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Hu C, Chen Y, Yin X, Xu R, Yin C, Wang C, Zhao Y. Pancreatic endocrine and exocrine signaling and crosstalk in physiological and pathological status. Signal Transduct Target Ther 2025; 10:39. [PMID: 39948335 PMCID: PMC11825823 DOI: 10.1038/s41392-024-02098-3] [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: 06/20/2024] [Revised: 10/20/2024] [Accepted: 12/03/2024] [Indexed: 02/16/2025] Open
Abstract
The pancreas, an organ with dual functions, regulates blood glucose levels through the endocrine system by secreting hormones such as insulin and glucagon. It also aids digestion through the exocrine system by secreting digestive enzymes. Complex interactions and signaling mechanisms between the endocrine and exocrine functions of the pancreas play a crucial role in maintaining metabolic homeostasis and overall health. Compelling evidence indicates direct and indirect crosstalk between the endocrine and exocrine parts, influencing the development of diseases affecting both. From a developmental perspective, the exocrine and endocrine parts share the same origin-the "tip-trunk" domain. In certain circumstances, pancreatic exocrine cells may transdifferentiate into endocrine-like cells, such as insulin-secreting cells. Additionally, several pancreatic diseases, including pancreatic cancer, pancreatitis, and diabetes, exhibit potential relevance to both endocrine and exocrine functions. Endocrine cells may communicate with exocrine cells directly through cytokines or indirectly by regulating the immune microenvironment. This crosstalk affects the onset and progression of these diseases. This review summarizes the history and milestones of findings related to the exocrine and endocrine pancreas, their embryonic development, phenotypic transformations, signaling roles in health and disease, the endocrine-exocrine crosstalk from the perspective of diseases, and potential therapeutic targets. Elucidating the regulatory mechanisms of pancreatic endocrine and exocrine signaling and provide novel insights for the understanding and treatment of diseases.
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Grants
- National High Level Hospital Clinical Research Funding (2022, 2022-PUMCH-D-001, to YZ), CAMS Innovation Fund for Medical Sciences (2021, 2021-I2M-1-002, to YZ), National Nature Science Foundation of China (2021, 82102810, to CW, the Fundamental Research Funds for the Central Universities(3332023123)
- cNational High Level Hospital Clinical Research Funding (2022, 2022-PUMCH-D-001, to YZ), CAMS Innovation Fund for Medical Sciences (2021, 2021-I2M-1-002, to YZ), National Nature Science Foundation of China (2021, 82102810, to CW, the Fundamental Research Funds for the Central Universities(3332023123)
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Affiliation(s)
- Chenglin Hu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Yuan Chen
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Xinpeng Yin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Chenxue Yin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Chengcheng Wang
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China.
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China.
- National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Beijing, PR China.
- Institute of Clinical Medicine, Peking Union Medical College Hospital, Beijing, PR China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, PR China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, PR China.
- State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China.
- National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Beijing, PR China.
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Zhao Z, He X, Sun Y. Hypoglycemic agents and incidence of pancreatic cancer in diabetic patients: a meta-analysis. Front Pharmacol 2023; 14:1193610. [PMID: 37497113 PMCID: PMC10366383 DOI: 10.3389/fphar.2023.1193610] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 06/28/2023] [Indexed: 07/28/2023] Open
Abstract
Background and aims: Hypoglycemic agents are the primary therapeutic approach for the treatment of diabetes and have been postulated to impact pancreatic cancer (PC) incidence in diabetic patients. We conducted a meta-analysis to further evaluate and establish the associations between four common types of hypoglycemic agents [metformin, sulfonylureas, thiazolidinediones (TZDs), and insulin] and PC incidence in individuals with diabetes mellitus (DM). Methods: A comprehensive literature search of PubMed, Web of Science, Embase, and the Cochrane Library identified studies that analyzed the relationship between hypoglycemic agents and PC published between January 2012 and September 2022. Randomized control trials (RCTs), cohorts, and case-control studies were included if there was clear and evaluated defined exposure to the involved hypoglycemic agents and reported PC outcomes in patients with DM. Furthermore, reported relative risks or odds ratios (ORs) or other provided data were required for the calculation of odds ratios. Summary odds ratio estimates with a 95% confidence interval (CI) were estimated using the random-effects model. Additionally, subgroup analysis was performed to figure out the source of heterogeneity. Sensitivity analysis and publication bias detection were also performed. Results: A total of 11 studies were identified that evaluated one or more of the hypoglycemic agents, including three case-control studies and eight cohort studies. Among these, nine focused on metformin, six on sulfonylureas, seven on TZDs, and seven on insulin. Meta-analysis of the 11 observational studies reported no significant association between metformin (OR = 1.04, 95% CI 0.73-1.46) or TZDs (OR = 1.13, 95% CI 0.73-1.75) and PC incidence, while the risk of PC increased by 79% and 185% with sulfonylureas (OR = 1.79, 95% CI 1.29-2.49) and insulin (OR = 2.85, 95% CI 1.75-4.64), respectively. Considerable heterogeneity was observed among the studies and could not be fully accounted for by study design, region, or adjustment for other hypoglycemic agents. Conclusion: Sulfonylureas and insulin may increase the incidence of pancreatic cancer in diabetic patients, with varying effects observed among different ethnicities (Asian and Western). Due to significant heterogeneity across studies, further interpretation of the relationship between hypoglycemic agents and pancreatic cancer incidence in diabetic patients requires well-adjusted data and better-organized clinical trials.
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Affiliation(s)
- Zimo Zhao
- First Clinical Medical College, China Medical University, Shenyang, China
| | - Xinyi He
- Clinical Department I, China Medical University, Shenyang, China
| | - Yan Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
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Tsai LJ, Chung CH, Lin CJ, Su SC, Kuo FC, Liu JS, Chen KC, Ho LJ, Kuo CC, Chang CY, Lin MH, Chu NF, Lee CH, Hsieh CH, Hung YJ, Hsieh PS, Lin FH, Lu CH, Chien WC. Traditional Chinese medicine attenuates hospitalization and mortality risks in diabetic patients with carcinoma in situ in Taiwan. Integr Med Res 2022; 11:100831. [PMID: 35059290 PMCID: PMC8760454 DOI: 10.1016/j.imr.2021.100831] [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] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 11/26/2021] [Accepted: 12/26/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Diabetic patients are at high risk of developing cancer. Traditional Chinese medicine (TCM) has become increasingly popular as an adjuvant treatment for patients with chronic diseases, and some studies have identified its beneficial effect in diabetic patients with cancer. The purpoes of this study was to outline the potential of TCM to attenuate hospitalization and mortality rates in diabetic patients with carcinoma in situ (CIS). METHODS A total of 6,987 diabetic subjects with CIS under TCM therapy were selected from the National Health Insurance Research Database of Taiwan, along with 38,800 of 1:1 sex-, age-, and index year-matched controls without TCM therapy. Cox proportional hazard analysis was conducted to compare hospitalization and mortality rates during an average of 15 years of follow-up. RESULTS A total of 3,999/1,393 enrolled-subjects (28.62%/9.97%) had hospitalization/mortality, including 1,777/661 in the TCM group (25.43%/9.46%) and 2,222/732 in the control group (31.80%/10.48%). Cox proportional hazard regression analysis showed a lower rate of hospitalization and mortality for subjects in the TCM group (adjusted HR=0.536; 95% CI=0.367-0.780, P<0.001; adjusted HR=0.783; 95% CI=0.574-0.974, P = 0.022). Kaplan-Meier analysis showed that the cumulative risk of hospitalization and mortality in the case and control groups was significantly different (log rank, P<0.001 and P = 0.011, respectively). CONCLUSIONS Diabetic patients with CIS under TCM therapy were associated with lower hospitalization and mortality rates compared to those without TCM therapy. Thus, TCM application may reduce the burden of national medical resources.
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Affiliation(s)
- Li-Jen Tsai
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan (Province of China)
| | - Chi-Hsiang Chung
- School of Public Health, National Defense Medical Center, Taipei, Taiwan (Province of China)
- Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan (Province of China)
| | - Chien-Jung Lin
- Department of Chinese Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (Province of China)
| | - Sheng-Chiang Su
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan (Province of China)
| | - Feng-Chih Kuo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan (Province of China)
| | - Jhih-Syuan Liu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan (Province of China)
| | - Kuan-Chan Chen
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan (Province of China)
| | - Li-Ju Ho
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan (Province of China)
| | - Chih-Chun Kuo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan (Province of China)
| | - Chun-Yung Chang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan (Province of China)
| | - Ming-Hsun Lin
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan (Province of China)
| | - Nain-Feng Chu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan (Province of China)
| | - Chien-Hsing Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan (Province of China)
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (Province of China)
| | - Chang-Hsun Hsieh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan (Province of China)
| | - Yi-Jen Hung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan (Province of China)
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan (Province of China)
| | - Po-Shiuan Hsieh
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (Province of China)
- Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan (Province of China)
| | - Fu-Huang Lin
- School of Public Health, National Defense Medical Center, Taipei, Taiwan (Province of China)
| | - Chieh-Hua Lu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan (Province of China)
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (Province of China)
| | - Wu-Chien Chien
- School of Public Health, National Defense Medical Center, Taipei, Taiwan (Province of China)
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (Province of China)
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Metformin Attenuates Osteoporosis in Diabetic Patients with Carcinoma in Situ: A Nationwide, Retrospective, Matched-Cohort Study in Taiwan. J Clin Med 2020; 9:jcm9092839. [PMID: 32887312 PMCID: PMC7565460 DOI: 10.3390/jcm9092839] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/24/2020] [Accepted: 08/30/2020] [Indexed: 02/07/2023] Open
Abstract
Patients with diabetes are at increased risk of cancer development and osteoporosis. Metformin is an effective agent for diabetes management. Epidemiological studies have identified an association between metformin use and cancer prevention. This article outlines the potential for metformin to attenuate the rate of osteoporosis in diabetic patients with carcinoma in situ (CIS). From the National Health Insurance Research Database of Taiwan, 7827 patients with diabetes with CIS who were receiving metformin therapy were selected, along with 23,481 patients as 1:3 sex-, age- and index year-matched controls, who were not receiving metformin therapy. A Cox proportional hazard analysis was used to compare the rate of osteoporosis during an average of 15-year follow-up. Of the subjects who were enrolled, 801 (2.56%) had osteoporosis, including 168 from the metformin group (2.15%) and 633 from the without metformin group (2.70%). The metformin group presented a lower rate of osteoporosis at the end of follow-up (p = 0.009). The Cox proportional hazard regression analysis revealed a lower rate of osteoporosis for the metformin group (adjusted hazard ratio of 0.820; 95% confidence interval = 0.691–0.972, p = 0.022). Diabetic patients with CIS under metformin therapy presented lower osteoporosis rate than those who were not receiving metformin therapy.
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Pradhan R, Yin H, Yu OHY, Azoulay L. The Use of Long-Acting Insulin Analogs and the Risk of Colorectal Cancer Among Patients with Type 2 Diabetes: A Population-Based Cohort Study. Drug Saf 2019; 43:103-110. [DOI: 10.1007/s40264-019-00892-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Lu CH, Chung CH, Lee CH, Su SC, Liu JS, Lin FH, Tsao CH, Hsieh PS, Hung YJ, Hsieh CH, Chien WC. Combination of COX-2 inhibitor and metformin attenuates rate of admission in patients with rheumatoid arthritis and diabetes in Taiwan. Medicine (Baltimore) 2019; 98:e17371. [PMID: 31593087 PMCID: PMC6799465 DOI: 10.1097/md.0000000000017371] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease associated with increased prevalence of type 2 diabetes mellitus (T2DM). Here, we investigated the effect of the combination of cyclooxygenase (COX)-2 inhibitors and metformin on the rate of admission in patients with RA and T2DM and compared it with that of only COX-2 inhibitors.In total, 1268 subjects with RA and T2DM under COX-2 inhibitor and metformin therapy were selected from the National Health Insurance Research Database of Taiwan, along with 2536 patients as 1:2 sex-, age-, and index year-matched controls without metformin therapy. Cox proportional hazard analysis was used to compare the rate of admission during the 10 years of follow-up.At the end of the follow-up, 72 enrolled subjects (1.89%) had admission, including 9 from the combination group (0.71%) and 63 from the COX-2 inhibitor group (2.48%). The combination group was associated with a lower rate of admission at the end of follow-up (P < .001). Cox proportional hazard regression analysis revealed the lower rate of admission for subjects under combination therapy (adjusted hazard ratio of 0.275; 95% confidence interval = 0.136-0.557, P < .001).Patients with RA and T2DM receiving the combination of COX-2 inhibitors and metformin were associated with lower admission rate than those on COX-2 inhibitors alone, and this effect may be attributed to the decrease in the levels of proinflammatory factors.
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Affiliation(s)
- Chieh-Hua Lu
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine
- Department of Medical Research, Tri-Service General Hospital
| | - Chi-Hsiang Chung
- School of Public Health, National Defense Medical Center
- Taiwanese Injury Prevention and Safety Promotion Association
| | - Chien-Hsing Lee
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine
| | - Sheng-Chiang Su
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine
| | - Jhih-Syuan Liu
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine
| | - Fu-Huang Lin
- School of Public Health, National Defense Medical Center
| | - Chang-Huei Tsao
- Department of Medical Research, Tri-Service General Hospital
- Department of Microbiology & Immunology
| | - Po-Shiuan Hsieh
- Department of Medical Research, Tri-Service General Hospital
- Department of Physiology and Biophysics
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Yi-Jen Hung
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine
| | - Chang-Hsun Hsieh
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine
| | - Wu-Chien Chien
- Department of Medical Research, Tri-Service General Hospital
- School of Public Health, National Defense Medical Center
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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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8
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Lu CH, Chung CH, Lee CH, Hsieh CH, Hung YJ, Lin FH, Tsao CH, Hsieh PS, Chien WC. Combination COX-2 inhibitor and metformin attenuate rate of joint replacement in osteoarthritis with diabetes: A nationwide, retrospective, matched-cohort study in Taiwan. PLoS One 2018; 13:e0191242. [PMID: 29385156 PMCID: PMC5791980 DOI: 10.1371/journal.pone.0191242] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Accepted: 12/20/2017] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Osteoarthritis (OA) is the most common form of arthritis associated with an increased prevalence of type 2 diabetes mellitus (T2DM), however their impact on decreasing joint replacement surgery has yet to be elucidated. This study aimed to investigate if the combination of COX-2 inhibitor and metformin therapy in OA with T2DM were associated with lower the rate of joint replacement surgery than COX-2 inhibitor alone. METHODS In total, 968 subjects with OA and T2DM under COX-2 inhibitor and metformin therapy (case group) between 1 January to 31 December 2000 were selected from the National Health Insurance Research Database of Taiwan, along with 1936 patients were the 1:2 gender-, age-, and index year-controls matched without metformin therapy (control group) in this study. Cox proportional hazards analysis was used to compare the rate of receiving joint replacement surgery during 10 years of follow-up. RESULTS At the end of follow-up, 438 of all enrolled subjects (15.08%) had received the joint replacement surgery, including 124 in the case group (12.81%) and 314 in the control group (16.22%). The case group tended to be associated with lower rate of receiving the joint replacement surgery at the end of follow-up than the control group (p = 0.003). Cox proportional hazards regression (HR) analysis revealed that study subjects under combination therapy with metformin had lower rate of joint replacement surgery (adjusted HR 0.742 (95% CI = 0.601-0.915, p = 0.005)). In the subgroups, study subjects in the combination metformin therapy who were female, good adherence (>80%), lived in the highest urbanization levels of residence, treatment in the hospital center and lower monthly insurance premiums were associated with a lower risk of joint replacement surgery than those without. CONCLUSIONS Patients who have OA and T2DM receiving combination COX-2 inhibitors and metformin therapy associated with lower joint replacement surgery rates than those without and this may be attributable to combination therapy much more decrease pro-inflammatory factors associated than those without metformin therapy.
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Affiliation(s)
- Chieh-Hua Lu
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC.,Department of Medical Research, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chi-Hsiang Chung
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, ROC.,Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan, ROC
| | - Chien-Hsing Lee
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chang-Hsun Hsieh
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Yi-Jen Hung
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Fu-Huang Lin
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chang-Huei Tsao
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.,Department of Microbiology & Immunology, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Po-Shiuan Hsieh
- Department of Medical Research, National Defense Medical Center, Taipei, Taiwan, ROC.,Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan, ROC.,Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Wu-Chien Chien
- Department of Medical Research, National Defense Medical Center, Taipei, Taiwan, ROC.,School of Public Health, National Defense Medical Center, Taipei, Taiwan, ROC
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Association between insulin therapy and risk of liver cancer among diabetics: a meta-analysis of epidemiological studies. Eur J Gastroenterol Hepatol 2018; 30:1-8. [PMID: 29064852 DOI: 10.1097/meg.0000000000001001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
As the results of the association between insulin therapy and risk of liver cancer among diabetics have been inconsistent in epidemiological studies, we conducted a meta-analysis to quantify this issue. Data of relevant epidemiological studies were collected by searching articles in PubMed, Web of Science, and Embase till 29 June 2017. Random-effects models were employed to combine study-specific risks. Five cohort studies and nine case-control studies were included in our meta-analysis with 285 008 patients with diabetes mellitus and 4329 liver cancer cases. When we compared insulin-use group with noninsulin use group in patients with diabetes mellitus, we observed a statistically significant association between insulin therapy and liver cancer, with an overall relative risk of 1.90 (95% confidence interval: 1.44-2.50, I=76.1%). We did not find heterogeneity between subgroups stratified by study characteristics and adjusted confounders, except for subgroups related to 'follow-up years' of cohort studies. The combined estimate was robust across sensitivity analysis, and no publication bias was detected. Our results indicated that insulin therapy was associated with elevated incidence of liver cancer among diabetics. Given the high prevalence of diabetes, avoiding excess or unnecessary insulin use to control the blood glucose may offer a potential public health benefit in reducing liver cancer risk. Further studies are warranted to investigate the types, doses, and treatment duration of insulin use in large sample size or cohort of diabetic patients.
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Wu JW, Azoulay L, Majdan A, Boivin JF, Pollak M, Suissa S. Long-Term Use of Long-Acting Insulin Analogs and Breast Cancer Incidence in Women With Type 2 Diabetes. J Clin Oncol 2017; 35:3647-3653. [DOI: 10.1200/jco.2017.73.4491] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Purpose The association between long-acting insulin analogs and increased breast cancer risk is uncertain, particularly with the short follow-up in previous studies. We assessed this risk long term in women with type 2 diabetes. Methods A population-based cohort of women 40 years or older, all of whom were treated with long-acting (glargine, detemir) or neutral protamine Hagedorn (NPH) insulin between 2002 and 2012, was formed using the United Kingdom’s Clinical Practice Research Datalink. Women were followed until February 2015 or breast cancer diagnosis. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% CIs of incident breast cancer, comparing long-acting insulin analogs with NPH overall, as well as by duration and cumulative dose. Results The cohort included 22,395 women who received insulin treatment, with 321 incident breast cancer events occurring during up to 12 years of follow-up (incidence rate 3.3 per 1,000 person-years). Compared with NPH insulin, insulin glargine was associated with an increased risk of breast cancer (HR, 1.44; 95% CI, 1.11 to 1.85), mainly increasing 5 years after glargine initiation (HR, 2.23; 95% CI, 1.32 to 3.77) and after > 30 prescriptions (HR, 2.29; 95% CI, 1.26 to 4.16). The risk was particularly elevated among prior insulin users (HR, 1.53; 95% CI, 1.10 to 2.12) but not for new users, which included fewer patients and for which one cannot rule out an HR of 1.81. The risk associated with insulin detemir was not significantly elevated (HR, 1.17; 95% CI, 0.77 to 1.77). Conclusion Long-term use of insulin glargine is associated with an increased risk of breast cancer in women with type 2 diabetes. The risk associated with insulin detemir remains uncertain because there are fewer users of this insulin.
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Affiliation(s)
- Jennifer W. Wu
- Jennifer W. Wu, Laurent Azoulay, Jean-François Boivin, and Samy Suissa, McGill University; Jewish General Hospital; Michael Pollak, McGill University; and Agnieszka Majdan, Jewish General Hospital, Montreal, Quebec, Canada
| | - Laurent Azoulay
- Jennifer W. Wu, Laurent Azoulay, Jean-François Boivin, and Samy Suissa, McGill University; Jewish General Hospital; Michael Pollak, McGill University; and Agnieszka Majdan, Jewish General Hospital, Montreal, Quebec, Canada
| | - Agnieszka Majdan
- Jennifer W. Wu, Laurent Azoulay, Jean-François Boivin, and Samy Suissa, McGill University; Jewish General Hospital; Michael Pollak, McGill University; and Agnieszka Majdan, Jewish General Hospital, Montreal, Quebec, Canada
| | - Jean-François Boivin
- Jennifer W. Wu, Laurent Azoulay, Jean-François Boivin, and Samy Suissa, McGill University; Jewish General Hospital; Michael Pollak, McGill University; and Agnieszka Majdan, Jewish General Hospital, Montreal, Quebec, Canada
| | - Michael Pollak
- Jennifer W. Wu, Laurent Azoulay, Jean-François Boivin, and Samy Suissa, McGill University; Jewish General Hospital; Michael Pollak, McGill University; and Agnieszka Majdan, Jewish General Hospital, Montreal, Quebec, Canada
| | - Samy Suissa
- Jennifer W. Wu, Laurent Azoulay, Jean-François Boivin, and Samy Suissa, McGill University; Jewish General Hospital; Michael Pollak, McGill University; and Agnieszka Majdan, Jewish General Hospital, Montreal, Quebec, Canada
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Vora J, Ray K, Kosiborod M, Poulter NR, Rajagopalan S, Leiter LA. Cancer risks of anti-hyperglycemic drugs for type 2 diabetes treatment - a clinical appraisal. J Diabetes Complications 2017; 31:1451-1457. [PMID: 28655490 DOI: 10.1016/j.jdiacomp.2017.06.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 06/07/2017] [Accepted: 06/07/2017] [Indexed: 12/18/2022]
Abstract
AIM A clinical appraisal of existing scientific literature sought to assess the need for long-term prospective epidemiological studies to investigate an increased cancer risk of anti-hyperglycemic medication in type 2 diabetes. METHOD A focus statement was formulated as: "With a higher risk of cancers in patients with type 2 diabetes, all anti-hyperglycemic drugs should undergo long-term, prospective epidemiological studies for cancer risks." Field surveys were sent to practicing physicians and endocrinologists to identify the currently prevalent level of acceptance of this statement. Subsequently, a meeting with a six-member panel of key opinion leaders was held to discuss published evidence in support and against the statement. This publication reviews the publications and discussion points brought forth in this meeting and their effect on statement acceptance by the panel. RESULTS Whereas the majority of field survey responders primarily agreed with the statement, panel members were divided in their statement support. This division remained intact after review of the literature. CONCLUSIONS While there was evidence that type 2 diabetes is associated with an increased risk of cancer, existing studies seemed insufficient to definitively demonstrate a link between cancer risk and use of specific anti-hyperglycemic therapies.
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Affiliation(s)
- Jiten Vora
- Department of Diabetes and Endocrinology, Royal Liverpool University Hospitals, Prescot Street, Liverpool, L7 8XP, UK.
| | - Kausik Ray
- Department of Primary Care and Public Health, School of Public Health, Imperial College London, St. Dunstan's Road, London, W6 8RP, UK.
| | - Mikhail Kosiborod
- Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City, 4401 Wornall Road, Kansas City, MO 64111, USA.
| | - Neil R Poulter
- International Centre for Circulatory Health, Imperial College London, London, W2 1PG, UK.
| | - Sanjay Rajagopalan
- University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD 21201, USA.
| | - Lawrence A Leiter
- Division of Endocrinology & Metabolism, Li Ka Shing Knowledge Institute and Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, 61 Queen St. East #6121, Toronto, ON, M5C 2T2, Canada.
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Chiang JK, Lin CW, Wang CL, Koo M, Kao YH. Cancer studies based on secondary data analysis of the Taiwan's National Health Insurance Research Database: A computational text analysis and visualization study. Medicine (Baltimore) 2017; 96:e6704. [PMID: 28445277 PMCID: PMC5413242 DOI: 10.1097/md.0000000000006704] [Citation(s) in RCA: 5] [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: 12/31/2022] Open
Abstract
There has been a surge in the academic publication output based on secondary analyses of the data from the Taiwan's National Health Insurance claim records. It has become a challenge to comprehend such a rapid expansion of the literature. Therefore, this study aimed to explore the conceptual content of National Health Insurance Research Database-based cancer research, using the abstract of articles extracted from PubMed between 2002 and 2015. Search terms including "National Health Insurance Research Database (NHIRD) AND Taiwan," "Taiwan AND population-based," and "Taiwan AND nationwide" were used to search in PubMed with the publication date limited to between 1997 and 2015. The retrieved articles were manually screened to retain only those that were cancer-related and were based on secondary data analysis of the NHIRD. A total 589 articles were selected for subsequent text mining using the R software. Among the 589 articles, the top 5 most studied cancer types were breast (16.3%), lung (11.4%), colorectal (10.4%), liver (8.3%), and prostate (7.5%). The articles that received the highest number of citations by PubMed Central articles were cited 92 times. The top 3 most frequently occurred keywords in the abstracts of the 589 articles were cancer, patient, and risk, with 3670, 2535, and 1652 times, respectively. Analysis of key conception indicated that the most common conceptions were diabetes, survival, breast cancer, lung cancer, and colorectal cancer. In conclusion, in this study of 589 published articles on secondary data analysis of the NHIRD, indexed by PubMed between 2002 and 2015, we found that while the risk factors of cancer, treatment of cancer, and survival of cancer patients were popular research topics, end-of-life cancer care issues were less studied. Further studies should explore these areas since they are as important as treatment of the disease itself for many patients.
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Affiliation(s)
- Jui-Kun Chiang
- Division of Family Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation
| | - Chih-Wen Lin
- Division of Medical Imaging, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Dalin, Chiayi
- School of Medicine, Tzu Chi University, Hualien
| | - Chun-Lung Wang
- Division of Pediatrics, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation
| | - Malcolm Koo
- Department of Medical Research, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Dalin, Chiayi, Taiwan
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Yee-Hsin Kao
- Division of Family Medicine, Tainan Municipal Hospital, Tainan City, Taiwan
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Camara SN, Yin T, Yang M, Li X, Gong Q, Zhou J, Zhao G, Yang ZY, Aroun T, Kuete M, Ramdany S, Camara AK, Diallo AT, Feng Z, Ning X, Xiong JX, Tao J, Qin Q, Zhou W, Cui J, Huang M, Guo Y, Gou SM, Wang B, Liu T, Olivier OET, Conde T, Cisse M, Magassouba AS, Ballah S, Keita NLM, Souare IS, Toure A, Traore S, Balde AK, Keita N, Camara ND, Emmanuel D, Wu HS, Wang CY. High risk factors of pancreatic carcinoma. JOURNAL OF HUAZHONG UNIVERSITY OF SCIENCE AND TECHNOLOGY. MEDICAL SCIENCES = HUA ZHONG KE JI DA XUE XUE BAO. YI XUE YING DE WEN BAN = HUAZHONG KEJI DAXUE XUEBAO. YIXUE YINGDEWEN BAN 2016; 36:295-304. [PMID: 27376795 DOI: 10.1007/s11596-016-1583-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2016] [Revised: 05/15/2016] [Indexed: 12/20/2022]
Abstract
Over the past decades, cancer has become one of the toughest challenges for health professionals. The epidemiologists are increasingly directing their research efforts on various malignant tumor worldwide. Of note, incidence of cancers is on the rise more quickly in developed countries. Indeed, great endeavors have to be made in the control of the life-threatening disease. As we know it, pancreatic cancer (PC) is a malignant disease with the worst prognosis. While little is known about the etiology of the PC and measures to prevent the condition, so far, a number of risk factors have been identified. Genetic factors, pre-malignant lesions, predisposing diseases and exogenous factors have been found to be linked to PC. Genetic susceptibility was observed in 10% of PC cases, including inherited PC syndromes and familial PC. However, in the remaining 90%, their PC might be caused by genetic factors in combination with environmental factors. Nonetheless, the exact mechanism of the two kinds of factors, endogenous and exogenous, working together to cause PC remains poorly understood. The fact that most pancreatic neoplasms are diagnosed at an incurable stage of the disease highlights the need to identify risk factors and to understand their contribution to carcinogenesis. This article reviews the high risk factors contributing to the development of PC, to provide information for clinicians and epidemiologists.
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Affiliation(s)
- Soriba Naby Camara
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Tao Yin
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Ming Yang
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiang Li
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qiong Gong
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jing Zhou
- Department of Breast and Thyroid Surgery, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Gang Zhao
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhi-Yong Yang
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Tajoo Aroun
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Martin Kuete
- Department of Planning Family and Reproductive Institute, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Sonam Ramdany
- Department of General Medicine, Sir Seewoosagur Ramgoolam National Hospital of Pamplemousses, Mauritius, 21017, Mauritius
| | | | - Aissatou Taran Diallo
- Department of General Surgery, National Hospital of Ignace Deen, Conakry, 1147, Guinea
| | - Zhen Feng
- Department of Gastroenterology and Hepatology, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xin Ning
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jiong-Xin Xiong
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jing Tao
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qi Qin
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Wei Zhou
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jing Cui
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Min Huang
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yao Guo
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shan-Miao Gou
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Bo Wang
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Tao Liu
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Ohoya Etsaka Terence Olivier
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Tenin Conde
- Department of Thoracic Surgery, National Hospital of Donka, Conakry, Guinea
| | - Mohamed Cisse
- Department of Dermatology, National Hospital of Donka, Conakry, Guinea
| | | | - Sneha Ballah
- Department of Internal Medicine, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Naby Laye Moussa Keita
- Department of Biochemistry, University Gamal Abdel Nasser of Conakry, Conakry, 1147, Guinea
| | - Ibrahima Sory Souare
- Department of Neurosurgery, Friendship Hospital Sino-Guinea of Kipe, Conakry, Guinea
| | - Aboubacar Toure
- Department of General Surgery, National Hospital of Ignace Deen, Conakry, 1147, Guinea
| | - Sadamoudou Traore
- Department of Medical Imaging, Good Shepherd Medical Center, The University of Texas, Longview, 75601, USA
| | | | - Namory Keita
- Department of Gynecology and Obstetrics, National Hospital of Donka, Conakry, Guinea
| | - Naby Daouda Camara
- Department of General Surgery, National Hospital of Ignace Deen, Conakry, 1147, Guinea
| | - Dusabe Emmanuel
- Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - He-Shui Wu
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chun-You Wang
- Department of General Surgery, Pancreatic Disease Institute, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Wu JW, Filion KB, Azoulay L, Doll MK, Suissa S. Effect of Long-Acting Insulin Analogs on the Risk of Cancer: A Systematic Review of Observational Studies. Diabetes Care 2016; 39:486-94. [PMID: 26740633 DOI: 10.2337/dc15-1816] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 11/10/2015] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Observational studies examining the association between long-acting insulin analogs and cancer incidence have produced inconsistent results. We conducted a systematic review of these studies, focusing on their methodological strengths and weaknesses. RESEARCH DESIGN AND METHODS We systematically searched MEDLINE and EMBASE from 2000 to 2014 to identify all observational studies evaluating the relationship between the long-acting insulin analogs and the risk of any and site-specific cancers (breast, colorectal, prostate). We included cohort and case-control studies published in English on insulin glargine and detemir and any cancer incidence among patients with type 1 or 2 diabetes. The methodological assessment involved the inclusion of prevalent users, inclusion of lag periods, time-related biases, and duration of follow-up between insulin initiation and cancer incidence. RESULTS A total of 16 cohort and 3 case-control studies met our inclusion criteria. All studies evaluated insulin glargine, and four studies also examined insulin detemir. Follow-up ranged from 0.9 to 7.0 years. Thirteen of 15 studies reported no association between insulin glargine and detemir and any cancer. Four of 13 studies reported an increased risk of breast cancer with insulin glargine. In the quality assessment, 7 studies included prevalent users, 11 did not consider a lag period, 6 had time-related biases, and 16 had short (<5 years) follow-up. CONCLUSIONS The observational studies examining the risk of cancer associated with long-acting insulin analogs have important methodological shortcomings that limit the conclusions that can be drawn. Thus, uncertainty remains, particularly for breast cancer risk.
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Affiliation(s)
- Jennifer W Wu
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
| | - Kristian B Filion
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada Division of Clinical Epidemiology, Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Laurent Azoulay
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada Department of Oncology, McGill University, Montreal, Quebec, Canada
| | - Margaret K Doll
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
| | - Samy Suissa
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada Division of Clinical Epidemiology, Department of Medicine, McGill University, Montreal, Quebec, Canada
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Deng D, Yang Y, Tang X, Skrip L, Qiu J, Wang Y, Zhang F. Association between metformin therapy and incidence, recurrence and mortality of prostate cancer: evidence from a meta-analysis. Diabetes Metab Res Rev 2015; 31:595-602. [PMID: 25708557 DOI: 10.1002/dmrr.2645] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Revised: 11/26/2014] [Accepted: 12/21/2014] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Previous studies suggested that metformin is associated with decreased risk of cancer; however, results specifically addressing the potential association with prostate cancer were limited and contradictory. This study considers the association between metformin and the incidence, mortality and recurrence of prostate cancer by performing a meta-analysis of observational studies. METHODS Literatures published before January 2014 were searched by using databases of PubMed and Embase. Pooled relative risks (RRs) were determined using a random effects model to evaluate the strength of association between metformin therapy and risk of prostate cancer. RESULTS Thirteen studies involving a total of 334 532 participants were included in this meta-analysis. Compared with the control group, metformin therapy was associated with significantly decreased incidence of prostate cancer [RR = 0.88, 95% confidence interval (CI) [0.78, 0.99], p = 0.03, I(2) = 74.7%]. However, metformin therapy was not associated with decreased all-cause mortality (RR = 1.07, 95% CI [0.86, 1.32], p = 0.55, I(2) = 58.2%) or decreased recurrence of prostate cancer (RR = 0.90, 95% CI [0.75, 1.09], p = 0.27, I(2) = 0.0%). No publication bias was detected (pBegg = 0.55, pEgger = 0.46). CONCLUSIONS The present study suggested that metformin therapy may decrease the incidence of prostate cancer but that there was no association between the treatment and all-cause mortality or recurrence. It is recommended that this finding should be considered carefully and confirmed with further studies.
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Affiliation(s)
- Dan Deng
- School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Yuan Yang
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaojun Tang
- School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Laura Skrip
- Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA
| | - Jingfu Qiu
- School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Yang Wang
- School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Fan Zhang
- School of Public Health and Management, Chongqing Medical University, Chongqing, China
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Bronsveld HK, ter Braak B, Karlstad Ø, Vestergaard P, Starup-Linde J, Bazelier MT, De Bruin ML, de Boer A, Siezen CLE, van de Water B, van der Laan JW, Schmidt MK. Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence. Breast Cancer Res 2015; 17:100. [PMID: 26242987 PMCID: PMC4531810 DOI: 10.1186/s13058-015-0611-2] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 07/07/2015] [Indexed: 12/29/2022] Open
Abstract
INTRODUCTION Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD A systematic literature search was performed on breast cell-line, animal and human studies using the key words 'insulin analogue' and 'breast neoplasia' in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due to a limited number of reported estimates, a meta-analysis was performed for glargine only. A comprehensive overview was composed for in vitro and animal studies. Protein and gene expression was analysed for the cell lines most frequently used in the included in vitro studies. RESULTS In total 16 in vitro, 5 animal, 2 in vivo human and 29 epidemiological papers were included. Insulin AspB10 showed mitogenic properties in vitro and in animal studies. Glargine was the only clinically available insulin analogue for which an increased proliferative potential was found in breast cancer cell lines. However, the pooled analysis of 13 epidemiological studies did not show evidence for an association between insulin glargine treatment and an increased breast cancer risk (HR 1.04; 95 % CI 0.91-1.17; p=0.49) versus no glargine in patients with diabetes mellitus. It has to be taken into account that the number of animal studies was limited, and epidemiological studies were underpowered and suffered from methodological limitations. CONCLUSION There is no compelling evidence that any clinically available insulin analogue (Aspart, Determir, Glargine, Glulisine or Lispro), nor human insulin increases breast cancer risk. Overall, the data suggests that insulin treatment is not involved in breast tumour initiation, but might induce breast tumour progression by up regulating mitogenic signalling pathways.
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Affiliation(s)
- Heleen K Bronsveld
- Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
- Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.
| | - Bas ter Braak
- Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
| | - Øystein Karlstad
- Department of Pharmacoepidemiology, Norwegian Institute of Public Health, Oslo, Norway.
| | - Peter Vestergaard
- Departments of Clinical Medicine and Endocrinology, Aalborg University, Aalborg, Denmark.
| | - Jakob Starup-Linde
- Departments of Clinical Medicine and Endocrinology, Aalborg University, Aalborg, Denmark.
- Department of Endocrinology and Internal Medicine (MEA), Aarhus University Hospital THG, Aarhus, Denmark.
| | - Marloes T Bazelier
- Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.
| | - Marie L De Bruin
- Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.
| | - Anthonius de Boer
- Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.
| | | | - Bob van de Water
- Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
| | - Jan Willem van der Laan
- Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
- Medicines Evaluation Board (MEB), Utrecht, The Netherlands.
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
| | - Marjanka K Schmidt
- Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
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Tokajuk A, Krzyżanowska-Grycel E, Tokajuk A, Grycel S, Sadowska A, Car H. Antidiabetic drugs and risk of cancer. Pharmacol Rep 2015; 67:1240-50. [PMID: 26481548 DOI: 10.1016/j.pharep.2015.05.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2014] [Revised: 05/11/2015] [Accepted: 05/14/2015] [Indexed: 12/18/2022]
Abstract
Antidiabetic drugs are an important group of medications used worldwide. They differ from each other in the mechanisms of lowering blood glucose as well as in adverse effects that may affect the course of the treatment and its efficacy. In recent years, new drugs have been discovered in order to improve the maintenance of proper blood glucose level and to reduce unwanted effects of these drugs. Their growing administration is related to the increasing incidence of diabetes observed in all countries in the world. Epidemiological data indicate that diabetes increases the risk of cancer, as well as the risk of death linked with neoplasms. It is still unknown whether this is an effect of antidiabetic drugs or just the effect of diabetes itself. In recent years there have been numerous investigations and meta-analyzes, based on both comparative and cohort studies trying to establish the relationship between antidiabetic pharmacotherapy and the incidence and mortality due to cancer. According to their findings, most of antidiabetic drugs increase the risk of cancer while only few of them show antitumor properties. Different mechanisms of action of glucose-lowering drugs may be responsible for these effects. However, most of the published studies concerning the influence of these drugs on cancer incidence were designed with some limitations and differed from each other in the approach. In this review, we discuss the association between antidiabetic drugs used in monotherapy or polytherapy and cancer risk, and consider potential mechanisms responsible for the observed effects.
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Affiliation(s)
- Anna Tokajuk
- Department of Experimental Pharmacology, Medical University of Białystok, Białystok, Poland.
| | | | - Adrian Tokajuk
- Department of Experimental Pharmacology, Medical University of Białystok, Białystok, Poland
| | - Sławomir Grycel
- Department of Diabetology, Endocrinology and Internal Medicine, J. Sniadecki Hospital, Białystok, Poland
| | - Anna Sadowska
- Department of Experimental Pharmacology, Medical University of Białystok, Białystok, Poland
| | - Halina Car
- Department of Experimental Pharmacology, Medical University of Białystok, Białystok, Poland
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Associations between diabetes medication use and risk of second breast cancer events and mortality. Cancer Causes Control 2015; 26:1065-77. [PMID: 25956271 DOI: 10.1007/s10552-015-0599-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 05/03/2015] [Indexed: 12/18/2022]
Abstract
PURPOSE Diabetes and certain diabetes medications have been shown to influence breast cancer (BC) risk. Less is known about their relation to BC outcomes. Our objective was to evaluate the effects of diabetes and diabetes medications on risk of second breast cancer events (SBCE) and mortality. METHODS This population-based cohort study was conducted among women diagnosed with early-stage (I-II) BC and enrolled in an integrated health plan. Exposures of interest were diabetes and medication classes including insulin, metformin, and sulfonylureas. Outcomes of interest were SBCE defined as recurrence or second primary BC, BC-specific mortality, and all-cause mortality. We used multivariable Cox proportional hazards models to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for diabetes and medication use while accounting for potential confounders and competing risks. RESULTS Among 4,216 women, 13 % developed SBCE during a median follow-up of 6.3 years. 610 women had diabetes of which 76 % used oral diabetes medication and/or insulin. Findings suggested that diabetes increased the risk of recurrence (HR = 1.57; 95 % CI 1.09-2.25) but not overall SBCE (HR = 1.29; 95 % CI 0.94-1.76) or second primary BC (HR = 0.74; 95 % CI 0.39-1.41). Among women with diabetes, insulin use was associated with increased risks of recurrence (HR = 1.94; 95 % CI 1.08-3.48) and all-cause mortality (HR = 2.33; 95 % CI 1.70-3.20). Metformin use was associated with lower all-cause mortality (HR = 0.55; 95 % CI 0.38-0.79). CONCLUSIONS Our findings show an association between diabetes and increased recurrence risk, and risk may be greater among insulin users. Metformin may reduce all-cause mortality among BC survivors. Given the growing breast cancer survivor population, further research in larger, more diverse populations is warranted.
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Electronic medical record cancer incidence over six years comparing new users of glargine with new users of NPH insulin. PLoS One 2014; 9:e109433. [PMID: 25329887 PMCID: PMC4203726 DOI: 10.1371/journal.pone.0109433] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2013] [Accepted: 09/06/2014] [Indexed: 12/13/2022] Open
Abstract
Background Recent studies suggested that insulin glargine use could be associated with increased risk of cancer. We compared the incidence of cancer in new users of glargine versus new users of NPH in a longitudinal clinical cohort with diabetes for up to 6 years. Methods and Findings From all patients who had been regularly followed at Massachusetts General Hospital from 1/01/2005 to 12/31/2010, 3,680 patients who had a medication record for glargine or NPH usage were obtained from the electronic medical record (EMR). From those we selected 539 new glargine users (age: 60.1±13.6 years, BMI: 32.7±7.5 kg/m2) and 343 new NPH users (61.5±14.1 years, 32.7±8.3 kg/m2) who had no prevalent cancer during 19 months prior to glargine or NPH initiation. All incident cancer cases were ascertained from the EMR requiring at least 2 ICD-9 codes within a 2 month period. Insulin exposure time and cumulative dose were validated. The statistical analysis compared the rates of cancer in new glargine vs. new NPH users while on treatment, adjusted for the propensity to receive one or the other insulin. There were 26 and 28 new cancer cases in new glargine and new NPH users for 1559 and 1126 person-years follow-up, respectively. There were no differences in the propensity-adjusted clinical characteristics between groups. The adjusted hazard ratio for the cancer incidence comparing glargine vs. NPH use was 0.65 (95% CI: 0.36–1.19). Conclusions Insulin glargine is not associated with development of cancers when compared with NPH in this longitudinal and carefully retrieved EMR data.
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Long-acting Insulin Analogues and Diabetic Retinopathy: A Retrospective Cohort Study. Clin Ther 2014; 36:1255-68. [DOI: 10.1016/j.clinthera.2014.06.031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 06/03/2014] [Accepted: 06/27/2014] [Indexed: 12/29/2022]
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Karlstad O, Starup-Linde J, Vestergaard P, Hjellvik V, Bazelier MT, Schmidt MK, Andersen M, Auvinen A, Haukka J, Furu K, de Vries F, De Bruin ML. Use of insulin and insulin analogs and risk of cancer - systematic review and meta-analysis of observational studies. Curr Drug Saf 2014; 8:333-48. [PMID: 24215311 PMCID: PMC3899599 DOI: 10.2174/15680266113136660067] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Revised: 10/29/2013] [Accepted: 10/31/2013] [Indexed: 12/12/2022]
Abstract
Background: An association of insulin use and risk of cancer has been reported but evidence is conflicting and methodological issues have been identified. Objective: To summarize results regarding insulin use and cancer risk by a systematic review and meta-analysis of cohort and case-control studies examining risk of cancer associated with insulin use in patients with diabetes. Data Sources: Systematic literature search in 5 databases: PubMed, Embase, Web of Science, Scopus and Cochrane Library. Study Eligibility Criteria (PICOS): Population: diabetes patients. Exposure: Users of any exogenous insulin. Comparison: Diabetes patients with or without use of antidiabetic drugs. Outcome: Any incident cancer. Study Design: Cohort and case-control studies. Results: 42 eligible studies examined risk of any cancer and 27 site-specific cancers. Results of individual studies were heterogeneous. Meta-analyses were significant for: Insulin vs No Insulin: Increased risk for pancreas, liver, kidney, stomach and respiratory cancer, decreased risk for prostate cancer. Insulin vs Non-Insulin Antidiabetics: Increased risk for any, pancreatic and colorectal cancer. Glargine vs Non-Glargine Insulin: Increased risk for breast cancer, decreased risk for colon cancer. Limitations: Few studies available for most cancer sites and exposure contrasts, and few assess effect of dose and duration of exposure. Methodological issues in several studies. Availability of confounders. Conclusions: Insulin use was associated with risk of cancer at several sites. Cautious interpretation of results is warranted as methodological issues and limitations in several of the included studies have been identified. Choice of study design may have a profound effect on estimated cancer risk.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Marie L De Bruin
- Norwegian Institute of Public Health, P.O.Box 4404 Nydalen, N-0403 Oslo, Norway.
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Balasubramanyam M. Diabetic oncopathy--one more yet another deadly diabetic complication! Indian J Med Res 2014; 140:15-8. [PMID: 25222773 PMCID: PMC4181152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Affiliation(s)
- M. Balasubramanyam
- Madras Diabetes Research Foundation (MDRF) No. 4 Conran Smith Road, Gopalapuram Chennai 600 086, India ;
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Franconi F, Campesi I. Sex and gender influences on pharmacological response: an overview. Expert Rev Clin Pharmacol 2014; 7:469-85. [DOI: 10.1586/17512433.2014.922866] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Cammarota S, Bruzzese D, Catapano AL, Citarella A, De Luca L, Manzoli L, Masulli M, Menditto E, Mezzetti A, Riegler S, Putignano D, Tragni E, Novellino E, Riccardi G. Lower incidence of macrovascular complications in patients on insulin glargine versus those on basal human insulins: a population-based cohort study in Italy. Nutr Metab Cardiovasc Dis 2014; 24:10-17. [PMID: 23806740 DOI: 10.1016/j.numecd.2013.04.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2012] [Revised: 02/25/2013] [Accepted: 04/05/2013] [Indexed: 10/26/2022]
Abstract
BACKGROUND AND AIM The aim of this study was to compare the use of insulin glargine and intermediate/long-acting human insulin (HI) in relation to the incidence of complications in diabetic patients. METHODS AND RESULTS A population-based cohort study was conducted using administrative data from four local health authorities in the Abruzzo Region (900,000 inhabitants). Diabetic patients without macrovascular diseases and treated with either intermediate/long-acting HI or glargine were followed for 3-years; the incidence of diabetic (macrovascular, microvascular and metabolic) complications was ascertained by hospital discharge claims and estimated using Cox proportional hazard models. Propensity score (PS) matching was also used to adjust for significant differences in the baseline characteristics between the two groups. RESULTS Overall, 1921 diabetic patients were included: 744 intermediate/long-acting HI and 1177 glargine users. During the 3-year follow-up, 209 (28.1%) incident events of any diabetic complication occurred in the intermediate/long-acting HI and 159 (13.5%) in the glargine group. After adjustment for covariates, glargine users had an HR (95% CI) of 0.57 (0.44-0.74) for any diabetic complication and HRs of 0.61 (0.44-0.84), 0.58 (0.33-1.04) and 0.35 (0.18-0.70) for macrovascular, microvascular and metabolic complications, respectively, compared to intermediate/long-acting HI users. PS analyses supported these findings. CONCLUSIONS The use of glargine is associated with a lower risk of macrovascular complications compared with traditional basal insulins. However, limitations inherent to the study design including the short length of observation and the lack of data on metabolic control or diabetes duration, do not allow us to consider this association as a proof of causality.
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Affiliation(s)
- S Cammarota
- CIRFF, "Federico II" University of Naples, Italy
| | - D Bruzzese
- Department of Preventive Medical Sciences, "Federico II" University of Naples, Italy
| | - A L Catapano
- SEFAP, Department of Pharmacological Sciences, University of Milan, Italy; Multimedica IRCCS, S.S. Giovanni, Italy
| | - A Citarella
- CIRFF, "Federico II" University of Naples, Italy
| | - L De Luca
- CIRFF, "Federico II" University of Naples, Italy
| | - L Manzoli
- Section of Hygiene, Epidemiology, Pharmacology and Legal Medicine, University of Chieti, and Regional Health Care Agency of Abruzzo, Italy
| | - M Masulli
- Department of Clinical and Experimental Medicine, "Federico II" University of Naples, Italy
| | - E Menditto
- CIRFF, "Federico II" University of Naples, Italy
| | - A Mezzetti
- Clinical Research Centre, "G. D'Annunzio" University Foundation, Chieti, Italy
| | - S Riegler
- CIRFF, "Federico II" University of Naples, Italy
| | - D Putignano
- CIRFF, "Federico II" University of Naples, Italy
| | - E Tragni
- SEFAP, Department of Pharmacological Sciences, University of Milan, Italy
| | - E Novellino
- CIRFF, "Federico II" University of Naples, Italy
| | - G Riccardi
- Department of Clinical and Experimental Medicine, "Federico II" University of Naples, Italy.
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Habel LA, Danforth KN, Quesenberry CP, Capra A, Van Den Eeden SK, Weiss NS, Ferrara A. Cohort study of insulin glargine and risk of breast, prostate, and colorectal cancer among patients with diabetes. Diabetes Care 2013; 36:3953-60. [PMID: 24170756 PMCID: PMC3836110 DOI: 10.2337/dc13-0140] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To examine whether use of insulin glargine, compared with another long-acting insulin, is associated with risk of breast, prostate, colorectal cancer, or all cancers combined. RESEARCH DESIGN AND METHODS Computerized health records from Kaiser Permanente Northern and Southern California regions starting in 2001 and ending in 2009 were used to conduct a population-based cohort study among patients with diabetes aged ≥18 years. With use of Cox regression modeling, cancer risk in users of insulin glargine (n = 27,418) was compared with cancer risk in users of NPH (n = 100,757). RESULTS The cohort had a median follow-up of 3.3 years during which there was a median of 1.2 years of glargine use and 1.4 years of NPH use. Among users of NPH at baseline, there was no clear increase in risk of breast, prostate, colorectal, or all cancers combined associated with switching to glargine. Among those initiating insulin, ever use or ≥2 years of glargine was not associated with increased risk of prostate or colorectal cancer or all cancers combined. Among initiators, the hazard ratio (HR) for breast cancer associated with ever use of glargine was 1.3 (95% CI 1.0-1.8); the HR for breast cancer associated with use of glargine for ≥2 years was 1.6 or 1.7 depending on whether glargine users had also used NPH. CONCLUSIONS Results of this study should be viewed cautiously, given the relatively short duration of glargine use to date and the large number of potential associations examined.
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Chen YB, Chen Q, Wang Z, Zhou J. Insulin therapy and risk of prostate cancer: a systematic review and meta-analysis of observational studies. PLoS One 2013; 8:e81594. [PMID: 24282613 PMCID: PMC3839878 DOI: 10.1371/journal.pone.0081594] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2013] [Accepted: 10/15/2013] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Previous observational studies have shown that insulin therapy may modify the risk of prostate cancer (PCa). However, these studies yielded controversial results. Thus, we performed this meta-analysis to determine whether insulin use was associated with PCa risk in patients with diabetes mellitus (DM). METHOD A literature search was carried out in PubMed, EMBASE, and Cochrane Library Central database between January 1966 and January 2013. Fixed-effect and random-effect models were used to estimate pooled relative risks (RR) and corresponding 95% confidence intervals (CIs). Subgroup analyses and sensitivity analyses were also performed. RESULT A total of 11 (10 cohorts, and one case-control) studies published between 2007 and 2013 were included in the meta-analysis, representing data for 205,523 male subjects and 7,053 PCa cases. There were five studies investigating the influence of insulin and other glucose-lowering agents on the risk of PCa , and six studies investigating the influence of glargine and non-glargine insulin. Insulin use was not associated with PCa risk when compared with other glucose-lowering agents (RR=0.89, 95% CI, 0.72-1.09). Use of insulin glargine did not contribute to susceptibility to PCa as compared with use of non-glargine insulin (RR=1.26, 95% CI, 0.86-1.84). Sensitivity analysis confirmed the stability of present results, since no individual study affected the pooled result significantly. CONCLUSIONS Our results suggest that, there may be no significant association between insulin use and risk of PCa as compared with other glucose-lowering agents in patients with DM, and there was no substantial evidence for increase risk of PCa among insulin glargine users as compared to non-glargine insulin users. Further studies are warranted to validate these conclusions.
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Affiliation(s)
- Yan-bo Chen
- Department of Urology and Andrology, Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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Impact of glucose-lowering agents on the risk of cancer in type 2 diabetic patients. The Barcelona case-control study. PLoS One 2013; 8:e79968. [PMID: 24278227 PMCID: PMC3836986 DOI: 10.1371/journal.pone.0079968] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Accepted: 10/08/2013] [Indexed: 12/18/2022] Open
Abstract
Background The aim of the present study is to evaluate the impact of glucose-lowering agents in the risk of cancer in a large type 2 diabetic population. Methods A nested case-control study was conducted within a defined cohort (275,164 type 2 diabetic patients attending 16 Primary Health Care Centers of Barcelona). Cases (n = 1,040) comprised those subjects with any cancer diagnosed between 2008 and 2010, registered at the Cancer Registry of Hospital Vall d'Hebron (Barcelona). Three control subjects for each case (n = 3,120) were matched by age, sex, diabetes duration, and geographical area. The treatments analyzed (within 3 years prior to cancer diagnosis) were: insulin glargine, insulin detemir, human insulin, fast-acting insulin and analogues, metformin, sulfonylureas, repaglinide, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and alpha glucosidase inhibitors. Conditional logistic regressions were used to calculate the risk of cancer associated with the use of each drug adjusted by age, BMI, dose and duration of treatment, alcohol use, smoking habit, and diabetes duration. Results No differences were observed between case and control subjects for the proportion, dose or duration of exposure to each treatment. None of the types of insulin and oral agents analyzed showed a significant increase in the risk of cancer. Moreover, no cancer risk was observed when glargine was used alone or in combination with metformin. Conclusions Our results suggest that diabetes treatment does not influence the risk of cancer associated with type 2 diabetes. Therefore, an eventual increase of cancer should not be a reason for biasing the selection of any glucose-lowering treatment in type 2 diabetic population.
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Stürmer T, Marquis MA, Zhou H, Meigs JB, Lim S, Blonde L, Macdonald E, Wang R, Lavange LM, Pate V, Buse JB. Cancer incidence among those initiating insulin therapy with glargine versus human NPH insulin. Diabetes Care 2013; 36:3517-25. [PMID: 23877991 PMCID: PMC3816915 DOI: 10.2337/dc13-0263] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To add to the evidence on comparative long-term effects of insulin analog glargine versus human NPH insulin on the risk for cancer. RESEARCH DESIGN AND METHODS We identified cohorts of initiators of glargine and human NPH without an insulin prescription during the prior 19 months among patients covered by the Inovalon Medical Outcomes Research for Effectiveness and Economics Registry (MORE2 Registry) between January 2003 and December 2010. Patients were required to have a second prescription of the same insulin within 180 days and to be free of cancer. We balanced cohorts on risk factors for cancer outcomes based on comorbidities, comedication, and health care use during the prior 12 months using inverse probability of treatment weighting. Incident cancer was defined as having two claims for cancer (any cancer) or the same cancer (breast, prostate, colon) within 2 months. We estimated adjusted hazard ratios (HRs) and their 95% CI using weighted Cox models censoring for stopping, switching, or augmenting insulin treatment, end of enrollment, and mortality. RESULTS More patients initiated glargine (43,306) than NPH (9,147). Initiators of glargine (NPH) were followed for 1.2 (1.1) years and 50,548 (10,011) person-years; 993 (178) developed cancer. The overall HR was 1.12 (95% CI 0.95-1.32). Results were consistent for breast cancer, prostate cancer, and colon cancer; various durations of treatment; and sensitivity analyses. CONCLUSIONS Patients initiating insulin glargine rather than NPH do not seem to be at an increased risk for cancer. While our study contributes significantly to our evidence base for long-term effects, this evidence is very limited mainly based on actual dynamics in insulin prescribing.
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Abstract
Diabetes, in particular type 2 diabetes, and cancer are two diseases that appear to be associated. Numerous epidemiological studies indicate indeed that diabetes increases the incidence of several tumors. Chronic hyperglycemia and/or insulin resistance with compensatory hyperinsulinemia could account for the association. On the other hand, the interpretation of the link between diabetes and cancer could be influenced by therapeutical interferences. Considering all these data together, cancer should be considered as a "new potential complication" of diabetes and integrated in the follow-up of diabetic subjects.
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Affiliation(s)
- M Buysschaert
- Université catholique de Louvain, Cliniques universitaires Saint-Luc, Avenue Hippocrate 54/UCL 5474, B-1200 Bruxelles, Belgium.
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Pezzilli R, Pagano N. Is diabetes mellitus a risk factor for pancreatic cancer? World J Gastroenterol 2013; 19:4861-4866. [PMID: 23946590 PMCID: PMC3740415 DOI: 10.3748/wjg.v19.i30.4861] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2013] [Revised: 04/21/2013] [Accepted: 05/08/2013] [Indexed: 02/06/2023] Open
Abstract
The relationship between diabetes mellitus and the risk of pancreatic cancer has been a matter of study for a long period of time. The importance of this topic is due to two main causes: the possible use of recent onset diabetes as a marker of the disease and, in particular, as a specific marker of pancreatic cancer, and the selection of a population at risk for pancreatic cancer. Thus, we decided to make an in-depth study of this topic; thus, we carried out an extensive literature search in order to re-assess the current knowledge on this topic. Even if diabetes is found a decade before the appearance of pancreatic cancer as reported in meta-analytic studies, we cannot select those patients already having non detectable pancreatic cancer, at least with the imaging and biological techniques available today. We believe that more studies are necessary in order to definitively identify diabetes mellitus as a risk factor for pancreatic cancer taking into consideration that approximately 10 years are needed to diagnose symptomatic pancreatic cancer. At present, the answer to the as to whether diabetes and pancreatic cancer comes first similar to the adage of the chicken and the egg is that diabetes is the egg.
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Chang CH, Kusama M, Ono S, Sugiyama Y, Orii T, Akazawa M. Assessment of statin-associated muscle toxicity in Japan: a cohort study conducted using claims database and laboratory information. BMJ Open 2013; 3:e002040. [PMID: 23585384 PMCID: PMC3641424 DOI: 10.1136/bmjopen-2012-002040] [Citation(s) in RCA: 36] [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: 08/31/2012] [Revised: 02/28/2013] [Accepted: 03/18/2013] [Indexed: 11/28/2022] Open
Abstract
OBJECTIVE To estimate the incidence of muscle toxicity in patients receiving statin therapy by examining study populations, drug exposure status and outcome definitions. DESIGN A retrospective cohort study. SETTING 16 medical facilities in Japan providing information on laboratory tests performed in and claims received by their facilities between 1 April 2004 and 31 December 2010. PARTICIPANTS A database representing a cohort of 35 903 adult statin (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin) users was studied. Use of interacting drugs (fibrates, triazoles, macrolides, amiodarone and ciclosporin) by these patients was determined. MAIN OUTCOME MEASURE Statin-associated muscle toxicity (the 'event') was identified based on a diagnosis of muscle-related disorders (myopathy or rhabdomyolysis) and/or abnormal elevation of creatine kinase (CK) concentrations. Events were excluded if the patients had CK elevation-related conditions other than muscle toxicity. Incidence rates for muscle toxicity were determined per 1000 person-years, with 95% CI determined by Poisson regression. RESULTS A total of 18 036 patients accounted for 42 193 person-years of statin therapy, and 43 events were identified. The incidence of muscle toxicity in the patients treated with statins was 1.02 (95% CI 0.76 to 1.37)/1000 person-years. The estimates varied when outcome definitions were modified from 0.09/1000 person-years, which met both diagnosis and CK 10× greater than the upper limit of normal range (ULN) criteria, to 2.06/1000 person-years, which met diagnosis or CK 5× ULN criterion. The incidence of muscle toxicity was also influenced by the statin therapies selected, but no significant differences were observed. Among 2430 patients (13.5%) received interacting drugs with statins, only three muscle toxicity cases were observed (incidence: 1.69/1000 person-years). CONCLUSIONS This database study suggested that statin use is generally well tolerated and safe; however, the risk of muscle toxicity related to the use of interacting drugs requires further exploration.
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Affiliation(s)
- Chia-Hsien Chang
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University, Tainan, Taiwan
- Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Makiko Kusama
- Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Shunsuke Ono
- Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Yuichi Sugiyama
- Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
- Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Kanagawa, Japan
| | - Takao Orii
- Pharmacy Department, NTT Medical Center Tokyo, Tokyo, Japan
| | - Manabu Akazawa
- Department of Public Health and Epidemiology, Meiji Pharmaceutical University, Tokyo, Japan
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Abstract
The growing epidemic of obesity has resulted in a large increase in multiple related diseases. Recent evidence has strengthened the proposed synergistic relationship between obesity-related insulin resistance (IR) and/or diabetes mellitus (DM) and cancer. Within the past year, many studies have examined this relationship. Although the precise mechanisms and pathways are uncertain, it is becoming clear that hyperinsulinemia and possibly sustained hyperglycemia are important regulators of not only the development of cancer but also of treatment outcome. Further, clinical decision-making regarding the treatment of choice for DM will likely be impacted as we learn more about the non-metabolic effects of the available hyperglycemic agents. In our review, we endeavored to synthesize the recent literature and provide a concise view of the journey from macro-level clinical associations to specific mechanistic relationships being elucidated in cell lines and animal models.
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Affiliation(s)
- Etan Orgel
- Jonathan Jaques Children’s Cancer Center, Keck School of Medicine, University of Southern California, Miller Children’s Hospital, 2801 Atlantic Avenue, Long Beach, CA 90806, 562-933-8600 phone
| | - Steven D. Mittelman
- Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, 4650 Sunset Blvd., MS #93, Los Angeles, CA 90027, 323-361-7653 phone
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Association of serum C-peptide concentrations with cancer mortality risk in pre-diabetes or undiagnosed diabetes. PLoS One 2013; 8:e55625. [PMID: 23405181 PMCID: PMC3566039 DOI: 10.1371/journal.pone.0055625] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2012] [Accepted: 01/02/2013] [Indexed: 11/19/2022] Open
Abstract
Background Known associations between diabetes and cancer could logically be attributed to hyperglycemia, hypersecretion of insulin, and/or insulin resistance. This study examined the relationship between initial glycemic biomarkers among men and women with impaired fasting glucose or undiagnosed diabetes and cancer mortality during follow up. Methods The cohort included subjects aged 40 years and above from the Third National Health and Nutrition Examination Survey (NHANES III) with fasted serum glucose >100 mg/dl without the aid of pharmaceutical intervention (insulin or oral hypoglycemics). Cancer mortality was obtained from the NHANES III-linked follow-up database (up to December 31, 2006). A Cox regression model was applied to test for the associations between cancer mortality and fasting serum glucose, insulin, glycosylated hemoglobin (HbA1c), C-peptide, insulin like growth factor (IGF-1), IGF binding protein 3 (IGFBP3) and estimated insulin resistance. Results A total of 158 and 100 cancer deaths were recorded respectively from 1,348 men and 1,161 women during the mean 134-month follow-up. After adjusting for the effect of age and smoking in women, all-cause cancer deaths (HR: 1.96 per pmol/ml, 95% CI: 1.02–3.77) and lung cancer deaths (HR: 2.65 per pmol/ml, 95% CI: 1.31–5.36) were specifically associated with serum C-peptide concentrations. Similar associations in men were not statistically significant. Serum glucose, HbA1c, IGF-1, IGFBP3 and HOMA were not independently related to long-term cancer mortality. Conclusion C-peptide analyses suggest a modest association with both all-cause and lung cancer mortality in women but not in men. Further studies will be required to explore the mechanisms.
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Tennagels N, Werner U. The metabolic and mitogenic properties of basal insulin analogues. Arch Physiol Biochem 2013; 119:1-14. [PMID: 23373726 PMCID: PMC3581051 DOI: 10.3109/13813455.2012.754474] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Revised: 11/21/2012] [Accepted: 11/26/2012] [Indexed: 12/28/2022]
Abstract
CONTEXT Retrospective, observational studies have reported an association between diabetes treatment with insulin and a higher incidence of cancer. OBJECTIVE Overview the literature for in vitro and in vivo studies of the metabolic and mitogenic properties of basal insulin analogues and assess the implications for clinical use. METHODS Relevant studies were identified through PubMed and congress abstract database searches; data on metabolic and mitogenic signalling in relation to insulin treatment of diabetes are included in this review. RESULTS The balance of evidence shows that although some analogues have demonstrated mitogenic potency in some in vitro studies in cancer cell lines, these findings do not translate to the in vivo setting in animals or to the clinical setting in humans. CONCLUSIONS The current consensus is that there is no clinical or in vivo evidence to indicate that any commercially available insulin analogue has carcinogenic effects. Large-scale, prospective clinical and observational studies will further establish any potential link.
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Affiliation(s)
- Norbert Tennagels
- R&D Diabetes Division, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany.
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Fagot JP, Blotière PO, Ricordeau P, Weill A, Alla F, Allemand H. Does insulin glargine increase the risk of cancer compared with other basal insulins?: A French nationwide cohort study based on national administrative databases. Diabetes Care 2013; 36:294-301. [PMID: 22966091 PMCID: PMC3554310 DOI: 10.2337/dc12-0506] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To explore in France the relationship between insulin glargine use and overall and specific cancer risks in type 2 diabetic patients compared with other basal insulins. RESEARCH DESIGN AND METHODS Data were extracted from French health insurance information system (Système National d'Information Inter-Régimes de l'Assurance Maladie) linked with data from the French Hospital Discharge database (Programme de Médicalisation des Systèmes d'Information). Included were 70,027 patients aged 40-79 years who started a basal insulin in 2007-2009. Cox proportional hazards models with age as time-scale were used to calculate multivariate-adjusted hazard ratios for associations between type of basal insulin and risk of overall cancer, breast cancer, and seven other cancer sites. RESULTS The median follow-up was 2.67 years in patients exposed to insulin glargine. Absolute event rates for all cancer in patients exposed to glargine versus other basal insulin users were 1,622 and 1,643 per 100,000 person-years, respectively. No significant association was observed between glargine exposure and overall cancer incidence after adjustment for sex, with a hazard ratio of 0.97 (95% CI 0.87-1.07), or after additional adjustment for any other hypoglycemic agent use and duration of diabetes. No increased risk of breast cancer was observed for glargine users compared with other basal insulins users, with a fully adjusted hazard ratio of 1.08 (0.72-1.62). CONCLUSIONS In a large cohort of patients newly treated by basal insulin, no increased risk of any cancer was observed in insulin glargine users compared with other basal insulin users. Because follow-up did not exceed 4 years, longer-term studies are needed.
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Affiliation(s)
- Jean-Paul Fagot
- Strategy and Research Department, National Health Insurance, Paris, Ile de France, France.
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Gu Y, Wang C, Zheng Y, Hou X, Mo Y, Yu W, Zhang L, Hu C, Nan H, Chen L, Li J, Liu Y, Huang Z, Han M, Bao Y, Zhong W, Jia W. Cancer incidence and mortality in patients with type 2 diabetes treated with human insulin: a cohort study in Shanghai. PLoS One 2013; 8:e53411. [PMID: 23308218 PMCID: PMC3538755 DOI: 10.1371/journal.pone.0053411] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Accepted: 11/30/2012] [Indexed: 12/13/2022] Open
Abstract
Aim The aim was to investigate the association between human insulin and cancer incidence and mortality in Chinese patients with type 2 diabetes. Methods We recruited 8,774 insulin-naïve diabetes patients from the Shanghai Diabetes Registry (SDR). The follow-up rate was 85.4%. All subjects were divided into the insulin use cohort (n = 3,639) and the non-insulin use cohort (n = 5,135). The primary outcome was the first diagnosis of any cancer. The secondary outcome was all-cause mortality. Cox proportional hazards model was used to estimate the relative risk (RR) of cancer and mortality. Results We observed 98 cancer events in the insulin use cohort and 170 in the non-insulin use cohort. Cancer incidence rates were 78.6 and 74.3 per 10,000 patients per year in the insulin users and the non-insulin users, respectively. No significant difference in cancer risk was observed between the two cohorts (adjusted RR = 1.20, 95% CI 0.89–1.62, P = 0.228). Regarding site-specific cancers, only the risk of liver cancer was significantly higher in the insulin users compared to that in the non-insulin users (adjusted RR = 2.84, 95% CI 1.12–7.17, P = 0.028). The risks of overall mortality (adjusted RR = 1.89, 95% CI 1.47–2.43, P<0.0001) and death from cancer (adjusted RR = 2.16, 95% CI 1.39–3.35, P = 0.001) were all significantly higher in the insulin users than in the non-insulin users. Conclusion There was no excess risk of overall cancer in patients with type 2 diabetes who were treated with human insulin. However, a significantly higher risk of liver cancer was found in these patients. Moreover, insulin users showed higher risks of overall and cancer mortality. Considering that individuals treated with insulin were more likely to be advanced diabetic patients, caution should be used in interpreting these results.
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Affiliation(s)
- Yunjuan Gu
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Centre of Diabetes, Shanghai, China
- Department of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
- Department of Endocrinology and Metabolism, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Chunfang Wang
- Department of Vital Statistics, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China
| | - Ying Zheng
- Department of Cancer Prevention and Control, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China
| | - Xuhong Hou
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Centre of Diabetes, Shanghai, China
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
| | - Yifei Mo
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Centre of Diabetes, Shanghai, China
- Department of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
| | - Weihui Yu
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Centre of Diabetes, Shanghai, China
- Department of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
| | - Lei Zhang
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Centre of Diabetes, Shanghai, China
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
| | - Cheng Hu
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Centre of Diabetes, Shanghai, China
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
| | - Hairong Nan
- Department of Community Medicine, School of Public Health, the University of Hong Kong, Hong Kong, China
| | - Lei Chen
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Centre of Diabetes, Shanghai, China
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
| | - Jie Li
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Centre of Diabetes, Shanghai, China
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
| | - Yuxiang Liu
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Centre of Diabetes, Shanghai, China
- Department of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
| | - Zhezhou Huang
- Department of Cancer Prevention and Control, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China
| | - Ming Han
- Department of Vital Statistics, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China
| | - Yuqian Bao
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Centre of Diabetes, Shanghai, China
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
| | - Weijian Zhong
- The vice-director of the Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China
| | - Weiping Jia
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Diabetes Institute; Shanghai Clinical Centre of Diabetes, Shanghai, China
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
- * E-mail:
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Zhang H, Gao C, Fang L, Zhao HC, Yao SK. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients: a meta-analysis. Scand J Gastroenterol 2013; 48:78-87. [PMID: 23137049 DOI: 10.3109/00365521.2012.719926] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVES Recent epidemiological studies suggest that metformin treatment may reduce the risks of cancer and overall cancer mortality among patients with diabetes mellitus (DM). However, data on hepatocellular carcinoma (HCC) are very limited and inconsistent. This meta-analysis was designed to pool data currently available to determine the association between metformin use and HCC among diabetic patients. METHODS The Medline and Embase databases were searched to identify the relevant studies between January 1966 and December 2011. The overall analysis was derived using a random-effects meta-analysis model (DerSimonian and Laird method). Subgroup analysis was performed to explore the source of heterogeneity and validate the results from overall analysis. The Newcastle-Ottawa Quality assessment scales were adopted for quality assessment; Begg's funnel plot and Egger's regression asymmetry test were used to detect the publication bias. RESULTS A total of seven studies were identified, including three cohort studies and four case-control studies. Based on the available data, the overall prevalence of HCC was 3.40% (562/16,549) in DM patients. The overall analysis showed a significantly reduced risk of HCC in metformin users versus nonusers in diabetic patients (relative risk (RR) 0.24, 95% confidence interval (CI) 0.13-0.46, p < 0.001). Fifteen subgroup analyses were performed, and most of them (12/15 = 80%) provided supporting evidence for the results of overall analysis. Begg's (Z = -0.15, p = 0.8819) and Egger's test (t = -0.79, p = 0.468) showed no significant risk of having a publication bias. CONCLUSION Metformin treatment was associated with reduced risk of HCC in diabetic patients. To clarify this relationship, more high-quality studies are required.
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Affiliation(s)
- Hui Zhang
- Department of Gastroenterology, China-Japan Friendship Hospital, Peking University Health Science Center, Beijing, PR China
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Tang X, Yang L, He Z, Liu J. Insulin glargine and cancer risk in patients with diabetes: a meta-analysis. PLoS One 2012; 7:e51814. [PMID: 23284776 PMCID: PMC3526637 DOI: 10.1371/journal.pone.0051814] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Accepted: 11/06/2012] [Indexed: 12/13/2022] Open
Abstract
AIM The role of insulin glargine as a risk factor for cancer is controversial in human studies. The aim of this meta-analysis was to evaluate the relationship between insulin glargine and cancer incidence. METHODS All observational studies and randomized controlled trials evaluating the relationship of insulin glargine and cancer risk were identified in PubMed, Embase, Web of Science, Cochrane Library and the Chinese Biomedical Medical Literature Database, through March 2012. Odds ratios (ORs) with corresponding 95% confidence interval (CI) were calculated with a random-effects model. Confidence in the estimates of the obtained effects (quality of evidence) was assessed by using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS A total of 11 studies including 448,928 study subjects and 19,128 cancer patients were finally identified for the meta-analysis. Insulin glargine use was associated with a lower odds of cancer compared with non-glargine insulin use (OR 0.81, 95% CI 0.68 to 0.98, P = 0.03; very low-quality evidence). Glargine did not increase the odds of breast cancer (OR 0.99, 95% CI 0.68 to 1.46, P = 0.966; very low-quality evidence). Compared with non-glargine insulin, no significant association was found between insulin glargine and prostate cancer, pancreatic cancer and respiratory tract cancer. Insulin glargine use was associated with lower odds of other site-specific cancer. CONCLUSIONS Results from the meta-analysis don't support the link between insulin glargine and an increased risk of cancer and the confidence in the estimates of the effects is very low. Further studies are needed to examine the relation between insulin glargine and cancer risk, especially breast cancer.
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Affiliation(s)
- Xulei Tang
- Department of Endocrinology, the First Hospital of Lanzhou University, Lanzhou, Gansu, China.
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Zhang F, Yang Y, Skrip L, Hu D, Wang Y, Wong C, Qiu J, Lei H. Diabetes mellitus and risk of prostate cancer: an updated meta-analysis based on 12 case-control and 25 cohort studies. Acta Diabetol 2012; 49 Suppl 1:S235-46. [PMID: 23124624 DOI: 10.1007/s00592-012-0439-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2012] [Accepted: 10/25/2012] [Indexed: 12/11/2022]
Abstract
The association between diabetes and risk of prostate cancer has been investigated widely. However, study results remain inconsistent and contradictory. Using a meta-analytic approach, the present study explore the relationship incorporating more recent studies and provide more powerful evidence without the limitations of any individual study. Relevant studies were identified by searching Pubmed and the Cochrane Central Register of Controlled Trials through May 18, 2012. The strength of the relationship between diabetes mellitus and risk of prostate cancer was assessed using relative risk (RR). Either a fixed effects or random effects model was used to calculate the pooled RRs. Stratification analyses and sensitivity analyses were conducted, and publication bias was assessed by Egger's test and Begg's test. Twelve case-control studies involving 9,767 cases and 19,790 controls, and 25 cohort studies involving 118,825 cases were included. The person-years of follow-up ranged from 29,963 to 6,264,890 among included cohort studies. Diabetes was not significantly associated with incidence of prostate cancer in our analysis of case-control studies only (RR = 0.846, 95 % CI [0.710, 1.009]) or that of cohort studies only (RR = 0.925, 95 % CI [0.811, 1.054]). However, through subgroup analyses, statistically significant associations between diabetes and prostate cancer were found when considering population-based studies only (RR = 0.719, 95 % CI [0.637, 0.812]), cohort studies conducted in the United States (RR = 0.789, 95 % CI [0.727, 0.857]), and studies with follow-up of more than 5 years. Compared to risk of prostate cancer among people without diabetes, diabetic patients using insulin treatment experienced reduced incidence of prostate cancer in both case-control and cohort studies. The results suggest that diabetes mellitus is associated with decreased incidence of prostate cancer, specifically in the population of the United States. In addition, the time since onset of diabetes was positively associated with decreasing incidence of prostate cancer. The present conclusions should be considered carefully, however, and confirmed with further studies.
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Affiliation(s)
- Fan Zhang
- School of Public Health and Management, Chongqing Medical University, Chongqing 400016, China
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40
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Colmers IN, Bowker SL, Tjosvold LA, Johnson JA. Insulin use and cancer risk in patients with type 2 diabetes: a systematic review and meta-analysis of observational studies. DIABETES & METABOLISM 2012; 38:485-506. [PMID: 23159131 DOI: 10.1016/j.diabet.2012.08.011] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Revised: 07/30/2012] [Accepted: 08/01/2012] [Indexed: 12/21/2022]
Abstract
AIMS To determine whether data from observational studies supports the hypothesis of an increased risk of overall and site-specific cancer among individuals with diabetes using exogenous insulin therapies. METHODS We conducted a comprehensive search of nine key biomedical databases for all years up to December 2011, restricted to the English language. Data from cohort and nested case-control studies were included in random effects meta-analyses of site-specific and overall cancer incidence comparing ever use and new use of: (1) insulin to no insulin and; (2) insulin glargine to other insulins. RESULTS The search yielded 3052 unique citations, of which 19 were selected for inclusion, representing data for 1,332,120 people and 41,947 cancers. Pancreatic cancer risk was increased among new users of insulin (RR: 3.18, 95%CI: 3.27-3.71, I(2)=32%). New use of insulin glargine was associated with an increased risk of pancreatic cancer (RR: 1.63, 95%CI: 1.05-2.51, I(2)=0%) and prostate cancers (RR: 2.68, 95%CI: 1.50-4.79, I(2)=0%) but a decreased risk of colorectal cancer (RR: 0.78, 95%CI: 0.64-0.94, I(2)=15%). CONCLUSION New use of insulin or insulin glargine was associated with an increased risk of pancreatic cancer, possibly due to reverse causality. New use of insulin glargine was associated with a decreased risk of colorectal cancer but an increased risk of prostate cancer. Our results should be interpreted with caution due to limitations of included studies.
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Affiliation(s)
- I N Colmers
- Department of Public Health Sciences, University of Alberta, 2-040 Li Ka Shing Center Edmonton, Alberta, T6G 2E1 Canada
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Mannucci E. Insulin therapy and cancer in type 2 diabetes. ISRN ENDOCRINOLOGY 2012; 2012:240634. [PMID: 23209929 PMCID: PMC3504371 DOI: 10.5402/2012/240634] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Accepted: 10/03/2012] [Indexed: 01/27/2023]
Abstract
Despite the availability of many other agents, insulin is widely used as a treatment for type 2 diabetes. In vitro, insulin stimulates the growth of cancer cells, through the interaction with insulin-like growth factor-1 (IGF-1) receptors and its own receptors. In observational surveys on type 2 diabetes, insulin therapy is associated with an increased incidence of several forms of cancer, although it is difficult to discriminate the effect of confounders from that of insulin itself. Randomized trials do not confirm the increased risk associated with insulin therapy, although they do not allow to rule out some negative effects on specific forms of cancer, at least at higher doses. Among insulin analogues, glargine has a higher affinity for the IGF-1 receptor and a greater mitogenic potency in vitro than human insulin, but it is extensively metabolized in vitro to products with low IGF-1 receptor affinity. Overall, epidemiological studies suggest a possible increase of risk with glargine, with respect to human insulin, only at high doses and for some forms of cancer (i.e., breast). Data from clinical trials do not confirm, but are still insufficient to totally exclude, such increased risk. However, beneficial effects of insulin outweigh potential cancer risks.
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Affiliation(s)
- Edoardo Mannucci
- Agenzia Diabetologia, Ponte Nuovo, Ospedale di Careggi, Via delle Oblate, 4-50141 Firenze, Italy
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Bhattacharyya R, Banerjee D. A docking study of insulin with LI-CR-L2 ecto domain of insulin receptor: an easy way for preliminary screening of novel anti-diabetic peptides. Bioinformation 2012; 8:1082-6. [PMID: 23251042 PMCID: PMC3523222 DOI: 10.6026/97320630081082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2012] [Accepted: 09/27/2012] [Indexed: 12/02/2022] Open
Abstract
Although interaction of human insulin with its receptor is studied to considerable extent such studies are currently lacking with recombinant insulin in-spite of its rampant clinical use. It is known that at molecular level the interaction of recombinant insulin with insulin receptor is similar to human insulin but not exactly same. With the increasing incidence of diabetes throughout the globe use of recombinant insulin is also increasing at a considerable rate. Therefore it is need of the hour to explore the recombinant insulin- insulin receptor interaction by all possible means. In this paper we have studied insulin receptor binding of lispro and glargine; the two commonly used recombinant insulins using tools of computational biology. We have observed that the binding pattern of insulin receptor (L1-CR-L2 ectodomain) with lispro and glargine is different when compared with human insulin. Analyzing the ligand receptor interactions we have hypothesized that the tail region of insulin beyond B26 is a critical regulator of insulin insulin receptor interactions detail of which cannot be understandable from docking studies due to lack of consideration of the flexibility of the tail region while docking studies. We have recommended experimental validation of our study. However, our docking procedure may also be explored for preliminary screening of novel anti-diabetic peptide.
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Affiliation(s)
- Rajasri Bhattacharyya
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh-160012
| | - Dibyajyoti Banerjee
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh-160012
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Li J, Cao G, Ma Q, Liu H, Li W, Han L. The bidirectional interation between pancreatic cancer and diabetes. World J Surg Oncol 2012; 10:171. [PMID: 22920886 PMCID: PMC3499274 DOI: 10.1186/1477-7819-10-171] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2012] [Accepted: 08/11/2012] [Indexed: 12/15/2022] Open
Abstract
The bidirectional interation between pancreatic cancer (PanCa) and diabetes has been confirmed by epidemiological studies, which provide evidence-based medical support for further research into the mechanisms involved in the interaction. We reviewed the literature regarding the role of diabetes in the generation and progression of PanCa and the mechanism by which PanCa induces diabetes for its malignant progression. The effect of antidiabetic drugs on the occurrence and prognosis of PanCa was also reviewed. Diabetes may directly promote the progression of PanCa by pancreatic duct enlargement and hypertension, as well as by enabling an increased tumor volume. Hyperinsulinemia, insulin resistance, cytokines, hyperglycemia and genotype change are also important factors in the progression of PanCa with diabetes. Hyperglycemia may be the first clinical manifestation and is helpful in the early diagnosis of PanCa. Furthermore, antidiabetic drugs can have different effects on the occurrence and prognosis of PanCa. The bidirectional interation between PanCa and diabetes is involved in the occurrence, proliferation, invasion, metastasis and prognosis of PanCa with diabetes. The discovery of biomarkers for the early diagnosis of PanCa, as well as the novel usage of metformin for its antitumor effects and determining the potential mechanisms of these effects, may be the next direction for PanCa research and treatment.
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Affiliation(s)
- Junhui Li
- Department of General Surgery, Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, 157 West 5th Road, Xi'an 710004, People's Republic of China
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Sheen YJ, Sheu WHH. Links among type 2 diabetes, cancer and metformin use: what have we learned? Diabetes Res Clin Pract 2012; 97:169-71. [PMID: 22497968 DOI: 10.1016/j.diabres.2012.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2012] [Accepted: 03/19/2012] [Indexed: 10/28/2022]
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Ruiter R, Visser LE, van Herk-Sukel MPP, Coebergh JWW, Haak HR, Geelhoed-Duijvestijn PH, Straus SMJM, Herings RMC, Stricker BHC. Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study. Diabetologia 2012; 55:51-62. [PMID: 21956710 PMCID: PMC3228952 DOI: 10.1007/s00125-011-2312-4] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2011] [Accepted: 08/19/2011] [Indexed: 12/13/2022]
Abstract
AIMS/HYPOTHESIS Several publications suggest an association between certain types of insulin and cancer, but with conflicting results. We investigated whether insulin glargine (A21Gly,B31Arg,B32Arg human insulin) is associated with an increased risk of cancer in a large population-based cohort study. METHODS Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. In a cohort of incident users of insulin, the association between insulin glargine and other insulin analogues, respectively, and cancer was analysed in comparison with human insulin using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant. The first hospital admission with a primary diagnosis of cancer was considered as the main outcome; secondary analyses were performed with specific cancers as outcomes. RESULTS Of the 19,337 incident insulin users enrolled, 878 developed cancer. Use of insulin glargine was associated with a lower risk of malignancies in general in comparison with human insulin (HR 0.75, 95% CI 0.71, 0.80). In contrast, an increased risk was found for breast cancer (HR 1.58, 95% CI 1.22, 2.05). Dose-response relationships could not be identified. CONCLUSION/INTERPRETATION Users of insulin glargine and users of other insulin analogues had a lower risk of cancer in general than those using human insulin. Both associations might be a consequence of residual confounding, lack of adherence or competing risk. However, as in previous studies, we demonstrated an increased risk of breast cancer in users of insulin glargine in comparison with users of human insulin.
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MESH Headings
- Breast Neoplasms/chemically induced
- Breast Neoplasms/complications
- Breast Neoplasms/epidemiology
- Cohort Studies
- Community Pharmacy Services
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/drug therapy
- Dose-Response Relationship, Drug
- Electronic Health Records
- Female
- Follow-Up Studies
- Humans
- Hypoglycemic Agents/administration & dosage
- Hypoglycemic Agents/adverse effects
- Hypoglycemic Agents/therapeutic use
- Incidence
- Insulin/administration & dosage
- Insulin/adverse effects
- Insulin/analogs & derivatives
- Insulin/therapeutic use
- Insulin Glargine
- Insulin, Long-Acting/administration & dosage
- Insulin, Long-Acting/adverse effects
- Insulin, Long-Acting/therapeutic use
- Insulin, Regular, Human/administration & dosage
- Insulin, Regular, Human/adverse effects
- Insulin, Regular, Human/therapeutic use
- Male
- Medical Record Linkage
- Middle Aged
- Neoplasms/chemically induced
- Neoplasms/complications
- Neoplasms/epidemiology
- Netherlands/epidemiology
- Patient Admission
- Proportional Hazards Models
- Risk
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Affiliation(s)
- R. Ruiter
- Department of Epidemiology, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands
- Drug Safety Unit, Inspectorate of Health Care, The Hague, the Netherlands
| | - L. E. Visser
- Department of Epidemiology, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands
- Department of Hospital Pharmacy, Erasmus MC, Rotterdam, the Netherlands
- Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands
| | | | | | - H. R. Haak
- Department of Internal Medicine, Maxima Medical Centre, Eindhoven, the Netherlands
| | | | - S. M. J. M. Straus
- The Dutch Medicines Evaluation Board, The Hague, the Netherlands
- Department of Medical Informatics, Erasmus MC, Rotterdam, the Netherlands
| | - R. M. C. Herings
- PHARMO Institute for Drug Outcomes Research, Utrecht, the Netherlands
- Department of Health Policy & Management, Erasmus MC, Rotterdam, the Netherlands
| | - B. H. Ch. Stricker
- Department of Epidemiology, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands
- Drug Safety Unit, Inspectorate of Health Care, The Hague, the Netherlands
- Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands
- Department of Medical Informatics, Erasmus MC, Rotterdam, the Netherlands
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