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      The Influence of Type 2 Diabetes and Glucose-Lowering Therapies on Cancer Risk in the Taiwanese

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          Abstract

          Objective. To investigate the association between type 2 diabetes, glucose-lowering therapies (monotherapy with either metformin, sulphonylurea or insulin) and cancer risk in Taiwan. Methods. Using Taiwan's National Health Research Institutes database of 1,000,000 random subjects from 2000–2008, we found 61777 patients with type 2 diabetes (age ≥20 years) and 677378 enrollees with no record of diabetes. Results. After adjusting for age and sex, we found patients with diabetes to have significantly higher risk of all cancers (OR: 1.176; 95% CI: 1.149–1.204, P < 0.001). Diabetic patients treated with insulin or sulfonylureas had significantly higher risk of all cancers, compared to those treated with metformin (OR: 1.583; 95% CI: 1.389–1.805, P < 0.001 and OR: 1.784; 95% CI: 1.406–2.262, P < 0.001). Metformin treatment was associated with a decreased risk of colon and liver cancer compared to sulphonylureas or insulin treatment. Sulfonylureas treatment was associated with an increased risk of breast and lung cancer compared to metformin therapy. Conclusions. Taiwanese with type 2 diabetes are at a high risk of breast, prostate, colon, lung, liver and pancreatic cancer. Those treated with insulin or sulfonylureas monotherapy are more likely to develop colon and liver cancer than those treated with metformin.

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          Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells.

          Mahvash Zakikhani, Ryan Dowling, I. George Fantus … (2006)
          Recent population studies provide clues that the use of metformin may be associated with reduced incidence and improved prognosis of certain cancers. This drug is widely used in the treatment of type 2 diabetes, where it is often referred to as an "insulin sensitizer" because it not only lowers blood glucose but also reduces the hyperinsulinemia associated with insulin resistance. As insulin and insulin-like growth factors stimulate proliferation of many normal and transformed cell types, agents that facilitate signaling through these receptors would be expected to enhance proliferation. We show here that metformin acts as a growth inhibitor rather than an insulin sensitizer for epithelial cells. Breast cancer cells can be protected against metformin-induced growth inhibition by small interfering RNA against AMP kinase. This shows that AMP kinase pathway activation by metformin, recently shown to be necessary for metformin inhibition of gluconeogenesis in hepatocytes, is also involved in metformin-induced growth inhibition of epithelial cells. The growth inhibition was associated with decreased mammalian target of rapamycin and S6 kinase activation and a general decrease in mRNA translation. These results provide evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent population studies and justify further work to explore potential roles for activators of AMP kinase in cancer prevention and treatment.
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            Fasting serum glucose level and cancer risk in Korean men and women.

            Sun Jee, Heechoul Ohrr, Jae Sull … (2005)
            Diabetes is a serious and costly disease that is becoming increasingly common in many countries. The role of diabetes as a cancer risk factor remains unclear. To examine the relationship between fasting serum glucose and diabetes and risk of all cancers and specific cancers in men and women in Korea. Ten-year prospective cohort study of 1,298,385 Koreans (829,770 men and 468,615 women) aged 30 to 95 years who received health insurance from the National Health Insurance Corp and had a biennial medical evaluation in 1992-1995 (with follow-up for up to 10 years). Death from cancer and registry-documented incident cancer or hospital admission for cancer. During the 10 years of follow-up, there were 20,566 cancer deaths in men and 5907 cancer deaths in women. Using Cox proportional hazards models and controlling for smoking and alcohol use, the stratum with the highest fasting serum glucose (> or =140 mg/dL [> or =7.8 mmol/L]) had higher death rates from all cancers combined (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.22-1.37 in men and HR, 1.23; 95% CI, 1.09-1.39 in women) compared with the stratum with the lowest level (<90 mg/dL [<5.0 mmol/L]). By cancer site, the association was strongest for pancreatic cancer, comparing the highest and lowest strata in men (HR, 1.91; 95% CI, 1.52-2.41) and in women (HR, 2.05; 95% CI, 1.43-2.93). Significant associations were also found for cancers of the esophagus, liver, and colon/rectum in men and of the liver and cervix in women, and there were significant trends with glucose level for cancers of the esophagus, colon/rectum, liver, pancreas, and bile duct in men and of the liver and pancreas in women. Of the 26,473 total cancer deaths in men and women, 848 were estimated as attributable to having a fasting serum glucose level of less than 90 mg/dL. For cancer incidence, the general patterns reflected those found for mortality. For persons with a diagnosis of diabetes or a fasting serum glucose level greater than 125 mg/dL (6.9 mmol/L), risks for cancer incidence and mortality were generally elevated compared with those without diabetes. In Korea, elevated fasting serum glucose levels and a diagnosis of diabetes are independent risk factors for several major cancers, and the risk tends to increase with an increased level of fasting serum glucose.
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              Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin.

              S Bowker, S Majumdar, P Veugelers … (2006)
              Numerous studies have identified an increased risk of cancer in type 2 diabetes. We explored the association between antidiabetic therapies and cancer-related mortality in patients with type 2 diabetes, postulating that agents that increase insulin levels might promote cancer. This was a population-based cohort study using administrative databases from Saskatchewan Health. Cancer-related mortality was compared among inception cohorts of metformin users and sulfonylurea monotherapy users. Multivariate Cox regression was used to estimate the hazard ratio (HR) of cancer-related mortality, after adjusting for age, sex, insulin use, and chronic disease score. All statistical tests were two-sided. We identified 10,309 new users of metformin or sulfonylureas with an average follow-up of 5.4 +/- 1.9 years (means +/- SD). The mean age for the cohort was 63.4 +/- 13.3 years, and 55% were men. Cancer mortality over follow-up was 4.9% (162 of 3,340) for sulfonylurea monotherapy users, 3.5% (245 of 6,969) for metformin users, and 5.8% (84 of 1,443) for subjects who used insulin. After multivariate adjustment, the sulfonylurea cohort had greater cancer-related mortality compared with the metformin cohort (adjusted HR 1.3 [95% CI 1.1-1.6]; P = 0.012). Insulin use was associated with an adjusted HR of cancer-related mortality of 1.9 (95% CI 1.5-2.4; P < 0.0001). Patients with type 2 diabetes exposed to sulfonylureas and exogenous insulin had a significantly increased risk of cancer-related mortality compared with patients exposed to metformin. It is uncertain whether this increased risk is related to a deleterious effect of sulfonylurea and insulin or a protective effect of metformin or due to some unmeasured effect related to both choice of therapy and cancer risk.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Exp Diabetes Res
                Journal ID (iso-abbrev): Exp Diabetes Res
                Journal ID (publisher-id): EDR
                Title: Experimental Diabetes Research
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 1687-5214
                ISSN (Electronic): 1687-5303
                Publication date (Print): 2012
                Publication date (Electronic): 5 June 2012
                Volume: 2012
                Electronic Location Identifier: 413782
                Affiliations
                1Division of Endocrinology and Metabolism, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
                2Graduate Institute of Integrated Medicine, China Medical University, Taiwan
                3Department of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan
                4School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
                5Department of Internal Medicine, National Taiwan University College of Medicine, No. 7 Chung-Shan South Road, Taipei 100, Taiwan
                Author notes
                *Chin-Hsiao Tseng: ccktsh@ 123456ms6.hinet.net

                Academic Editor: Chien-Jen Chen

                Article
                DOI: 10.1155/2012/413782
                PMC ID: 3374948
                PubMed ID: 22719752
                SO-VID: 89f1dfe7-6e7d-48d0-a98f-0b977ffe528d
                Copyright © Copyright © 2012 Ming-Chia Hsieh et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 24 February 2012
                Date accepted : 2 April 2012
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Endocrinology & Diabetes
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes

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