Diabetes mellitus: influences on cancer risk

Szablewski, Leszek

doi:10.1002/dmrr.2573

Cited by 56 publications

(68 citation statements)

References 137 publications

(186 reference statements)

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“…Unopposed estrogen has been shown to increase the risk of EC development, as estrogens stimulate endometrial cell proliferation and inhibit apoptosis (3). Additionally, diseases associated with insulin resistance, such as obesity, type II diabetes mellitus and polycystic ovary syndrome (PCOS), are considered significant risk factors for the development and progression of type I EC (4)(5)(6). Insulin resistance is a condition in which target tissues have decreased sensitivity to insulin, and blood insulin levels consequently increase to maintain normal glucose levels.…”

Section: Introductionmentioning

confidence: 99%

Proliferation and metastatic potential of endometrial cancer cells in response to metformin treatment in a high versus normal glucose environment

et al. 2016

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Abstract. In order to improve our understanding of the potential preventive and therapeutic role of metformin, the present study aimed to investigate the capability of low-dose metformin in the efficient inhibition of cancer development and the reduction of the metastasis of endometrial adenocarcinoma type I and primary endometrial epithelial cells (eEPs), with the drug acting as a treatment in a hyperinsulinemic environment exposed to high and normal glucose conditions. The Ishikawa endometrial adenocarcinoma cell line and primary eEPs were exposed to an environment with high (17 mM) or normal glucose (5 mM) and treated with insulin, low-dose metformin (0.1 mM) or a combined treatment. Metastatic potential was assessed by migration and invasion assays, and relative cell proliferation was determined. Metformin at a low dose potently inhibited the insulin action, decreasing the ability of the endometrial cancer (EC) cell line to migrate and invade in a high and normal glucose environment, and decreasing the migration ability of the primary eEPs. In the EC cell line, the insulin treatment increased the proliferation, without any subsequent reduction of proliferation by the addition of 0.1 mM metformin; however, relative cell proliferation sensitivity to metformin was observed in the range between 1 and 5 mM regardless of the glucose concentration present. Overall, metformin at 0.1 mM is not efficient enough to decrease the proliferation in an EC cell line. However, at this concentration, metformin can inhibit the insulin action in endometrial epithelial cancer cells, demonstrating an anti-metastatic effect in high and normal glucose environments.

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Section: Introductionmentioning

confidence: 99%

Proliferation and metastatic potential of endometrial cancer cells in response to metformin treatment in a high versus normal glucose environment

et al. 2016

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“…Conversely, although there are limited studies, Zendehdel et al (11) reported that T1DM can increase the incidence risk ≤20% for gastric, endometrial and cervical cancer in the general Swedish population. T1DM appeared to be correlated with a moderate excess cancer risk overall, and risks of specific types of cancer that differ from those associated with T2DM (12). To the best of our knowledge, the exact values of estimated risk, however, may vary due to study design, the impact of confounding factors and ethnic differences, including genetic susceptibility, life-style behaviors, specific environmental exposures and varying biological effects of diabetes across populations.…”

Section: Diabetes and Risk Ratio To Cancermentioning

confidence: 90%

“…According to several meta-analyses, an increased frequency of malignancies in diabetic patients has been attributed to various general and local mechanisms (1,3,4,10,12).…”

Section: Incidence Of Different Types Of Cancer Among Diabetic Patientsmentioning

confidence: 99%

“…Notably, while the physiological pattern of insulin secretion to the portal vein includes degradation and utilization of a significant proportion of the hormone in the liver, exogenous administration allows higher availability of insulin to the peripheral tissues (12). However, a Chinese cohort study demonstrated that there was no excess risk of overall cancer in T2DM patients treated with human insulin, regardless of an increased overall and cancer mortality among insulin users (29).…”

Section: Diabetes Cancer and Therapiesmentioning

confidence: 99%

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Diabetes and cancer: A critical appraisal of the pathogenetic and therapeutic links

Gristina¹,

Cupri²,

Torchio³

et al. 2014

Biomedical Reports

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Abstract. Diabetes and cancer represent two common, multifactorial, chronic and potentially fatal diseases, not infrequently co-diagnosed in the same patient. Epidemiological data demonstrate significant increases of the cancer incidence in patients with obesity and diabetes, which is more evident for certain site-specific cancers. Although there is increasing evidence that strongly indicates an augmented risk of cancer in diabetic patients, several confounding factors complicate the ability to precisely assess the risk. Mainly in insulin-resistant states (such as in type 2 diabetes mellitus and in metabolic syndrome), direct associations between obesity-related hyperinsulinemia and increasing circulating insulin-like growth factor-1 (IGF-1) levels have been implicated as key factors in the mechanisms involved in carcinogenesis. Whilst anti-diabetic drugs can increase the cancer risk, anti-proliferative drugs may cause diabetes or aggravate pre-existing diabetes. Additionally, an increasing number of targeted anti-cancer therapies may interfere with the pathways shared by IGF-1 and insulin receptors, showing a adverse effect on glucose metabolism through various mechanisms. Although there is a requirement for large-scale randomized evidence, the present review summarizes the majority of the epidemiological association studies between diabetes and various types of cancer, discussing the pathophysiological mechanisms that may be involved in promoting carcinogenesis in diabetes and the potential impact of different anti-diabetic therapies on cancer risk.

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“…1,2 Current researches show that especially pancreatic, liver, endometrial, colorectal, bladder and breast cancer incidences are increased by the presence of diabetes. 3,4 Multiple and complex mechanisms were postulated for the association between diabetes and cancer. These associations could be causal or because of common risk factors since type 2 diabetes and cancer are common chronic disorders.…”

Section: Type 2 Diabetes Mellitus and Cancermentioning

confidence: 99%

Metformin: Hype or Hope for Cancer

Nar¹

2017

UHOD

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Current studies show that especially pancreatic, liver, endometrial, colorectal, bladder and breast cancer incidences are increased by the presence of type 2 diabetes mellitus (T2DM). Possible links between T2DM and cancer include hyperinsulinemia, dysregulation of adipocytokines and hyperglycemia as well as shared confounding risk factors. There is evidence emerging from experimental and clinical studies that metformin can play a crucial anti-cancereous role. Since 2005, multiple studies showed the association between metformin and the reduction of risk in cancers of pancreas, colorectal, stomach, liver, breast and esophagus in diabetes cases. It was also claimed to improve survival in some cancers. Metformin is an insulin sensitizer and mainly acts through inhibiting hepatic gluconeogenesis by activating LKB1/AMP-activated protein kinase (AMPK). Metformin was found to have anti-cancerous and antimetastatic effects mainly through activating AMPK dependent and independent signaling; inhibiting mTOR, MAPK, HER2, NF-κB, IGF signaling pathways and with its possible immuno-modulatory effects. Further studies are needed to evaluate the potential of metformin as adjuvant therapy for cancer especially in non-diabetic patients. Keywords: Type 2 diabetes mellitus, Cancer, Metformin ÖZET Metforminin Kanserdeki Muhtemel Rolü: Aldatmaca mı Yoksa Gerçek bir Umut mu?Son dönemde yapılan çalışmalar, tip 2 diabetes mellitus (T2DM) varlığında özelllikle pankreas, karaciğer, endometrium, kolorektal, mesane ve meme kanseri insidanslarının arttığını göstermektedir. T2DM ve kanser arasındaki muhtemel bağlantılar; hiperinsülinemi, adipositokinlerin regülasyonunda sorunlar ve hiperglisemi ile birlikte paylaşılan karıştırıcı risk faktörlerini kapsamaktadır. Deneysel ve klinik çalışmalar metforminin çok önemli anti-kanseröz etkileri olduğunu ispatlamaktadır. 2005'den itibaren yapılan çok sayıda çalışma, diyabetik olgularda metformin ile pankreas, kolorektal, mide, karaciğer, meme ve ösefagus kanser riskinde azalma arasında ilişkiyi göstermiştir. Bazı kanserlerde sürviyi arttırdığı da iddia edilmektedir. Metformin, başlıca etkisini LKB1/AMP-activated protein kinase (AMPK) aktivasyonu aracılığı ile hepatik glukoneogenezi inhibe ederek insülin duyarlılığını arttıran bir ilaçtır. Metforminin, AMPK bağımlı ve bağımsız sinyaller aracılığı ile mTOR, MAPK, HER2, NF-κB, IGF sinyal yolaklarını inhibe ederek ve muhtemel immün-modülatuvar etkileri ile anti-kanseröz ve anti-metastatik etkiler gösterdiği saptanmıştır. Adjuvan kanser tedavisinde, özellikle diyabetik olmayan hastalarda metforminin etkilerini değerlendirmek için daha fazla çalışmaya gereksinim vardır.Anahtar Kelimeler: Tip 2 diabetes mellitus, Kanser, Metformin

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Diabetes mellitus: influences on cancer risk

Cited by 56 publications

References 137 publications

Proliferation and metastatic potential of endometrial cancer cells in response to metformin treatment in a high versus normal glucose environment

Proliferation and metastatic potential of endometrial cancer cells in response to metformin treatment in a high versus normal glucose environment

Diabetes and cancer: A critical appraisal of the pathogenetic and therapeutic links

Metformin: Hype or Hope for Cancer

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