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      Diabetes and cancer: two diseases with obesity as a common risk factor

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          Abstract

          There is a growing body of evidence to support a connection between diabetes (predominantly type 2), obesity and cancer. Multiple meta-analyses of epidemiological data show that people with diabetes are at increased risk of developing many different types of cancers, along with an increased risk of cancer mortality. Several pathophysiological mechanisms for this relationship have been postulated, including insulin resistance and hyperinsulinaemia, enhanced inflammatory processes, dysregulation of sex hormone production and hyperglycaemia. In addition to these potential mechanisms, a number of common risk factors, including obesity, may be behind the association between diabetes and cancer. Indeed, obesity is associated with an increased risk of cancer and diabetes. Abdominal adiposity has been shown to play a role in creating a systemic pro-inflammatory environment, which could result in the development of both diabetes and cancer. Here, we examine the relationship between diabetes, obesity and cancer, and investigate the potential underlying causes of increased cancer risk in individuals with diabetes. Current treatment recommendations for reducing the overall disease burden are also explored and possible areas for future research are considered.

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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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            Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells.

            Ryan J O Dowling, Mahvash Zakikhani, I. George Fantus … (2007)
            Metformin is used for the treatment of type 2 diabetes because of its ability to lower blood glucose. The effects of metformin are explained by the activation of AMP-activated protein kinase (AMPK), which regulates cellular energy metabolism. Recently, we showed that metformin inhibits the growth of breast cancer cells through the activation of AMPK. Here, we show that metformin inhibits translation initiation. In MCF-7 breast cancer cells, metformin treatment led to a 30% decrease in global protein synthesis. Metformin caused a dose-dependent specific decrease in cap-dependent translation, with a maximal inhibition of 40%. Polysome profile analysis showed an inhibition of translation initiation as metformin treatment of MCF-7 cells led to a shift of mRNAs from heavy to light polysomes and a concomitant increase in the amount of 80S ribosomes. The decrease in translation caused by metformin was associated with mammalian target of rapamycin (mTOR) inhibition, and a decrease in the phosphorylation of S6 kinase, ribosomal protein S6, and eIF4E-binding protein 1. The effects of metformin on translation were mediated by AMPK, as treatment of cells with the AMPK inhibitor compound C prevented the inhibition of translation. Furthermore, translation in MDA-MB-231 cells, which lack the AMPK kinase LKB1, and in tuberous sclerosis complex 2 null (TSC2(-/-)) mouse embryonic fibroblasts was unaffected by metformin, indicating that LKB1 and TSC2 are involved in the mechanism of action of metformin. These results show that metformin-mediated AMPK activation leads to inhibition of mTOR and a reduction in translation initiation, thus providing a possible mechanism of action of metformin in the inhibition of cancer cell growth.
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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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                Author and article information

                Journal
                Journal ID (nlm-ta): Diabetes Obes Metab
                Journal ID (iso-abbrev): Diabetes Obes Metab
                Journal ID (publisher-id): dom
                Title: Diabetes, Obesity & Metabolism
                Publisher: Blackwell Publishing Ltd (Oxford, UK )
                ISSN (Print): 1462-8902
                ISSN (Electronic): 1463-1326
                Publication date (Print): February 2014
                Publication date (Electronic): 12 June 2013
                Volume: 16
                Issue: 2
                Pages: 97-110
                Affiliations
                [1 ]Barbara Davis Center for Diabetes, University of Colorado Denver Aurora, CO, USA
                [2 ]Diabetes Technology and Therapeutics New Rochelle, NY, USA
                [3 ]Medicine and Pediatrics, University of Colorado Denver Aurora, CO, USA
                [4 ]Boston University Boston, MA, USA
                Author notes
                Correspondence to: Satish K. Garg, Barbara Davis Center for Diabetes, University of Colorado, Denver, Anschutz Medical Campus, Mail Stop A140, P.O. Box 6511, 1775 Aurora Court, Aurora, CO 80045, USA. E-mail: satish.garg@ 123456ucdenver.edu
                Article
                DOI: 10.1111/dom.12124
                PMC ID: 3904746
                PubMed ID: 23668396
                SO-VID: c994334d-77a2-4f97-9e7a-f72dd38405a8
                Copyright © © 2013 The Authors. Diabetes, Obesity and Metabolism published by JohnWiley & Sons Ltd.
                License:

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                Date received : 18 December 2012
                Date revision received : 13 February 2013
                Date accepted : 13 May 2013
                Categories
                Subject: Review Articles

                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: diabetes complications,antidiabetic drug,type 2 diabetes,diabetes mellitus
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: diabetes complications, antidiabetic drug, type 2 diabetes, diabetes mellitus

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