTC). Observational study reveals that insulin is associated with an increased risk of extrahepatic cholangiocarcinoma (ECC), but not intrahepatic cholangiocarcinoma (ICC) or gallbladder cancer (GBC). This type-specific effect can be partly explained by the cell of origin and heterogeneous genome landscape of the three subtypes of BTC. Similar to insulin, incretin-based drugs also exhibit very interesting contradictions and inconsistencies in response to different cancer phenotypes, including BTC. Both epidemiological and experimental evidence suggests that incretin-based drugs can be a promoter of some cancers and an inhibitor of others. It is now more apparent that this type of drugs has a broader range of physiological effects on the body, including regulation of endoplasmic reticulum stress, autophagy, metabolic reprogramming, and gene expression. In particular, dipeptidyl peptidase-4 inhibitors (DPP-4i) have a more complex effect on cancer due to the multi-functional nature of DPP-4. DPP-4 exerts both catalytic and non-enzymatic functions to regulate metabolic homeostasis, immune reaction, cell migration, and proliferation. In this review, we collate the epidemiological and experimental evidence regarding the effect of these two classes of drugs on BTC to provide valuable information.
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Affiliation(s)
- Hua Sun
- Department of Geriatrics, Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine, No.208 East Huancheng Road, Hangzhou, Zhejiang, China
| | - Xiaohui Qi
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No.197 Ruijin Er Road, Shanghai, China.
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No.573 Xujiahui Road, Shanghai, China.
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12
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Yen FS, Wei JCC, Liu JS, Hsu CC, Hwu CM. Clinical course of adolescents with type 2 diabetes mellitus: A nationwide cohort study in Taiwan. J Diabetes Investig 2022; 13:1905-1913. [PMID: 35726692 DOI: 10.1111/jdi.13873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 06/15/2022] [Accepted: 06/17/2022] [Indexed: 11/30/2022] Open
Abstract
AIMS/INTRODUCTION The global incidence of adolescents with type 2 diabetes mellitus (T2DM) is increasing. We conducted this cohort study aiming to describe the characteristics, drug-use condition, and long-term outcomes of adolescents with T2DM. MATERIALS AND METHODS 2755 newly diagnosed adolescents with T2DM (using ICD-9-CM: 250.x and having ≧3 clinic visits) were identified from the national health insurance dataset during 2000-2014. We classified treatments into 4 groups: metformin, sulfonylurea (SU), metformin plus SU, and insulin with or without oral antidiabetic drugs. Multiple Cox regression model was used to compare the risks of mortality and hospitalization among these 4 groups. RESULTS The mean follow-up period was 5.4 years. After 1 year of antidiabetic treatment, they gradually needed intensified therapy, and at 3 years, half of them showed treatment failure. The mortality rate was 2.08 per 1000 person-years. Respiratory diseases (36.2%) and dysglycemia (16.4%) were the most common causes of hospitalization among these adolescents. Compared with persons taking metformin plus SU, metformin users were associated with a lower risk of all-cause hospitalization [0.82 (0.67-0.99)]; insulin users were associated with a higher risk of dysglycemia [4.38 (2.14-8.96)], cancer [3.76 (1.39-10.1)], and respiratory hospitalization [1.66 (1.14-2.41)]; and SU users were associated with a higher risk of hospitalization for respiratory diseases [1.91 (1.13-3.23)]. CONCLUSIONS This nationwide cohort study demonstrated that adolescents with T2DM were prone to treatment failure. Furthermore, respiratory diseases and dysglycemia were the most common causes of hospitalization.
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Affiliation(s)
| | - James Cheng-Chung Wei
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.,Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Jia-Sin Liu
- Institute of Population Health Sciences, National Health Research Institutes, Miaoli County, Taiwan
| | - Chih-Cheng Hsu
- Institute of Population Health Sciences, National Health Research Institutes, Miaoli County, Taiwan.,Department of Health Services Administration, China Medical University, Taichung, Taiwan.,Department of Family Medicine, Min-Sheng General Hospital, Taoyuan, Taiwan.,National Center for Geriatrics and Welfare Research, National Health Research Institutes, Miaoli County, Taiwan
| | - Chii-Min Hwu
- Department of Medicine, National Yang-Ming Chiao Tung University School of Medicine, Taipei, Taiwan.,Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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13
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Shen GL, Lu Y, Liang L, Lu WF, Diao YK, Xiao ZQ, Zhang KJ, Zhang JG, Zhang CW, Liu J. Impact of diabetes mellitus on the long-term prognosis of patients with hepatocellular carcinoma after hepatectomy. Expert Rev Gastroenterol Hepatol 2022; 16:473-478. [PMID: 35387530 DOI: 10.1080/17474124.2022.2063837] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The impact of diabetes mellitus (DM) on the survival of patients with hepatocellular carcinoma (HCC) is still unclear. The present study aims to draw a firm conclusion in terms of evaluating the impact of DM on the prognosis of HCC after hepatectomy. METHODS The pattern of recurrence for HCC was often stratified into early-stage (<2 years) and late-stage (≥2 years) recurrence. Because the early-stage recurrence was mainly attributed to aggressive tumor pathological characteristics, patients who recurrence or die within 2 years were excluded. Cumulative overall survival (OS) and recurrence-free survival (RFS) were determined by the method of Kaplan-Meier, and the independent risk factors of OS/RFS were determined by Cox regression analysis. RESULTS A total of 426 patients were eventually included. The 3- and 5-year OS in patients with and without DM was 83.7%, 55.1%; and 90.9%, 77.4%, respectively. Multivariate analysis showed that DM was an independent risk factor for OS (HR 1.166, 95% CI 1.056-2.036, P = 0.022) and RFS (HR 1.365, 95% CI 1.043-1.787, P = 0.023). CONCLUSION DM is an independent risk factor for long-term prognosis in patients with HCC. Patients with DM after hepatectomy for HCC, thus, need to actively control DM and closer follow-up.
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Affiliation(s)
- Guo-Liang Shen
- General Surgery, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yi Lu
- General Surgery, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Lei Liang
- General Surgery, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.,Department of Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, China
| | - Wen-Feng Lu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, Zhejiang, China
| | - Yong-Kang Diao
- General Surgery, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Zun-Qiang Xiao
- General Surgery, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Kang-Jun Zhang
- General Surgery, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Jun-Gang Zhang
- General Surgery, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Cheng-Wu Zhang
- General Surgery, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Junwei Liu
- General Surgery, Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
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14
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Qi X, He P, Yao H, Sun H, Qi J, Cao M, Cui B, Ning G. Insulin therapy and biliary tract cancer: insights from real-world data. Endocr Connect 2022; 11:EC-21-0546.R2. [PMID: 35148280 PMCID: PMC8942312 DOI: 10.1530/ec-21-0546] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 02/11/2022] [Indexed: 11/22/2022]
Abstract
OBJECTIVE The association between insulin therapy and the risk of biliary tract cancer (BTC) is uncertain. We aimed to assess this risk in type 2 diabetic patients. METHODS Using electronic medical data from the Shanghai Hospital Link database, 202,557 patients with type 2 diabetes (164,997 insulin never-users and 37,560 insulin ever-users) were identified in this study between January 1, 2013, and December 31, 2016, with follow-up until December 31, 2019. By propensity score matching, an ever-user was matched with a never-user. Cox proportional hazards regression analysis was used to estimate risk ratios (HRs) and 95% CIs for three subtypes of BTC (intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC)). RESULTS At a mean follow-up of 5.33 years, 143 cases of BTC were observed. The crude incidence rates (per 100,000 person-years) of ECC, ICC, and GBC in ever-users:never-users were 10.22:3.63, 2.04:2.04, and 8.17:6.01, respectively. Insulin therapy was associated with an increased risk of ECC (HR, 4.10; 95% CI, 1.54-10.92; P = 0.005) compared to patients who never used insulin. No statistically significant results were observed for insulin and ICC/GBC. Consistent results were also found in the original cohort. CONCLUSIONS The relationship between insulin therapy and BTC is type-specific. Further studies are warranted to provide evidence on the identification of ECC risk groups among type 2 diabetic patients.
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Affiliation(s)
- Xiaohui Qi
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ping He
- Shanghai Hospital Link Center, Shanghai Hospital Development Center, Shanghai, China
| | - Huayan Yao
- Computer Net Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | | | - Jiying Qi
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Cao
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bin Cui
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Correspondence should be addressed to B Cui or G Ning: or
| | - Guang Ning
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Correspondence should be addressed to B Cui or G Ning: or
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15
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Targeting the IGF-1R in prostate and colorectal cancer: reasons behind trial failure and future directions. Ther Deliv 2022; 13:167-186. [PMID: 35029130 DOI: 10.4155/tde-2021-0060] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
IGF-1Rs enact a significant part in cancer growth and its progress. IGF-1R inhibitors were encouraged in the early trials, but the patients did not benefit due to the unavailability of predictive biomarkers and IGF-1R system complexity. However, the linkage between IGF-1R and cancer was reported three decades ago. This review will shed light on the IGF-1R system, targeting IGF-1R through monoclonal antibodies, reasons behind IGF-1R trial failure and future directions. This study presented that targeting IGF-1R through monoclonal antibodies is still effective in cancer treatment, and there is a need to look for future directions. Cancer patients may benefit from using mAbs that target existing and new cancer targets, evidenced by promising results. It is also essential that the academician, trial experts and pharmaceutical companies play their role in finding a treatment for this deadly disease.
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16
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Yu GH, Li SF, Wei R, Jiang Z. Diabetes and Colorectal Cancer Risk: Clinical and Therapeutic Implications. J Diabetes Res 2022; 2022:1747326. [PMID: 35296101 PMCID: PMC8920658 DOI: 10.1155/2022/1747326] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 02/19/2022] [Indexed: 12/24/2022] Open
Abstract
Several epidemiological studies have identified diabetes as a risk factor for colorectal cancer (CRC). The potential pathophysiological mechanisms of this association include hyperinsulinemia, insulin-like growth factor (IGF) axis, hyperglycemia, inflammation induced by adipose tissue dysfunction, gastrointestinal motility disorder, and impaired immunological surveillance. Several studies have shown that underlying diabetes adversely affects the prognosis of patients with CRC. This review explores the novel anticancer agents targeting IGF-1R and receptor for advanced glycation end products (RAGE), both of which play a vital role in diabetes-induced colorectal tumorigenesis. Inhibitors of IGF-1R and RAGE are expected to become promising therapeutic choices, particularly for CRC patients with diabetes. Furthermore, hypoglycemic therapy is associated with the incidence of CRC. Selection of appropriate hypoglycemic agents, which can reduce the risk of CRC in diabetic patients, is an unmet issue. Therefore, this review mainly summarizes the current studies concerning the connections among diabetes, hypoglycemic therapy, and CRC as well as provides a synthesis of the underlying pathophysiological mechanisms. Our synthesis provides a theoretical basis for rational use of hypoglycemic therapies and early diagnosis and treatment of diabetes-related CRC.
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Affiliation(s)
- Guan-Hua Yu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Shuo-Feng Li
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ran Wei
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zheng Jiang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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17
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Liu M, White BF, Praveen P, Li W, Lin F, Wu H, Li R, Delaine C, Forbes BE, Wade JD, Hossain MA. Engineering of a Biologically Active Insulin Dimer. J Med Chem 2021; 64:17448-17454. [PMID: 34797669 DOI: 10.1021/acs.jmedchem.1c01594] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The growing epidemic of diabetes means that there is a need for therapies that are more efficacious, safe, and convenient. Here, we report the efficient synthesis of a novel disulfide dimer of human insulin tethered at the N-terminus of its B-chain through placement of a cysteine residue. The resulting peptide was shown to bind to both the insulin receptor isoform B and insulin-like growth factor-1 receptor with comparable affinity to native insulin. In in vivo insulin tolerance tests, the dimer was equipotent to Actrapid insulin and possessed a sustained duration of action greater than that of Actrapid and Glargine. While the secondary structure of our dimeric insulin was similar to that of insulin, it was more resistant to proteolysis. More importantly, our analogue was produced in quantitative yield from a monomeric thiol insulin scaffold. Our results suggest that this dimer has significant potential to address the clinical needs in the treatment of diabetes.
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Affiliation(s)
- Mengjie Liu
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010, Australia
| | - Barbara F White
- Department of Medicine (Austin Health), The University of Melbourne, Victoria 3010, Australia
| | - Praveen Praveen
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010, Australia
| | - Wenyi Li
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010, Australia
| | - Feng Lin
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010, Australia
| | - Hongkang Wu
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010, Australia
| | - Rong Li
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010, Australia
| | - Carlie Delaine
- Discipline of Medical Biochemistry, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia
| | - Briony E Forbes
- Discipline of Medical Biochemistry, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia
| | - John D Wade
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010, Australia.,The Florey Department of Neuroscience and Mental Health, The University Melbourne, Victoria 3010, Australia.,School of Chemistry, The University of Melbourne, Victoria 3010, Australia
| | - Mohammed Akhter Hossain
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010, Australia.,The Florey Department of Neuroscience and Mental Health, The University Melbourne, Victoria 3010, Australia.,School of Chemistry, The University of Melbourne, Victoria 3010, Australia
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18
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Yu GH, Jiang Z. Progress in understanding of relationship between diabetes and colorectal cancer. Shijie Huaren Xiaohua Zazhi 2021; 29:1323-1333. [DOI: 10.11569/wcjd.v29.i23.1323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Several epidemiological studies have suggested that diabetes is closely associated with an increased risk of colorectal cancer and diabetes could be regarded as an independent risk factor for colorectal cancer. Potential pathophysiological mechanisms connecting diabetes and colorectal cancer include hyperglycemia, hyperinsulinemia, and insulin-like growth factor axis, chronic inflammation and oxidative stress, gastrointestinal motility disorder, and impaired immunological surveillance. Meanwhile, multiple studies have revealed that diabetes is negatively related to the prognosis of patients with colorectal cancer. This review mainly summarizes the current studies concerning the linkages between diabetes and colorectal cancer and the underlying pathophysiological mechanisms, so as to provide a theoretical basis for rational use of antidiabetic drugs and early diagnosis of diabetes-related colorectal cancer.
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Affiliation(s)
- Guan-Hua Yu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zheng Jiang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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19
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Pretta A, Ziranu P, Puzzoni M, Lai E, Orsi G, Liscia N, Molinaro E, Mariani S, Riggi L, Rovesti G, Dubois M, Migliari M, Persano M, Saba G, Impera V, Musio F, Batzella E, Demurtas L, Pusceddu V, Astara G, Faloppi L, Casadei Gardini A, Andrikou K, Cascinu S, Scartozzi M. Retrospective survival analysis in patients with metastatic pancreatic ductal adenocarcinoma with insulin-treated type 2 diabetes mellitus. TUMORI JOURNAL 2021; 107:550-555. [PMID: 33243068 DOI: 10.1177/0300891620976945] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
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.
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Affiliation(s)
- Andrea Pretta
- Medical Oncology Unit, Sapienza University of Rome, Roma, Italy
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Giulia Orsi
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Nicole Liscia
- Medical Oncology Unit, Sapienza University of Rome, Roma, Italy
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Eleonora Molinaro
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Laura Riggi
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Rovesti
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Valentino Impera
- Medical Oncology Unit, Sapienza University of Rome, Roma, Italy
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Francesca Musio
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Erich Batzella
- Department of Statistical Science, University of Padova, Padova, Veneto, Italy
| | - Laura Demurtas
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Giorgio Astara
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
| | - Luca Faloppi
- Department of Medical Oncology, Macerata General Hospital, Macerata, Italy
| | - Andrea Casadei Gardini
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Kalliopi Andrikou
- Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy
| | - Stefano Cascinu
- IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy
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20
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Antidiabetic drugs and the risk of cancer: beneficial, neutral, or detrimental? FORUM OF CLINICAL ONCOLOGY 2021. [DOI: 10.2478/fco-2021-0014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Abstract
The prevalence of diabetes mellitus is rapidly rising, especially in low- and middle-income countries. Also, early-onset diabetes is on the rise, and millions of individuals have to be on antidiabetic medications for a prolonged period. Therefore, more people are getting exposed to the adverse effects of antidiabetic medications.
Cancer is among the top ranking causes of death worldwide. Researches are still ongoing to understand the etiologies, precipitants, risk factors, correlates, and predictors of cancers. Diabetes mellitus is associated with various cancers, as extensively documented in the literature. There are conflicting reports about the association between antidiabetic drugs and cancer. This is even of crucial importance, considering that the prevalence of diabetes is rising.
Insulin glargine is reported to be associated with cancers, but clinical trials have not confirmed this. Metformin is largely believed to be beneficial in oncologic practice. Glibenclamide is reported to reduce tumor growth. The association between pioglitazone and bladder cancer is still an area for further research. Meglitinides have also been associated with cancers. Incretin-based therapy and the α-glucosidase inhibitors appear to have beneficial effects on cancers.
There is still a need for randomized multicentric clinical trials to further substantiate and clarify reports from epidemiological studies. Further in vitro studies will also be necessary to characterize the interaction of these pharmacological agents with other molecules in the body.
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21
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Jones GR, Molloy MP. Metformin, Microbiome and Protection Against Colorectal Cancer. Dig Dis Sci 2021; 66:1409-1414. [PMID: 32533543 DOI: 10.1007/s10620-020-06390-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 06/03/2020] [Indexed: 01/02/2023]
Abstract
Metformin is widely used as a firstline therapy to improve insulin sensitivity in type 2 diabetes mellitus (T2DM) patients. This is achieved primarily through regulating AMP-activated protein kinase (AMPK)-dependent pathways leading to reduced hepatic gluconeogenesis and improved muscular uptake of glucose. Epidemiological studies first recognized a relationship with metformin use in T2DM patients and reduced colorectal cancer (CRC) risk. Thereafter, metformin has gained wide attention as a candidate CRC chemopreventative agent; however, the molecular mechanisms underlying its gastrointestinal anti-cancer properties appear multi-faceted and are not well understood. An intriguing area of research is the growing evidence of metformin's metabolic juncture with gut microbiota at the intestinal mucosal interface. This review examines the mechanistic evidence which may account for metformin's protection against CRC through interactions between the drug, gut microbiota and the colonic epithelial mucosa.
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Affiliation(s)
- Georgina R Jones
- Bowel Cancer and Biomarker Laboratory, Kolling Institute, Northern Clinical School, The University of Sydney, St.Leonards, Australia
| | - Mark P Molloy
- Bowel Cancer and Biomarker Laboratory, Kolling Institute, Northern Clinical School, The University of Sydney, St.Leonards, Australia.
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22
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Zorron Cheng Tao Pu L, Rana K, Singh G, Nakamura M, Yamamura T, Koay DSC, Ovenden A, Edwards S, Ruszkiewicz A, Hirooka Y, Fujishiro M, Burt AD, Singh R. Different factors are associated with conventional adenoma and serrated colorectal neoplasia. NAGOYA JOURNAL OF MEDICAL SCIENCE 2021; 82:335-343. [PMID: 32581412 PMCID: PMC7276409 DOI: 10.18999/nagjms.82.2.335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
Current data shows there are differences in factors associated with colorectal neoplasia based on geographical location and cultural settings. There are no studies focusing on the association between environmental factors and colorectal polyps in Australia. The aim of this study was to prospectively evaluate the association of various factors with different colorectal neoplasia histology. We utilized a simplified one-page questionnaire for patients undergoing colonoscopy for information on age; gender; comorbidities; family history of colorectal cancer; physical activity; smoking; diet; alcohol intake; and body mass index. Factors were then evaluated for association with the presence of: (1) neoplastic lesions; (2) conventional adenomas; (3) neoplastic serrated polyps; (4) any lesions (past and present); and (5) hyperplastic polyps. 291 procedures and 260 patients were included. Factors with a p-value < 0.2 in a univariate regression were included in an initial multivariable regression model. Backwards elimination was then performed, removing one predictor at a time until only significant predictors remained. In the final multivariable model, age≥65, male gender, type-2 diabetes mellitus, active smoking and family history of colorectal cancer were found to be statistically significant predictors for the presence of colorectal neoplasia. However, the significant predictors found for conventional adenomas (older age, male gender and smoking) were different from the significant predictors for neoplastic serrated polyps (type-2 diabetes mellitus and family history of colorectal cancer). Older age, male gender, type-2 diabetes mellitus, and smoking were significantly associated with the presence of colorectal neoplasia. The factors associated with conventional adenomas differed from those associated with neoplastic serrated polyps.
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Affiliation(s)
- Leonardo Zorron Cheng Tao Pu
- Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia.,Department of Gastroenterology and Hepatology, Nagoya University, Nagoya, Japan
| | - Khizar Rana
- Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
| | - Gurfarmaan Singh
- Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
| | - Masanao Nakamura
- Department of Gastroenterology and Hepatology, Nagoya University, Nagoya, Japan
| | - Takeshi Yamamura
- Department of Endoscopy, Nagoya University Hospital, Nagoya, Japan
| | | | - Amanda Ovenden
- Gastroenterology Department, Lyell McEwin Hospital, Adelaide, Australia
| | - Suzanne Edwards
- Adelaide Health Technology Assessment (AHTA), School of Public Health, University of Adelaide, Adelaide, Australia
| | - Andrew Ruszkiewicz
- Pathology Department, Lyell McEwin Hospital, Adelaide, South Australia, Australia
| | - Yoshiki Hirooka
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology and Hepatology, Nagoya University, Nagoya, Japan
| | - Alastair D Burt
- Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
| | - Rajvinder Singh
- Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia.,Gastroenterology Department, Lyell McEwin Hospital, Adelaide, Australia
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23
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Dąbrowski M. Diabetes, Antidiabetic Medications and Cancer Risk in Type 2 Diabetes: Focus on SGLT-2 Inhibitors. Int J Mol Sci 2021; 22:ijms22041680. [PMID: 33562380 PMCID: PMC7915237 DOI: 10.3390/ijms22041680] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/31/2021] [Accepted: 02/03/2021] [Indexed: 12/14/2022] Open
Abstract
In the last decade, cancer became the leading cause of death in the population under 65 in the European Union. Diabetes is also considered as a factor increasing risk of cancer incidence and mortality. Type 2 diabetes is frequently associated with being overweight and obese, which also plays a role in malignancy. Among biological mechanisms linking diabetes and obesity with cancer hyperglycemia, hyperinsulinemia, insulin resistance, increased levels of growth factors, steroid and peptide hormones, oxidative stress and increased activity of pro-inflammatory cytokines are listed. Antidiabetic medications can modulate cancer risk through directly impacting metabolism of cancer cells as well as indirectly through impact on risk factors of malignancy. Some of them are considered beneficial (metformin and thiazolidinedions—with the exception of bladder cancer); on the other hand, excess of exogenous insulin may be potentially harmful, while other medications seem to have neutral impact on cancer risk. Inhibitors of the sodium-glucose cotransporter-2 (SGLT-2) are increasingly used in the treatment of type 2 diabetes. However, their association with cancer risk is unclear. The aim of this review was to analyze the anticancer potential of this class of drugs, as well as risks of site-specific malignancies associated with their use.
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Affiliation(s)
- Mariusz Dąbrowski
- College of Medical Sciences, University of Rzeszów, Al. Rejtana 16C, 35-959 Rzeszów, Poland
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24
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Leng W, Jiang J, Chen B, Wu Q. Metformin and Malignant Tumors: Not Over the Hill. Diabetes Metab Syndr Obes 2021; 14:3673-3689. [PMID: 34429626 PMCID: PMC8380287 DOI: 10.2147/dmso.s326378] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 08/06/2021] [Indexed: 12/11/2022] Open
Abstract
Malignant tumors are a major cause of death, and their incidence is increasing worldwide. Although the survival rate for some cancers has improved, treatments for other malignant tumors are limited, and their mortality rate continues to increase. People with type 2 diabetes have a higher risk of malignant tumors and a higher mortality rate than those without diabetes. Metformin is a commonly used hypoglycemic drug. In recent years, a growing number of studies have indicated that metformin has antitumor effects and increases the sensitivity of malignant tumors to chemotherapy. However, the effect of metformin on different tumors is currently controversial, and the mechanism of metformin's antitumor action is not fully understood. Insights into the effect of metformin on malignant tumors and the possible mechanism may contribute to the development of antitumor drugs.
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Affiliation(s)
- Weiling Leng
- Endocrinology Department, The First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Juan Jiang
- Endocrinology and Nephrology Department, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing, People’s Republic of China
| | - Bing Chen
- Endocrinology Department, The First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
- Bing Chen Endocrinology Department, The First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China Email
| | - Qinan Wu
- Endocrinology Department, Dazu Hospital of Chongqing Medical University, The People’s Hospital of Dazu, Chongqing, People’s Republic of China
- Correspondence: Qinan Wu Endocrinology Department, Dazu Hospital of Chongqing Medical University, The People’s Hospital of Dazu, Chongqing, People’s Republic of China Email
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25
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Engin O, Kilinc G, Salimoglu S. Trends, Risk Factors, and Preventions in Colorectal Cancer. COLON POLYPS AND COLORECTAL CANCER 2021:213-233. [DOI: 10.1007/978-3-030-57273-0_10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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26
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Common targets for a deadly duo of diabetes mellitus and colon cancer: Catching two fish with one worm. Eur J Pharmacol 2021; 893:173805. [PMID: 33359221 DOI: 10.1016/j.ejphar.2020.173805] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 11/05/2020] [Accepted: 12/08/2020] [Indexed: 12/21/2022]
Abstract
Colon cancer is a major health issue and number of cases are increasing every year. Diabetes mellitus is also a significant health issue that is growing day by day worldwide having negative influences on the survival of individuals. Research has shown a strong relationship between the two malignant diseases. The risk of colon cancer with patients who have type 2 diabetes mellitus has spiked by 30%. The scientific research suggests insulin has a major role in the spread of cancer and the condition unifying between the two diseases is hyperinsulinemia. Several anti-diabetic agents are used for the treatment of type 2 diabetesmellitus. However, their mechanism of action against cancer activity is a question and only a few agents have shown positive signs of action in colon cancer associated with type 2 diabetesmellitus. Hence, the identification of targets, which is common for both colon cancer, associated with type 2 diabetesmellitus has become an urgent requirement. Novel targets such as Liver X receptors, Histone deacetylase inhibitors (HDACi), Glucose Transporters (GLUTs), Peroxisome proliferator activator receptors (PPARs), Dipeptidyl peptidase-IV inhibitors (DPP4i), Cyclin-dependent kinase 4 inhibitors (CDK4i), Estrogen receptors,Mechanistic target of rapamycin (mTOR), Insulin-like growth factor receptors (IGF) are some of the targets which are common for both, type 2 diabetesmellitus and colon cancer. This current review gives an overview of the targets (using one worm) which are common for both viz. diabetes mellitus and colon cancer (two fish).
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27
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Affiliation(s)
- Anne Kilvert
- Consultant Physician, Northampton Community Diabetes Team UK
| | - Charles Fox
- Honorary Lecturer, Leicester Diabetes Centre Leicester UK
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28
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Zhou X, Lin N, Zhang M, Wang X, An Y, Su Q, Du P, Li B, Chen H. Circulating soluble receptor for advanced glycation end products and other factors in type 2 diabetes patients with colorectal cancer. BMC Endocr Disord 2020; 20:170. [PMID: 33187505 PMCID: PMC7666469 DOI: 10.1186/s12902-020-00647-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 10/31/2020] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Recent study showed that individuals with type 2 diabetes have a high risk of developing colorectal cancer (CRC), in which Receptor for Advanced Glycation End Products (RAGE) plays a pivotal role. We conducted a cross-sectional study to examine the relationships of circulating sRAGE, CRC and other clinical factors in type2 diabetes patients. METHODS A total of 150 type 2 diabetes patients aged 50 years and older were enrolled, including 50 patients with CRC and 100 patients without CRC. We measured Serum levels of sRAGE and interleukin-6(IL-6) using an enzyme-linked immunosorbent assay (ELISA). In addition, other clinical parameters were also measured during hospitalization. RESULTS Type 2 diabetes patients with CRC had higher triglyceride, total cholesterol, IL-6, and circulating sRAGE levels and lower use of medicines than type 2 diabetes patients without CRC. Circulating sRAGE was associated with an increased risk for CRC (OR = 2.289 for each SD increase in sRAGE, 95% CI = 1.037-5.051; P = 0.04) among Type 2 diabetes patients after adjustment for confounders. Furthermore, circulating sRAGE levels among type 2 diabetes patients were positively correlated with triglyceride (r = 0.377, P < 0.001), total cholesterol (r = 0.491, P < 0.001), and low-density lipoprotein cholesterol (LDL-c)(r = 0.330, P < 0.001) levels; the homeostatic model assessment for insulin resistance(HOMA-IR)score (r = 0.194, P = 0.017); and fasting serum insulin (r = 0.167, P = 0.041) and IL-6 (r = 0.311, P < 0.001) concentrations. CONCLUSIONS Our results suggested that circulating sRAGE is independently risk factor for CRC, and also closely related to inflammation, dyslipidemia in type 2 diabetes patients.
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Affiliation(s)
- Xiaohai Zhou
- Department of Endocrinology, Xinhua Hospital affiliated with Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, China
| | - Ning Lin
- Department of Endocrinology, Xinhua Hospital affiliated with Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, China
| | - Mingjie Zhang
- Shanghai Jiahui International Hospital, 689 Guiping Road, Xuhui District, Shanghai, China
| | - Xiaoling Wang
- Department of Endocrinology, Xinhua Hospital affiliated with Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, China
| | - Ye An
- Department of Endocrinology, Xinhua Hospital affiliated with Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, China
| | - Qing Su
- Department of Endocrinology, Xinhua Hospital affiliated with Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, China
| | - Peng Du
- Department of Colorectal Surgery, Xinhua Hospital affiliated with Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, China.
| | - Bo Li
- Department of Endocrinology, Xinhua Hospital affiliated with Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, China.
| | - Hanbei Chen
- Department of Endocrinology, Xinhua Hospital affiliated with Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai, China.
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Ma JW, Lai TJ, Hu SY, Lin TC, Ho WC, Tsan YT. Effect of ambient air pollution on the incidence of colorectal cancer among a diabetic population: a nationwide nested case-control study in Taiwan. BMJ Open 2020; 10:e036955. [PMID: 33115890 PMCID: PMC7594369 DOI: 10.1136/bmjopen-2020-036955] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVES An increasing number of studies had shown that air pollution exposure may aggravate blood glucose control in patients with diabetes, an independent risk factor for colorectal cancer (CRC) proposed by some researchers. This study aimed to investigate the impact of exposure to ambient particulate matter with aerodynamic diameters ≤2.5 μm (PM2.5) on the incidence of CRC among a diabetic population. DESIGN A nested case-control study. SETTING A subset data retrieved from the Taiwan's National Health Insurance Research Database. PARTICIPANTS We identified patients with newly diagnosed diabetes (n=1 164 962) during 1999-2013. Participants who had subsequently developed an incident of CRC were placed into the case group, while controls were matched to the cases at a 4:1 ratio by age, gender, date of diabetes diagnosis and the index date of CRC diagnosis. METHODS AND OUTCOME MEASURES All variables associated with the risk of CRC entered into a multinomial logistic regression model. The dose-response relationship between various average concentrations of PM2.5 exposure and the incidence of CRC was estimated by logistic regression. RESULTS The study included a total of 7719 incident CRC cases matched with 30 876 controls of random sampling. The mean annual concentration of PM2.5 was 35.3 µg/m3. After adjusting for potential confounders, a dose-response relationship was observed between the CRC risks and each interquartile increase of PM2.5 concentration (Q1-Q2: 1.03 (0.95-1.11), Q2-Q3: 1.06 (0.98-1.15), ≥Q3: 1.19 (1.10-1.28) in model 2. The adjusted ORs (95% CI) of CRC incidence for each 10 µg/m3 increment of PM2.5 was 1.08 (1.04-1.11). Moreover, a faster growing adapted Diabetes Complications Severity Index (aDCSI) score was noticed in CRC group compared with the controls, which also showed a significant association in our multivariate analysis (adjusted OR=1.28, 95% CI 1.18 to 1.38). CONCLUSIONS Long-term exposure to high concentrations of PM2.5 may contribute to an increased incidence of CRC among diabetic populations.
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Affiliation(s)
- Jen-Wen Ma
- Department of Emergency Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Ting-Ju Lai
- Department of Public Health, China Medical University, Taichung, Taiwan
| | - Sung-Yuan Hu
- Department of Emergency Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Tzu-Chieh Lin
- Department of Emergency Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Wen-Chao Ho
- Department of Public Health, China Medical University, Taichung, Taiwan
| | - Yu-Tse Tsan
- Department of Emergency Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Division of Occupational Medicine, Department of Emergency Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
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30
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Chinese herbal medicine promote tissue differentiation in colorectal cancer by activating HSD11B2. Arch Biochem Biophys 2020; 695:108644. [PMID: 33098869 DOI: 10.1016/j.abb.2020.108644] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/14/2020] [Accepted: 10/16/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Colorectal cancer is a common malignant tumor of the digestive tract. In recent years, the incidence rate has increased year by year and is showing a younger trend. The application of Chinese herbal medicine (CHM) is one of the important methods for the treatment of colorectal cancer. CHM refers to the main therapeutic drugs based on traditional Chinese medicine (TCM), which is still valued. Many effective anticancer small-molecule compounds are derived from CHMs, and their effective anticancer ingredients and targets must be clarified and to further understand the molecular mechanisms by which CHM affects cancer. METHODS We analyzed the ingredients in CHM that were found to be effective against colorectal cancer and constructed an interaction network among these ingredients and the target protein. By analyzing the number of connections in the network and their type of interaction, we identified the key target protein Corticosteroid 11-beta-dehydrogenase isozyme 2, the enzyme encoded by HSD11B2. Analyses of HSD11B2 expression, survival curve, and co-expressed genes helped clarify the correlation between HSD11B2 and colorectal cancer as well as its underlying molecular mechanism. RESULTS We determined that the anticancer ingredients contained in Sanguisorba officinalis, Patrinia scabiosaefolia, and Smilax china had more connections to the target proteins found in colorectal cancer. In the interaction network, eight small-molecule compounds had an activating effect on HSD11B2. The expression of the HSD11B2 was markedly decreased in colorectal cancer tissues and was positively correlated with the overall survival time of patients. In addition, co-expression analyses showed a close relationship between HSD11B2 and tissue-specific genes in colorectal tissues. The expression levels of HSD11B2 in well-, moderately, and poorly differentiated tissues progressively decreased. CONCLUSION The HSD11B2 protein was a key CHM target for treating colorectal cancer. The key role of CHM may lie in activating HSD11B2 and further promoting tissue differentiation in colorectal cancer.
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Deshpande RP, Sharma S, Watabe K. The Confounders of Cancer Immunotherapy: Roles of Lifestyle, Metabolic Disorders and Sociological Factors. Cancers (Basel) 2020; 12:E2983. [PMID: 33076303 PMCID: PMC7602474 DOI: 10.3390/cancers12102983] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 10/06/2020] [Accepted: 10/12/2020] [Indexed: 02/06/2023] Open
Abstract
Checkpoint blockade immunotherapy (CPI) is an effective treatment option for many types of cancers. Irrespective of its wide clinical implications, the overall efficacy remains unpredictable and even poor in certain pathologies such as breast cancer. Thus, it is imperative to understand the role of factors affecting its responsiveness. In this review, we provide an overview on the involvement of sociological factors, lifestyles and metabolic disorders in modulating the CPI response in patients from multiple malignancies. Lifestyle habits including exercise, and diet promoted therapeutic responsiveness while alcohol consumption mitigated the CPI effect by decreasing mutational burden and hampering antigen presentation by dendritic cells. Metabolic disorder such as obesity was recognized to enhance the PD-1 expression while diabetes and hypertension were consequences of CPI therapy rather than causes. Among the sociologic factors, sex and race positively influenced the CPI effectiveness on account of increased effector T cell activity and increased PD-1 expression while ageing impaired CPI responsiveness by decreasing functional T cell and increased toxicity. The combined effect of these factors was observed for obesity and gender, in which obese males had the most significant effect of CPI. Therefore these variables should be carefully considered before treating patients with CPI for optimal treatment outcome.
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Affiliation(s)
| | | | - Kounosuke Watabe
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC 27157, USA; (R.P.D.); (S.S.)
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Colorectal Cancer Risks According to Sex Differences in Patients With Type II Diabetes Mellitus: A Korean Nationwide Population-Based Cohort Study. Clin Transl Gastroenterol 2020; 10:e00090. [PMID: 31651449 PMCID: PMC6884353 DOI: 10.14309/ctg.0000000000000090] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION: Developing colorectal cancer (CRC) poses challenges for patients with type II diabetes mellitus (T2DM). We investigated CRC risk factors in patients with T2DM. METHODS: We retrospectively collected data from the National Health Insurance Corporation database, comprising approximately 97% of the Korean population. T2DM and CRC were defined according to International Classification of Disease codes (10th Revision) and claims data. Obesity was defined using body mass index (BMI); abdominal obesity was defined according to waist circumference. Other variables were defined using demographic, anthropometric, and laboratory data. RESULTS: Overall, 2,591,149 patients with T2DM were analyzed. During the follow-up period (median, 5.4 years), 24,236 CRC cases were identified. Aging (≥70 years), male sex, smoking, alcohol consumption, hypertension, and insulin and/or sulfonylurea use were significant risk factors for CRC. In males, smoking and alcohol consumption were more likely to lead to CRC, whereas a BMI increase was a more significant risk factor in females. Females with a BMI ≥ 25 kg/m2 and abdominal obesity were associated with an 18% increased risk of CRC compared with patients with normal weight and normal waist circumference (hazard ratio = 1.184, 95% confidence interval 1.123–1.25), whereas male patients with a BMI ≥ 25 kg/m2 and abdominal obesity were associated with an 8% increased risk (hazard ratio = 1.087, 95% confidence interval 1.049–1.127). DISCUSSION: Patients had CRC risk factors that differed according to sex. Smoking and heavy alcohol consumption were risks of CRC in males. Female patients with a BMI ≥ 25 kg/m2 and abdominal obesity were at a higher risk of developing CRC than males.
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Wong CKH, Man KKC, Chan EWY, Wu T, Tse ETY, Wong ICK, Lam CLK. DPP4i, thiazolidinediones, or insulin and risks of cancer in patients with type 2 diabetes mellitus on metformin-sulfonylurea dual therapy with inadequate control. BMJ Open Diabetes Res Care 2020; 8:8/1/e001346. [PMID: 32532851 PMCID: PMC7295418 DOI: 10.1136/bmjdrc-2020-001346] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 04/15/2020] [Accepted: 05/04/2020] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION This study aims to compare the risks of cancer among patients with type 2 diabetes mellitus (T2DM) on metformin-sulfonylurea dual therapy intensified with dipeptidyl peptidase 4 inhibitors (DPP4i), thiazolidinediones, or insulin. RESEARCH DESIGN AND METHODS We assembled a retrospective cohort data of 20 577 patients who were free of cancer and on metformin-sulfonylurea dual therapy, and whose drug treatments were intensified with DPP4i (n=9957), insulin (n=7760), or thiazolidinediones (n=2860) from January 2006 to December 2017. Propensity-score weighting was used to balance out baseline covariates across the three groups. HRs for any types of cancer, cancer mortality, and all-cause mortality were assessed using Cox proportional-hazards models. RESULTS Over a mean follow-up period of 34 months with 58 539 person-years, cumulative incidences of cancer, cancer mortality, and all-cause mortality were 0.028, 0.009, and 0.072, respectively. Patients intensified with insulin had the highest incidence of all-cause mortality (incidence rate=3.22/100 person-years) and the insulin itself posed the greatest risk (HR 2.46, 95% CI 2.25 to 2.70, p<0.001; 2.44, 95% CI 2.23 to 2.67) compared with thiazolidinediones and DPP4i, respectively. Comparing between thiazolidinediones and DPP4i, thiazolidinediones was associated with higher risk of cancer (HR 1.43, 95% CI 1.25 to 1.63) but not cancer mortality (HR 1.21, 95% CI 0.92 to 1.58) and all-cause mortality (HR 0.99, 95% CI 0.88 to 1.11). Insulin was associated with the greatest risk of cancer mortality (HR 1.36, 95% CI 1.09 to 1.71; 1.65, 95% CI 1.31 to 2.07) compared with thiazolidinediones and DPP4i, respectively. CONCLUSIONS For patients with T2DM on metformin-sulfonylurea dual therapy, the addition of DPP4i was the third-line medication least likely to be associated with cancer mortality and cancer effect among three options, and posed no increased risk for all-cause mortality when compared with thiazolidinediones.
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Affiliation(s)
- Carlos K H Wong
- Department of Family Medicine and Primary Care, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Kenneth K C Man
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China
- Research Department of Policy and Practice, University College London School of Pharmacy, London, UK
| | - Esther W Y Chan
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China
| | - Tingting Wu
- Department of Family Medicine and Primary Care, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Emily T Y Tse
- Department of Family Medicine and Primary Care, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Ian C K Wong
- Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China
- Research Department of Policy and Practice, University College London School of Pharmacy, London, UK
| | - Cindy L K Lam
- Department of Family Medicine and Primary Care, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
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Oh HJ, Lee HA, Moon CM, Ryu DR. The Combined Impact of Chronic Kidney Disease and Diabetes on the Risk of Colorectal Cancer Depends on Sex: A Nationwide Population-Based Study. Yonsei Med J 2020; 61:506-514. [PMID: 32469174 PMCID: PMC7256003 DOI: 10.3349/ymj.2020.61.6.506] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 04/11/2020] [Accepted: 04/20/2020] [Indexed: 12/16/2022] Open
Abstract
PURPOSE Although both chronic kidney disease (CKD) and diabetes mellitus (DM) are considered factors increasing the risk of colorectal cancer (CRC), their impact on CRC is not fully understood. This study was aimed to investigate the impact of CKD, DM, or both diseases on the risk of CRC and to evaluate sex differences therein. MATERIALS AND METHODS Using data from the National Health Insurance Service-Health Examination Cohort in Korea, we conducted a 1:2 matched case-control study. The disease groups consisted of CKD-/DM+ (n=17700), CKD+/DM- (n=22643), and CKD+/DM+ groups (n=8506). After 1:2 matching by age, sex, and health examination year and month, the healthy control group consisted of 97698 individuals. RESULTS Multivariate Cox regression analysis showed that the CKD-/DM+, CKD+/DM-, and CKD+/DM+ groups were independently associated with an increased incidence of CRC, compared with controls [hazard ratio (HR), 1.34, 1.31, and 1.63, respectively; all p<0.001]. Compared to the controls, adjusted HRs for the cumulative incidence of CRC in the CKD-/DM+, CKD+/DM-, and CKD+/DM+ groups were, respectively, 1.32, 1.26, and 1.43 in male and 1.38, 1.39, and 2.00 in female. The HR for CRC incidence was significantly higher for the CKD+/DM+ group than for the CKD-/DM+ or CKD+/DM- group in female; however, this significant difference was not observed in male. CONCLUSION In female, having both CKD and DM significantly increases the risk of CRC, compared with having CKD or DM alone. This study suggests a significant difference in the effect of CKD or DM on the risk of CRC according to sex.
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Affiliation(s)
- Hyung Jung Oh
- Ewha Institute of Convergence Medicine, Ewha Womans University Mokdong Hospital, Seoul, Korea
- Research Institute for Human Health Information, Ewha Womans University Mokdong Hospital, Seoul, Korea
| | - Hye Ah Lee
- Clinical Trial Center, Ewha Womans University Mokdong Hospital, Seoul, Korea
| | - Chang Mo Moon
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea
- Tissue Injury Defense Research Center, Ewha Womans University, Seoul, Korea.
| | - Dong Ryeol Ryu
- Research Institute for Human Health Information, Ewha Womans University Mokdong Hospital, Seoul, Korea
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea
- Tissue Injury Defense Research Center, Ewha Womans University, Seoul, Korea.
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Jhang JS, Livneh H, Yang SY, Huang HJ, Chan MWY, Lu MC, Yeh CC, Tsai TY. Decreased risk of colorectal cancer among patients with type 2 diabetes receiving Chinese herbal medicine: a population-based cohort study. BMJ Open Diabetes Res Care 2020; 8:8/1/e000732. [PMID: 32169932 PMCID: PMC7069272 DOI: 10.1136/bmjdrc-2019-000732] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 12/11/2019] [Accepted: 01/04/2020] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES Patients with type 2 diabetes have a higher risk of colorectal cancer (CRC), but whether Chinese herbal medicines (CHMs) can reduce this risk is unknown. This study investigated the effect that CHMs have on CRC risk in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This cohort study used the Taiwanese National Health Insurance Research Database to identify 54 744 patients, newly diagnosed with type 2 diabetes, aged 20-70 years, who were receiving treatment between 1998 and 2007. From this sample, we randomly selected 14 940 CHMs users and 14 940 non-CHMs users, using propensity scores matching. All were followed through 2012 to record CRC incidence. Cox proportional hazards regression was used to compute the hazard ratio (HR) of CRC by CHMs use. RESULTS During follow-up, 235 CHMs users and 375 non-CHMs users developed CRC, incidence rates of 1.73% and 2.47% per 1000 person-years, respectively. CHM users had a significantly reduced risk of CRC compared with non-CHM users (adjusted HR=0.71; 95% CI 0.60 to 0.84). The greatest effect was in those receiving CHMs for more than 1 year. Huang-Qin, Xue-Fu-Zhu-Yu-Tang, Shu-Jing-Huo-Xue-Tang, Liu-Wei-Di-Huang-Wan, Ji-Sheng-Shen-Qi-Wan, Gan-Lu-Yin, Shao-Yao-Gan-Cao-Tang and Ban-Xia-Xie-Xin-Tang were significantly associated with lower risk of CRC. CONCLUSION Integrating CHMs into the clinical management of patients with type 2 diabetes may be beneficial in reducing the risk of CRC.
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Affiliation(s)
- Jing-Siang Jhang
- Department of Chinese Medicine, Dalin Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Chiayi, Taiwan
- Department of Biomedical Sciences, National Chung Cheng University, Chiayi, Taiwan
| | - Hanoch Livneh
- Rehabilitation Counseling Program, Portland State University, Portland, Oregon, USA
| | - Shu-Yi Yang
- Department of Chinese Medicine, Dalin Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Chiayi, Taiwan
- Department of Biomedical Sciences, National Chung Cheng University, Chiayi, Taiwan
| | - Hui-Ju Huang
- Department of Nursing, Dalin Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Chiayi, Taiwan
| | - Michael W Y Chan
- Department of Biomedical Sciences, National Chung Cheng University, Chiayi, Taiwan
- Epigenomics and Human Diseases Research Center, National Chung Cheng University, Chiayi, Taiwan
| | - Ming-Chi Lu
- Division of Allergy, Immunology and Rheumatology, Dalin Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Chiayi, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Chia-Chou Yeh
- Department of Chinese Medicine, Dalin Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Chiayi, Taiwan
- School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan
| | - Tzung-Yi Tsai
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Nursing, Tzu Chi University of Science and Technology, Hualien, Taiwan
- Department of Medical Research, Dalin Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Chiayi, Taiwan
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Xu X, Si M, Lou H, Yan Y, Liu Y, Zhu H, Lou X, Ma J, Zhu D, Wu H, Yang B, Wu H, Ding L, He Q. Hyperglycemia decreases anti-cancer efficiency of Adriamycin via AMPK pathway. Endocr Relat Cancer 2020; 27:X3-X4. [PMID: 32022504 DOI: 10.1530/erc-18-0036] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The authors and journal apologise for an error in the above paper, which appeared in volume 25 part 11, pages 955–966. The error relates to the artwork of Fig. 5 on page 963, in which the blots given in panel E were mistakenly replicated in panel F.
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Affiliation(s)
- Xiaqing Xu
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Meimei Si
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Honggang Lou
- Department of Clinical Pharmacology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Youyou Yan
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yunxi Liu
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Hong Zhu
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Xiaoe Lou
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Jian Ma
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Difeng Zhu
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Honghai Wu
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Bo Yang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Haoshu Wu
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Ling Ding
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Qiaojun He
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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Kung FP, Tsai CF, Lu CL, Huang LC, Lu CH. Diabetes pay-for-performance program can reduce all-cause mortality in patients with newly diagnosed type 2 diabetes mellitus. Medicine (Baltimore) 2020; 99:e19139. [PMID: 32049836 PMCID: PMC7035087 DOI: 10.1097/md.0000000000019139] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
This study aimed to examine the effect of a diabetes pay-for-performance (P4P) program on all-cause mortality in patients with newly diagnosed type 2 diabetes mellitus. Using a Taiwanese representative nationwide cohort, we recruited 5478 patients with newly diagnosed type 2 diabetes enrolled in the P4P program within 5 years after a diagnosis of diabetes between January 1, 2002 and December 31, 2010 and individuals not enrolled in the P4P program were recruited as the control group matched 1:1 with the study group. We used multivariate Cox proportional hazard models analysis to investigate the effect of the P4P program and adherence on all-cause mortality. A total of 250 patients died in the P4P group compared to 395 in the control group (mortality rate 104 vs 169 per 10,000 person-years, respectively, P < .0001). The control group also had more comorbidities. Patients enrolled in the P4P program demonstrated significant long-term survival benefits, of which the adjusted hazard ratio (aHR) for all-cause mortality was 0.58 [95% CI (0.48-0.69)]. In the study group, better adherence to the P4P program resulted in a greater reduction in mortality, with aHRs [95% CI] of 0.48 [0.38-0.62] and 0.36 [0.26-0.49] in subjects with a minimum 1-year and 2-year good P4P adherence, respectively. Participating in the P4P program within 5 years after the diagnosis of diabetes resulted in a significant reduction in all-cause mortality, and this effect was particularly pronounced in the patients with better adherence to the P4P program.
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Affiliation(s)
- Fang-Ping Kung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Ditmanson Chia-Yi Christian Hospital
| | - Ching-Fang Tsai
- Department of Medical Research, Ditmanson Chia-Yi Christian Hospital, Chia-Yi City
| | - Chin-Li Lu
- Department of Medical Research, Ditmanson Chia-Yi Christian Hospital, Chia-Yi City
- Graduate Institute of Food Safety, College of Agriculture and Natural Resources, National Chung-Hsing University, Taichung
| | - Li-Chung Huang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Ditmanson Chia-Yi Christian Hospital
- Division of Psychiatry, Ditmanson Chia-Yi Christian Hospital, Chia-Yi City
| | - Chieh-Hsiang Lu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Ditmanson Chia-Yi Christian Hospital
- Kaohsiung Christian Hospital, Kaohsiung City, Taiwan
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Abstract
Metformin is a widely used biguanide drug due to its safety and low cost. It has been used for over 60 years to treat type 2 diabetes at the early stages because of its outstanding ability to decrease plasma glucose levels. Over time, different uses of metformin were discovered, and the benefits of metformin for various diseases and even aging were verified. These diseases include cancers (e.g., breast cancer, endometrial cancer, bone cancer, colorectal cancer, and melanoma), obesity, liver diseases, cardiovascular disease, and renal diseases. Metformin exerts different effects through different signaling pathways. However, the underlying mechanisms of these different benefits remain to be elucidated. The aim of this review is to provide a brief summary of the benefits of metformin and to discuss the possible underlying mechanisms.
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Affiliation(s)
- Ziquan Lv
- Department of Molecular Epidemiology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Yajie Guo
- The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
- *Correspondence: Yajie Guo
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Wang Y, Nasiri AR, Damsky WE, Perry CJ, Zhang XM, Rabin-Court A, Pollak MN, Shulman GI, Perry RJ. Uncoupling Hepatic Oxidative Phosphorylation Reduces Tumor Growth in Two Murine Models of Colon Cancer. Cell Rep 2019; 24:47-55. [PMID: 29972790 DOI: 10.1016/j.celrep.2018.06.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 05/07/2018] [Accepted: 06/01/2018] [Indexed: 10/28/2022] Open
Abstract
Obesity is associated with colon cancer pathogenesis, but the underlying mechanism is actively debated. Here, we confirm that diet-induced obesity promotes tumor growth in two murine colon cancer models and show that this effect is reversed by an orally administered controlled-release mitochondrial protonophore (CRMP) that acts as a liver-specific uncoupler of oxidative phosphorylation. This agent lowered circulating insulin, and the reduction of tumor growth was abrogated by an insulin infusion raising plasma insulin to the level of high-fat-fed mice. We also demonstrate that hyperinsulinemia increases glucose uptake and oxidation in vivo in tumors and that CRMP reverses these effects. This study provides evidence that perturbations of whole-organism energy balance or hepatic energy metabolism can influence neoplastic growth. Furthermore, the data show that glucose uptake and utilization by cancers in vivo are not necessarily constitutively high but rather may vary according to the hormonal milieu.
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Affiliation(s)
- Yongliang Wang
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Ali R Nasiri
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - William E Damsky
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Curtis J Perry
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Xian-Man Zhang
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Aviva Rabin-Court
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Michael N Pollak
- Department of Oncology, McGill University, Montreal, Quebec H3T 1E2, Canada; Department of Medicine, McGill University, Montreal, Quebec H3T 1E2, Canada; Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada
| | - Gerald I Shulman
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Rachel J Perry
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
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Deng M, Lei S, Huang D, Wang H, Xia S, Xu E, Wu Y, Zhang H. Suppressive effects of metformin on colorectal adenoma incidence and malignant progression. Pathol Res Pract 2019; 216:152775. [PMID: 31818523 DOI: 10.1016/j.prp.2019.152775] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/18/2019] [Accepted: 12/01/2019] [Indexed: 01/04/2023]
Abstract
BACKGROUND The linear progression from normal colonic epithelium to adenoma initiation, carcinoma transformation and metastasis is considered the classical model of colorectal cancer (CRC) development. Although metformin has been extensively reported to be negatively related to cancer incidence, the effect of metformin on CRC development remains unclear. We aimed to evaluate the role of metformin in the entire CRC linear progression. METHODS Systematic searches and data extraction were performed in the PubMed, Embase, and Cochrane Library databases on Jan 31, 2019. The combined relative ratios (RRs) of colorectal tumor incidence and the hazard ratios (HRs) of overall survival (OS) and cancer-specific survival (CSS) were evaluated by a random-effects model. Then, the effects of metformin were further assessed through stratified analyses by population, medication duration and dosage, dose-response analysis and comparison with other antidiabetic agents. RESULTS A total of 50 studies consisting of 238,540 cases of diabetes mellitus (DM) were included in this study. Metformin use was negatively associated with the incidence of colorectal adenoma (RR: 0.75, 95% CI: 0.65-0.86) and CRC (RR: 0.73, 95% CI: 0.58-0.90). Moreover, CRC patients benefited from metformin in terms of both OS (HR: 0.73, 95% Cl: 0.63-0.84) and CSS (HR: 0.60, 95% Cl: 0.50-0.73). Stratified analyses suggested that a long duration of high-dose metformin (RR: 0.52, 95% Cl: 0.36-0.83) was more effective than a short duration in Asian populations against colorectal adenoma (RR: 0.66, 95% Cl: 056-0.70) and CRC (RR: 0.45, 95% Cl: 0.29-0.70). Interestingly, metformin use decreased CRC risk in a dose-dependent manner (RR: 0.91, 95% CI: 0.87-0.95). In addition, the benefit of metformin on CRC was more significant than that of other antidiabetic agents, including insulin. CONCLUSIONS The use of metformin is associated with a lower incidence of adenoma and CRC and a better prognosis, especially in Asian populations.
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Affiliation(s)
- Min Deng
- Department of Pathology, The First People's Hospital of Fuyang, Hangzhou, 311400, PR China.
| | - Siqin Lei
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Dongdong Huang
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Hui Wang
- Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, 310058, China
| | - Shuli Xia
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Enping Xu
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Yihua Wu
- Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, 310058, China
| | - Honghe Zhang
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
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Krasanakis T, Nikolouzakis TK, Sgantzos M, Mariolis-Sapsakos T, Souglakos J, Spandidos DA, Tsitsimpikou C, Tsatsakis A, Tsiaoussis J. Role of anabolic agents in colorectal carcinogenesis: Myths and realities (Review). Oncol Rep 2019; 42:2228-2244. [PMID: 31578582 PMCID: PMC6826302 DOI: 10.3892/or.2019.7351] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 10/01/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the four leading causes of cancer‑related mortality worldwide. Even though over the past few decades the global scientific community has made tremendous efforts to understand this entity, many questions remain to be raised on this issue and even more to be answered. Epidemiological findings have unveiled numerous environmental and genetic risk factors, each one contributing to a certain degree to the final account of new CRC cases. Moreover, different trends have been revealed regarding the age of onset of CRC between the two sexes. That, in addition to newly introduced therapeutic approaches for various diseases based on androgens, anti‑androgens and anabolic hormones has raised some concerns regarding their possible carcinogenic effects or their synergistic potential with other substances/risk factors, predisposing the individual to CRC. Notably, despite the intense research on experimental settings and population studies, the conclusions regarding the majority of anabolic substances are ambiguous. Some of these indicate the carcinogenic properties of testosterone, dihydrotestosterone (DHT), growth hormone and insulin‑like growth factor (IGF) and others, demonstrating their neutral nature or even their protective one, as in the case of vitamin D. Thus, the synergistic nature of anabolic substances with other CRC risk factors (such as type 2 diabetes mellitus, metabolic syndrome and smoking) has emerged, suggesting a more holistic approach.
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Affiliation(s)
- Theodore Krasanakis
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, 71110 Heraklion, Greece
| | | | - Markos Sgantzos
- Faculty of Medicine, Department of Anatomy, Faculty of Medicine, University of Thessaly, 41221 Larissa, Greece
| | - Theodore Mariolis-Sapsakos
- National and Kapodistrian University of Athens, Agioi Anargyroi General and Oncologic Hospital of Kifisia, 14564 Athens, Greece
| | - John Souglakos
- Department of Medical Oncology, University General Hospital of Heraklion, 71110 Heraklion, Greece
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71409 Heraklion, Greece
| | | | - Aristidis Tsatsakis
- Department of Forensic Sciences and Toxicology, Medical School, University of Crete, 71409 Heraklion, Greece
| | - John Tsiaoussis
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, 71110 Heraklion, Greece
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Mroueh FM, Noureldein M, Zeidan YH, Boutary S, Irani SAM, Eid S, Haddad M, Barakat R, Harb F, Costantine J, Kanj R, Sauleau EA, Ouhtit A, Azar ST, Eid AH, Eid AA. Unmasking the interplay between mTOR and Nox4: novel insights into the mechanism connecting diabetes and cancer. FASEB J 2019; 33:14051-14066. [PMID: 31661292 DOI: 10.1096/fj.201900396rr] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Accepted: 09/17/2019] [Indexed: 01/03/2025]
Abstract
Cancer was recently annexed to diabetic complications. Furthermore, recent studies suggest that cancer can increase the risk of diabetes. Consequently, diabetes and cancer share many risk factors, but the cellular and molecular pathways correlating diabetes and colon and rectal cancer (CRC) remain far from understood. In this study, we assess the effect of hyperglycemia on cancer cell aggressiveness in human colon epithelial adenocarcinoma cells in vitro and in an experimental animal model of CRC. Our results show that Nox (NADPH oxidase enzyme) 4-induced reactive oxygen species (ROS) production is deregulated in both diabetes and CRC. This is paralleled by inactivation of the AMPK and activation of the mammalian target of rapamycin (mTOR) C1 signaling pathways, resulting in 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) accumulation, induction of DNA damage, and exacerbation of cancer cell aggressiveness, thus contributing to the genomic instability and predisposition to increased tumorigenesis in the diabetic milieu. Pharmacologic activation of AMPK, inhibition of mTORC1, or blockade of Nox4 reduce ROS production, restore the homeostatic signaling of 8-oxoguanine DNA glycosylase/8-oxodG, and lessen the progression of CRC malignancy in a diabetic milieu. Taken together, our results identify the AMPK/mTORC1/Nox4 signaling axis as a molecular switch correlating diabetes and CRC. Modulating this pathway may be a strategic target of therapeutic potential aimed at reversing or slowing the progression of CRC in patients with or without diabetes.-Mroueh, F. M., Noureldein, M., Zeidan, Y. H., Boutary, S., Irani, S. A. M., Eid, S., Haddad, M., Barakat, R., Harb, F., Costantine, J., Kanj, R., Sauleau, E.-A., Ouhtit, A., Azar, S. T., Eid, A. H., Eid, A. A. Unmasking the interplay between mTOR and Nox4: novel insights into the mechanism connecting diabetes and cancer.
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Affiliation(s)
- Fatima Mohsen Mroueh
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Mohamed Noureldein
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Youssef H Zeidan
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine and Medical Center, Beirut, Lebanon
- Department of Radiation Oncology, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Suzan Boutary
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Sara Abou Merhi Irani
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Stéphanie Eid
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Mary Haddad
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Rasha Barakat
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Frederic Harb
- Department of Life and Earth Sciences, Faculty of Sciences, Lebanese University, Fanar, Lebanon
| | - Joseph Costantine
- Department of Electrical and Computer Engineering, Maroun Semaan Faculty of Engineering and Architecture, Beirut, Lebanon
| | - Rouwaida Kanj
- Department of Electrical and Computer Engineering, Maroun Semaan Faculty of Engineering and Architecture, Beirut, Lebanon
| | - Erik-Andre Sauleau
- Department of Biostatistics, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7357 ICube, University of Strasbourg, Strasbourg, France
| | - Allal Ouhtit
- Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha, Qatar
| | - Sami T Azar
- Department of Internal Medicine, Faculty of Medicine and Medical Center, Beirut, Lebanon
- American University of Beirut (AUB) Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ali H Eid
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, Doha, Qatar
| | - Assaad A Eid
- Department of Anatomy, Cell Biology, and Physiological Sciences, Faculty of Medicine and Medical Center, Beirut, Lebanon
- American University of Beirut (AUB) Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
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Bykov K, He M, Franklin JM, Garry EM, Seeger JD, Patorno E. Glucose-lowering medications and the risk of cancer: A methodological review of studies based on real-world data. Diabetes Obes Metab 2019; 21:2029-2038. [PMID: 31062453 PMCID: PMC6684441 DOI: 10.1111/dom.13766] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 04/23/2019] [Accepted: 05/02/2019] [Indexed: 12/13/2022]
Abstract
AIM To review the methodology of observational studies examining the association between glucose-lowering medications and cancer to identify the most common methodological challenges and sources of bias. METHODS We searched PubMed systematically to identify observational studies on glucose-lowering medications and cancer published between January 2000 and January 2016. We assessed the design and analytical methods used in each study, with a focus on their ability to achieve study validity, and further evaluated the prevalence of major methodological choices over time. RESULTS Of 155 studies evaluated, only 26% implemented a new-user design, 41% used an active comparator, 33% implemented a lag or latency period, and 51% adjusted for diabetes duration. Potential for immortal person-time bias was identified in 63% of the studies; 55% of the studies adjusted for variables measured during the follow-up without appropriate statistical methods. Aside from a decreasing trend in adjusting for variables measured during the follow-up, we observed no trends in methodological choices over time. CONCLUSIONS The prevalence of well-known design and analysis flaws that may lead to biased results remains high among observational studies on glucose-lowering medications and cancer, limiting the conclusions that can be drawn from these studies. Avoiding known pitfalls could substantially improve the quality and validity of real-world evidence in this field.
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Affiliation(s)
- Katsiaryna Bykov
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Mengdong He
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jessica M Franklin
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | | | | | - Elisabetta Patorno
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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Mi Z, Guo B, Yin Z, Li J, Zheng Z. Disease classification via gene network integrating modules and pathways. ROYAL SOCIETY OPEN SCIENCE 2019; 6:190214. [PMID: 31417727 PMCID: PMC6689581 DOI: 10.1098/rsos.190214] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 06/04/2019] [Indexed: 06/10/2023]
Abstract
Disease classification based on gene information has been of significance as the foundation for achieving precision medicine. Previous works focus on classifying diseases according to the gene expression data of patient samples, and constructing disease network based on the overlap of disease genes, as many genes have been confirmed to be associated with diseases. In this work, the effects of diseases on human biological functions are assessed from the perspective of gene network modules and pathways, and the distances between diseases are defined to carry out the classification models. In total, 1728 diseases are divided into 12 and 14 categories by the intensity and scope of effects on pathways, respectively. Each category is a mix of several types of diseases identified based on congenital and acquired factors as well as diseased tissues and organs. The disease classification models on the basis of gene network are parallel with traditional pathology classification based on anatomic and clinical manifestations, and enable us to look at diseases in the viewpoint of commonalities in etiology and pathology. Our models provide a foundation for exploring combination therapy of diseases, which in turn may inform strategies for future gene-targeted therapy.
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Affiliation(s)
- Zhilong Mi
- Beijing Advanced Innovation Center for Big Data and Brain Computing, Beihang University, Beijing 100191, People’s Republic of China
- LMIB and School of Mathematics and Systems Science, Beihang University, Beijing 100191, People’s Republic of China
- Peng Cheng Laboratory, Shenzhen, Guangdong Province 518055, People’s Republic of China
| | - Binghui Guo
- Beijing Advanced Innovation Center for Big Data and Brain Computing, Beihang University, Beijing 100191, People’s Republic of China
- LMIB and School of Mathematics and Systems Science, Beihang University, Beijing 100191, People’s Republic of China
- Peng Cheng Laboratory, Shenzhen, Guangdong Province 518055, People’s Republic of China
| | - Ziqiao Yin
- Beijing Advanced Innovation Center for Big Data and Brain Computing, Beihang University, Beijing 100191, People’s Republic of China
- LMIB and School of Mathematics and Systems Science, Beihang University, Beijing 100191, People’s Republic of China
- Shenyuan Honors College, Beihang University, Beijing 100191, People’s Republic of China
- Peng Cheng Laboratory, Shenzhen, Guangdong Province 518055, People’s Republic of China
| | - Jiahui Li
- Beijing Advanced Innovation Center for Big Data and Brain Computing, Beihang University, Beijing 100191, People’s Republic of China
- LMIB and School of Mathematics and Systems Science, Beihang University, Beijing 100191, People’s Republic of China
- Peng Cheng Laboratory, Shenzhen, Guangdong Province 518055, People’s Republic of China
| | - Zhiming Zheng
- Beijing Advanced Innovation Center for Big Data and Brain Computing, Beihang University, Beijing 100191, People’s Republic of China
- LMIB and School of Mathematics and Systems Science, Beihang University, Beijing 100191, People’s Republic of China
- Peng Cheng Laboratory, Shenzhen, Guangdong Province 518055, People’s Republic of China
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Bradley MC, Ferrara A, Achacoso N, Ehrlich SF, Quesenberry CP, Habel LA. A Cohort Study of Metformin and Colorectal Cancer Risk among Patients with Diabetes Mellitus. Cancer Epidemiol Biomarkers Prev 2019; 27:525-530. [PMID: 29716927 DOI: 10.1158/1055-9965.epi-17-0424] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 09/05/2017] [Accepted: 11/22/2017] [Indexed: 12/29/2022] Open
Abstract
Background: Several epidemiologic studies have reported strong inverse associations between metformin use and risk of colorectal cancer, although time-related biases, such as immortal time bias, may in part explain these findings. We reexamined this association using methods to minimize these biases.Methods: A cohort study was conducted among 47,351 members of Kaiser Permanente Northern California with diabetes and no history of cancer or metformin use. Follow-up for incident colorectal cancer occurred from January 1, 1997, until June 30, 2012. Cox regression was used to calculate HRs and 95% confidence intervals (CIs) for colorectal cancer risk associated with metformin use (ever use, total duration, recency of use, and cumulative dose).Results: No association was observed between ever use of metformin and colorectal cancer risk (HR, 0.90; 95% CI, 0.76-1.07) and there was no consistent pattern of decreasing risk with increasing total duration, dose, or recency of use. However, long-term use (≥5.0 years) appeared to be associated with reduced risk of colorectal cancer in the full population (HR, 0.78; 95% CI, 0.60-1.02), among current users (HR, 0.78; 95% CI, 0.59-1.04), and in men (HR, 0.65; 95% CI, 0.45-0.94) but not in women. Higher cumulative doses of metformin were associated with reduced risk. In initial users of sulfonylureas, switching to or adding metformin was also associated with decreased colorectal cancer risk.Conclusions: Our findings showed an inverse association between long-term use of metformin and colorectal cancer risk. Findings, especially the risk reduction among men, need to be confirmed in large, well-conducted studies.Impact: If our findings are confirmed, metformin may have a role in the chemoprevention of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 27(5); 525-30. ©2018 AACRSee related commentary by Jackson and García-Albéniz, p. 520.
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Affiliation(s)
- Marie C Bradley
- Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, Maryland
| | - Assiamira Ferrara
- Division of Research, Kaiser Permanente Northern California, Oakland, California
| | - Ninah Achacoso
- Division of Research, Kaiser Permanente Northern California, Oakland, California
| | - Samantha F Ehrlich
- Division of Research, Kaiser Permanente Northern California, Oakland, California
| | | | - Laurel A Habel
- Division of Research, Kaiser Permanente Northern California, Oakland, California.
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Kim D, Ahn BN, Kim Y, Hur DY, Yang JW, Park GB, Jang JE, Lee EJ, Kwon MJ, Kim TN, Kim MK, Park JH, Rhee BD, Lee SH. High Glucose with Insulin Induces Cell Cycle Progression and Activation of Oncogenic Signaling of Bladder Epithelial Cells Cotreated with Metformin and Pioglitazone. J Diabetes Res 2019; 2019:2376512. [PMID: 30729133 PMCID: PMC6343135 DOI: 10.1155/2019/2376512] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Accepted: 11/25/2018] [Indexed: 12/13/2022] Open
Abstract
Metformin and pioglitazone are two commonly prescribed oral hypoglycemic agents for diabetes. Recent evidence suggests that these drugs may contribute to bladder cancer. This study investigated molecular mechanism underlying effects of metformin and pioglitazone in bladder epithelial carcinogenesis in type 2 diabetes. The cells derived from human bladder epithelial cells (HBlEpCs) were treated with metformin or pioglitazone with high glucose and insulin. Cell viability and proliferation were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and a bromodeoxyuridine incorporation assay, respectively, while cell cycle regulatory factors and oncogene expression were analyzed using western blotting. Metformin or pioglitazone suppressed cell viability concentration and time dependently, which was reversed by exposure to high glucose with or without insulin. Prolonged exposure to high glucose and insulin enhanced cyclin D, cyclin-dependent kinase 4 (Cdk4), and Cdk2 expression and suppressed cyclin-dependent kinase inhibitors p21 and p15/16 in HBlEpC cotreated with pioglitazone and metformin. Levels of tumor suppressor proteins p53 and cav-1 were downregulated while those of the oncogenic protein as c-Myc were upregulated under high glucose and insulin supplementation in HBlEpC cotreated with pioglitazone and metformin. Prolonged exposure to high glucose with or without insulin downregulated B cell lymphoma 2-associated X (Bax) and failed to enhance the expression of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) in drug-treated cells. These results suggest that hyperglycemic and insulinemic conditions promote cell cycle progression and oncogenic signaling in drug-treated bladder epithelial cells and uncontrolled hyperglycemia and hyperinsulinemia are probably greater cancer risk factors than diabetes drugs.
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Affiliation(s)
- Daejin Kim
- Department of Anatomy, Inje University College of Medicine, Busan 614-735, Republic of Korea
| | - Byul-Nim Ahn
- T2B Infrastructure Center for Ocular Disease, Inje University Busan Paik Hospital, Busan, Republic of Korea
| | - YeongSeok Kim
- Department of Anatomy, Inje University College of Medicine, Busan 614-735, Republic of Korea
| | - Dae Young Hur
- Department of Anatomy, Inje University College of Medicine, Busan 614-735, Republic of Korea
| | - Jae Wook Yang
- T2B Infrastructure Center for Ocular Disease, Inje University Busan Paik Hospital, Busan, Republic of Korea
- Department of Ophthalmology, Inje University College of Medicine, Inje University Busan Paik Hospital, Busan, Republic of Korea
| | - Ga Bin Park
- Department of Biochemistry, Kosin University College of Medicine, Busan 49267, Republic of Korea
| | - Jung Eun Jang
- Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea
| | - Eun Ju Lee
- Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea
| | - Min Jeong Kwon
- Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea
| | - Tae Nyun Kim
- Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea
| | - Mi Kyung Kim
- Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea
| | - Jeong Hyun Park
- Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea
| | - Byoung Doo Rhee
- Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea
| | - Soon Hee Lee
- Department of Internal Medicine, College of Medicine, Inje University, Busan, Republic of Korea
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Antidiabetic Drugs in NAFLD: The Accomplishment of Two Goals at Once? Pharmaceuticals (Basel) 2018; 11:ph11040121. [PMID: 30413050 PMCID: PMC6316860 DOI: 10.3390/ph11040121] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 11/02/2018] [Accepted: 11/03/2018] [Indexed: 02/06/2023] Open
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver disease in Western countries, accounting for 20–30% of general population and reaching a prevalence of 55% in patients with type 2 diabetes mellitus (T2DM). Insulin resistance plays a key role in pathogenic mechanisms of NAFLD. Many drugs have been tested but no medications have yet been approved. Antidiabetic drugs could have a role in the progression reduction of the disease. The aim of this review is to summarize evidence on efficacy and safety of antidiabetic drugs in patients with NAFLD. Metformin, a biguanide, is the most frequently used drug in the treatment of T2DM. To date 15 randomized controlled trials (RCTs) and four meta-analysis on the use of metformin in NAFLD are available. No significant improvement in histological liver fibrosis was shown, but it can be useful in the treatment of co-factors of NAFLD, like body weight, transaminase or cholesterol levels, and HbA1c levels. A possible protective role in various types of cancer has been reported for Metformin. Thiazolidinediones modulate insulin sensitivity by the activation of PPAR-γ. The RCTs and the meta-analysis available about the role of these drugs in NAFLD show an improvement in ballooning, lobular inflammation, and perhaps fibrosis, but some side effects, in particular cardiovascular, were showed. GLP-1 analogues stimulate insulin secretion by pancreatic beta cell and inhibit glucagon release; Liraglutide is the most used drug in this class and significantly improves steatosis, hepatocyte ballooning and transaminase levels. Scanty data about the role of DPP-4 and SGLT inhibitors were published. No data about insulin effects on NAFLD are available but it was showed a possible association between insulin use and the development of solid neoplasms, in particular HCC. In conclusion, antidiabetic drugs seem to be promising drugs, because they are able to treat both NAFLD manifestations and diabetes, preventing worsening of hepatic damage, but data are still conflicting. All antidiabetic drugs can be safely used in patients with compensated cirrhosis, while insulin is the preferred drug in decompensated Child C cirrhosis.
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Restifo D, Williams JS, Garacci E, Walker RJ, Ozieh MN, Egede LE. Differential relationship between colorectal cancer and diabetes in a nationally representative sample of adults. J Diabetes Complications 2018; 32:819-823. [PMID: 30099983 PMCID: PMC8011301 DOI: 10.1016/j.jdiacomp.2018.06.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 05/21/2018] [Accepted: 06/10/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Diabetes has been identified as a risk factor for developing colorectal cancer (CRC); however, the literature identifying groups most at risk is sparse. This study aims to understand the relationship between CRC and diabetes by age and race/ethnicity. METHODS This is a cross-sectional study of data from the 2001-2014 National Health and Nutrition Examination Survey (unweighted n = 37,173; weighted n = 214,363,348). Individuals were categorized as having CRC if diagnosed with colon or rectal cancer and as having diabetes if told by a doctor they had diabetes, were taking insulin, or had an HbA1c ≥ 6.5%. Covariates included gender, age, race, marital status, educational level and income as a ratio of the poverty line. Multivariable logistic regression was used to assess the relationship between CRC and diabetes overall and stratified by age and by race. RESULTS 24.32% of the sample with CRC also had diabetes. After adjusting for covariates, individuals with diabetes had a 47% greater probability of having CRC (p = 0.03). While significance did not persist after stratification for those ≥65 years (OR = 1.06, p = 0.74), those <65 years with diabetes had nearly 5-times higher odds of having CRC (OR = 4.78, p < 0.001). When stratified by race, both groups had statistically higher odds of having CRC; however, the odds for non-whites (OR = 1.87, p = 0.04) were higher compared to whites (OR = 1.54, p = 0.03). CONCLUSION Individuals younger than 65 and racial/ethnic minorities have higher odds of CRC when also diagnosed with diabetes. Targeted interventions for these populations, especially regarding screening recommendations, may result in earlier detection of CRC and improved health outcomes.
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Affiliation(s)
- Daniel Restifo
- Fordham University, Departments of Biological Sciences and Philosophy, Bronx, NY, United States of America
| | - Joni S Williams
- Center for Patient Care and Outcomes Research, Medical College of Wisconsin, Milwaukee, WI, United States of America; Division of General Internal Medicine, Department of Medicine, Froedtert & The Medical College of Wisconsin, Milwaukee, WI, United States of America
| | - Emma Garacci
- Center for Patient Care and Outcomes Research, Medical College of Wisconsin, Milwaukee, WI, United States of America
| | - Rebekah J Walker
- Center for Patient Care and Outcomes Research, Medical College of Wisconsin, Milwaukee, WI, United States of America; Division of General Internal Medicine, Department of Medicine, Froedtert & The Medical College of Wisconsin, Milwaukee, WI, United States of America
| | - Mukoso N Ozieh
- Division of Nephrology, Department of Medicine, Froedtert & The Medical College of Wisconsin, Milwaukee, WI, United States of America; Division of Nephrology, Clement J. Zablocki VA Medical Center, Milwaukee, WI, United States of America
| | - Leonard E Egede
- Center for Patient Care and Outcomes Research, Medical College of Wisconsin, Milwaukee, WI, United States of America; Division of General Internal Medicine, Department of Medicine, Froedtert & The Medical College of Wisconsin, Milwaukee, WI, United States of America.
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Budzynska K, Passerman D, White-Perkins D, Rees DA, Xu J, Lamerato L, Schooley S. Diabetes mellitus and hyperglycemia control on the risk of colorectal adenomatous polyps: a retrospective cohort study. BMC FAMILY PRACTICE 2018; 19:145. [PMID: 30157768 PMCID: PMC6116428 DOI: 10.1186/s12875-018-0835-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 08/16/2018] [Indexed: 12/23/2022]
Abstract
Background Colorectal cancer (CRC) develops from colorectal adenomatous polyps. This study is to determine if diabetes mellitus (DM), its treatment, and hemoglobin A1c (HbA1c) level are associated with increased risk of colorectal adenomatous polyps. Methods This was a retrospective cohort study that included patients who had at least one colonoscopy and were continuously enrolled in a single managed care organization during a 10-year period (2002–2012). Of these patients (N = 11,933), 1800 were randomly selected for chart review to examine the details of colonoscopy and pathology findings and to confirm the diagnosis of DM. Multivariable logistic regression analyses were performed to assess the associations between DM, its treatment, HbA1c level and adenomatous polyps (our main outcome). Results Among the total of 11,933 patients with a mean (standard deviation) age of 56 (± 8.8) years, 2306 (19.3%) had DM and 75 (0.6%) had CRC. Among the 1800 under chart review, 445 (24.7%) had DM, 11 (0.6%) had CRC and 537 (29.8%) had adenomatous polyps. In bivariate analysis, patients with DM had 1.45 odds of developing adenomatous polyps compared to those without DM. This effect was attenuated (odds ratio = 1.25, 95% CI: 0.96–1.62, p = 0.09) after adjusting for confounders such as age, gender, race/ethnicity, and body mass index. There was no significant association between type or duration of DM treatment or HbA1c level and adenomatous polyps. Conclusions Our study confirmed the known increased risk of adenomatous polyps with advancing age, male gender, Hispanic race/ethnicity and higher body mass index. Although it suggested an association between DM and adenomatous polyps, a statistically significant association was not observed after controlling for other potential confounders. Further studies with a larger sample size are needed to further elucidate this relationship.
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Affiliation(s)
- Katarzyna Budzynska
- Department of Family Medicine, Henry Ford Hospital, Detroit, MI, USA. .,Department of Family Medicine, Henry Ford Health System, 3370 E Jefferson, Detroit, MI, 48207, USA.
| | - Daniel Passerman
- Department of Family Medicine, Henry Ford Hospital, Detroit, MI, USA
| | | | - Della A Rees
- Department of Family Medicine, Henry Ford Hospital, Detroit, MI, USA
| | - Jinping Xu
- Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, MI, USA
| | - Lois Lamerato
- Department of Family Medicine, Henry Ford Hospital, Detroit, MI, USA
| | - Susan Schooley
- Department of Family Medicine, Henry Ford Hospital, Detroit, MI, USA
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Juárez-Vázquez CI, Gurrola-Díaz CM, Vargas-Guerrero B, Domínguez-Rosales JA, Rodriguez-Ortiz JF, Barros-Núñez P, Flores-Martínez SE, Sánchez-Corona J, Rosales-Reynoso MA. Insulin glargine affects the expression of Igf-1r, Insr, and Igf-1 genes in colon and liver of diabetic rats. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2018; 21:489-494. [PMID: 29922429 PMCID: PMC6000212 DOI: 10.22038/ijbms.2018.24867.6185] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Objective(s): The mitogenic effect of the analogous insulin glargine is currently under debate since several clinical studies have raised the possibility that insulin glargine treatment has a carcinogenic potential in different tissues. This study aimed to evaluate the Igf-1r, Insr, and Igf-1 gene expression in colon and liver of streptozotocin-induced diabetic rats in response to insulin glargine, neutral protamine Hagedorn (NPH) insulin, and metformin treatments. Materials and Methods: Male Wistar rats were induced during one week with streptozotocin to develop Type 2 Diabetes (T2D) and then randomly distributed into four groups. T2D rats included in the first group received insulin glargine, the second group received NPH insulin, the third group received metformin; finally, untreated T2D rats were included as the control group. All groups were treated for seven days; after the treatment, tissue samples of liver and colon were obtained. Quantitative PCR (qPCR) was performed to analyze the Igf-1r, Insr and Igf-1 gene expression in each tissue sample. Results: The liver tissue showed overexpression of the Insr and Igf-1r genes (P>0.001) in rats treated with insulin glargine in comparison with the control group. Similar results were observed for the Insr gene (P>0.011) in colonic tissue of rats treated with insulin glargine. Conclusion: These observations demonstrate that insulin glargine promote an excess of insulin and IGF-1 receptors in STZ-induced diabetic rats, which could overstimulate the mitogenic signaling pathways.
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Affiliation(s)
- Clara I Juárez-Vázquez
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente. Instituto Mexicano del Seguro Social. Guadalajara, Jalisco, México
| | - Carmen M Gurrola-Díaz
- Instituto de Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, C.U.C.S, Universidad de Guadalajara. Guadalajara, Jalisco, México
| | - Belinda Vargas-Guerrero
- Instituto de Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, C.U.C.S, Universidad de Guadalajara. Guadalajara, Jalisco, México
| | - José A Domínguez-Rosales
- Instituto de Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, C.U.C.S, Universidad de Guadalajara. Guadalajara, Jalisco, México
| | - Jessica F Rodriguez-Ortiz
- División de Genética, Centro de Investigación Biomédica de Occidente. Instituto Mexicano del Seguro Social. Guadalajara, Jalisco, México
| | - Patricio Barros-Núñez
- División de Genética, Centro de Investigación Biomédica de Occidente. Instituto Mexicano del Seguro Social. Guadalajara, Jalisco, México
| | - Silvia E Flores-Martínez
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente. Instituto Mexicano del Seguro Social. Guadalajara, Jalisco, México
| | - José Sánchez-Corona
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente. Instituto Mexicano del Seguro Social. Guadalajara, Jalisco, México
| | - Mónica A Rosales-Reynoso
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente. Instituto Mexicano del Seguro Social. Guadalajara, Jalisco, México
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