REVIEW

Impactul metforminului în tratamentul şi evoluţia pacienţilor oncologici cu diabet zaharat de tip 2

 The impact of metformin in the treatment and evolution of oncological patients with type 2 diabetes

First published: 27 octombrie 2017

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/OnHe.40.3.2017.1157

Abstract

Metformin is an oral antidiabetic agent widely used in the treatment of type 2 diabetes mellitus, where it is commonly used as an insulin sensitizer since not only it has a function of lowering blood sugar, but also of reducing insulin resistance associated to hyperinsulinemia. It has been recently demonstrated that the use of metformin as an insulin sensitizer reduces incidence, progression and even mortality through cancer (Evans JM et al., 2005), while insulin and sulphonylureas have been associated with high incidence and mortality. Although the exact mechanism by which metformin has a protective role with respect to neoplasia is not precisely known, it has been established that its role of inhibiting cancerogenesis is due to its impact on the AMPK/LKB1 metabolism. A significant number of studies mention the beneficial effect that metformin has on the treatment and prognosis of certain neoplastic localizations (mammary, pancreas, colorectal, hepatic), most frequently by interfering with cell cycle regulation. Thus, the study of the effects of oral anti-diabetic drugs is worth being continued, as they can bring multiple benefits to administered oncological treatments. 
 

Keywords
metformin, cancer, type II diabetes mellitus

Rezumat

Metforminul este un agent antidiabetic oral utilizat pe scară largă în tratamentul diabetului zaharat de tip 2, unde este utilizat în mod obișnuit ca agent de sensibilizare la insulină, deoarece nu numai că are o funcție de scădere a zahărului din sânge, ci și de reducere a hiperinsulinemiei asociate rezistenței la insulină. Recent, s-a demonstrat că utilizarea metforminului ca agent de sensibilizare la insulină reduce incidența, progresia și chiar mortalitatea prin cancer (Evans JM et al., 2005), în timp ce insulina și sulfonilureea au fost asociate cu incidență și mortalitate ridicate. Deși mecanismul exact prin care metforminul are un rol de protecție în ceea ce privește neoplazia nu este exact cunoscut, s-a stabilit că rolul său de inhibare a cancerogenezei se datorează im­pac­tului asupra metabolismului AMPK / LKB1. Un număr sem­ni­ficativ de studii menționează efectul benefic pe care met­forminul îl are asupra tratamentului și prognosticului anumitor localizări neoplazice (mamare, pancreas, colorectal, hepatic), cel mai frecvent prin interferența cu reglarea ciclului celular. Astfel, studiul efectelor medicamentelor antidiabetice orale merită să fie continuat, deoarece acestea pot aduce beneficii multiple tratamentelor oncologice administrate. 
 

Cancer and diabetes are on the list of the top 10 causes of global mortality, thus representing a real public health issue (WHO, 2011), which determines major costs for the population, both in terms of treatment expenditures and workforce shortages (ADA, 2008).
A significant number of cancers are attributed to the sedentary lifestyle that entails the early appearance of metabolic syndrome and insulin resistance, along with the onset of diabetes, cardiovascular disease and cancer. Hyperinsulinism negatively affects the prognosis of oncological patients and is an independent risk factor for several types of cancers, thus explaining the frequent association of obesity with neoplasia.
Insulin can promote cancerogenesis by the direct effect on epithelial tissues that act on the insulin receptor family (Belfiore et al., 2009) or indirectly by affecting the levels of other modulators such as IGF-1, sex hormones and adipokines (Wolf I. et al., 2005; Pollak M.N. et al., 2004). Recent evidence indicates that the abnormally high level of proliferative activity of premalignant and malignant cells requires high levels of nutrients to meet increased energy demand and protein biosynthesis demands (Vander Heiden M.G., 2009).
Following epidemiological studies, it was established that patients with type 2 diabetes have an increased risk of developing some types of solid and haematological malignancies, including non-Hodgkin’s lymphoma or bladder, endometrium, liver, pancreas, or mammary gland tumors - through hyperinsulinism and the mechanism of IGF 1 system activation (Pollak, 2008).
Metformin is a widely used oral antidiabetic agent in the treatment of type 2 diabetes mellitus, where it is commonly used as an insulin sensitizer since it has not only a function of lowering blood sugar, but also of reducing insulin resistance associated by hyperinsulinemia. This medicine acts as a growth inhibitor, rather than an insulin sensitizer with respect to epithelial cells (Zakikhani M. et al., 2006).
It has been recently demonstrated that the use of metformin as an insulin sensitizer reduces incidence, progression and even mortality through cancer (Evans J.M. et al., 2005), while insulin and sulphonylureas have been associated with high incidence and mortality.
Although the exact mechanism by which metformin has a protective role with respect to neoplasia is not precisely known, it has been established that its role of inhibiting cancerogenesis is due to its impact on the AMPK/LKB1 metabolism – either directly, by inhibiting the activation of adenosine monophosphate kinase, or indirectly, by lowering the level of insulin in the systemic circulation. Regarding the direct effects of metformin, LKB1, which is a downstream signaling molecule in the AMPK pathway, functions as a tumor suppressor protein (p. 53). Thus, AMPK-induced metformin activation could lead to increased LKB1-mediated tumor suppression which would directly inhibit cell proliferation and colony formation and promote partial cell cycle arrest in cancer cell lines (Alinova et al., 2009).
Metformin can exert similar antineoplastic effects through an indirect mechanism: metformin activates the AMPK pathway in hepatocytes and skeletal muscles. Thus, it inhibits hepatic gluconeogenesis and glucose efflux from skeletal muscles and consequently reduces circulating glucose and insulin concentrations, both contributing to cancerogenesis (Shaw R.J. et al., 2005).
Metformin is the first option in the treatment of type 2 diabetes mellitus, prescribed as a single agent for patients in the initial stage of the disease, or in combination with other oral antidiabetics in patients with advanced disease (Kowall B. et al., 2015). Metformin has been shown to reduce the incidence of type 2 diabetes in patients at high risk (Knowler W.C. et al., 2002) with beneficial effects for at least 10 years (Knowler W.C. et al., 2009). It is an inexpensive and well tolerated drug, whose side effects are very rare, which determine its widespread use.
The idea that the use of metformin is associated with a decrease in malignancy risk for certain organs can be explained by the fact that metformin works by using the nutrients needed to produce a new cell, starting from a proliferative cell (Vander Heiden M.G., 2009). Metformin appears to be associated with a decrease of cancer risk in the colon, pancreas and mammary gland, because diabetes or elevated blood glucose and insulin levels play an important role in the development of these types of tumors (Xue F., Michels K.B., 2007; Raimondi S. et al., 2009). Regarding colon cancer, it has been shown that metformin potentiates the effects of hypercaloric nutrition that stimulate tumor growth (Zakikhani M. et al, 2008).
In the case of mammary gland neoplasm, it was observed that diabetic patients treated with metformin had a higher rate of complete response to neoadjuvant chemotherapy than the patients treated with other types of antidiabetic agents. In patients differentiated by many variables - Body Mass Index, stage of the disease, degree of tumor differentiation, HER2 status, estrogen and progesterone receptors, age and use of neoadjuvant treatment with taxanes, metformin remained an independent predictor of the therapeutic response. The use of metformin was a much better predictor than certain tumor characteristics, including differentiation, hormone receptor status, or overexpression of HER2 neu (Goodwin P., Ligibel J., Stambolic Vuc, 2009).
Breast cancer cells can be protected against growth inhibition induced by metformin by diminishing RNA against AMP-kinase. This demonstrates that metformin-activated AMP-kinase, recently demonstrated to be necessary for the metformin inhibition of gluconeogenesis in hepatocytes, is also involved in the metformin-induced growth inhibition of epithelial cells (Zakikhani M. et al., 2006).
In the case of patients diagnosed with bronchopulmonary neoplasm, whose frequency is significant with associated type 2 diabetes mellitus, it has been shown that their response to treatment is influenced by metformin by increasing sensitivity to external irradiation, given that irradiation is a known inducer of AMPK, and metformin can modulate this effect, thus improving the response to radiotherapy. This hypothesis was tested using cell lines from the breast, lung and prostate. After confirming induction of AMPK in these cell lines with irradiation treatment independent of LKB1 status, induction of resistance to ionizing radiation by the AMPK inhibitor was demonstrated. It has also been demonstrated that metformin increases sensitivity to ionizing radiation, increase assessed by increasing the duration of irradiation after exposure to 2 Gy, supporting this hypothesis (Sanli T. et al., 2010).
According to some studies, in patients with non-small cell lung cancer and type 2 diabetes mellitus, chemotherapy in combination with metformin increased the survival rate compared to the same chemotherapy, but in combination with insulin or other oral anti-diabetic treatments (8.4 months for chemotherapy + metformin versus 4.7 months for chemotherapy + insulin versus 6.4 months for chemotherapy + other oral anti-diabetic) (Tan B. et al., 2011).
The use of metformin as a prevention and treatment agent of certain neoplastic locations has also gained considerable interest in hepatic neoplasms, due to the increased frequency of diabetes associated with this type of cancer. 
Some studies thus confirm the improvement in survival rate of patients with primitive hepatic neoplasms associated with type 2 diabetes and treated with metformin (Shu-Juan Ma et al., 2016).
A significant number of studies on pancreatic neoplasm and the treatment of type 2 diabetes discuss the effect that metformin has on inhibiting the cell proliferation, migration and invasion process by destroying neoplastic stem cells, intervening at the microRNA level. 
Oral administration of metformin in diabetic patients suffering from pancreatic neoplasm increased the prognosis of oncologic treatment in these patients. By its mode of action, in the case of the pancreas, metformin decreased the expression of neoplastic stem cell markers: CD 44, EpCAM, EZH2, Notch-1, Nanog and Oct4 (Bao B. et al., 2012). Studies in diabetic patients treated with different classes of oral antidiabetic agents have shown a lower risk of developing pancreatic adenocarcinoma if the anti-diabetic treatment was metformin (Yu-Yang, 2009).
Also, in the case of rectal neoplasm, as well as the aforementioned neoplastic localizations, the studies conducted so far associate the use of metformin with a low rate of appearance of this type of neoplasia. As well as for the bronchopulmonary neoplasm, the mechanism of action of metformin coincides with that from colorectal neoplasm. Metformin decreases AMPK, which is intended to activate the mTOR pathway that has been shown to influence cellular proliferation (Caroline Cao et al., 2014).
The study of metformin role as an oral antidiabetic in the management of neoplastic disease in patients with type 2 diabetes is particularly important and requires further consideration, given the studies that perpetuate the idea that metformin reduces inflammation and prevents cancer development, or potentiates oncological treatment where the oncological disease has already begun. 
 

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