Metformin is a biguanide widely used for the therapy of type 2 diabetes mellitus. It has been shown that this compound ameliorates hyperglycemia without promoting insulin secretion, causing weight gain or generating hypoglycemia. Convincing data place energy metabolism at the center of metformin’s mechanism of action in diabetes, which may also be of importance in cardiovascular diseases and cancer.
Several different mechanisms are included in the reduction of serum glucose level by metformin without increasing insulin secretion, predominantly via non-pancreatic pathways. The compound is often called insulin sensitizer as it increases the effects of insulin. Metformin also suppresses the endogenous glucose production in the liver by reducing the rate of gluconeogenesis with a little impact on cellular ATP levels.
AMP-activated protein kinase (AMPK) represents a target capable of mediating the beneficial metabolic effects of metformin. AMPK is a multisubunit enzyme that is recognized as a major regulator of lipid biosynthetic mechanisms due to its role in the phosphorylation and subsequent inactivation of pivotal enzymes (such as acetyl-CoA carboxylase). A plethora of pharmacological and genetic studies demonstrate that AMPK is required for maintaining glucose homeostasis.
Recent research strongly suggests that AMPK has a wider role in metabolic regulation, which includes muscle glucose uptake, fatty acid oxidation, expression of specific gluconeogenic genes (such as G6Pase) and glucose-stimulated genes linked to hepatic lipogenesis – including fatty acid synthase, Spot-14 and pyruvate kinase. Thus it is an ideal therapeutic target for type 2 diabetes mellitus.
Chronic activation of AMPK may also induce the expression of muscle hexokinase and glucose transporters, mimicking the effects of extensive exercise training. Metformin also showed protective properties against diabetic complications, especially by reducing the diabetes-related death rate.
Polycystic ovary syndrome
Women with polycystic ovary syndrome (PCOS) present with diverse phenotypic and clinical features that may guide therapeutic options for metabolic protection and ovulation induction. Eventual presence of hyperinsulinemia is an important parameter to decide whether or not to initiate metformin therapy to women with PCOS, in order to prevent or delay the onset of type 2 diabetes mellitus.
Lifestyle interventions such as dietary improvement and aerobic exercise remain the cornerstone of effective long-term health improvement for overweight women with PCOS. Still, studies have shown that metformin improves the ovulation, hyperandrogenisim and abnormal lipid profile in these patients. Based on these data, the use of metformin is often recommended for the treatment of metabolic syndrome, which may act as a suitable alternative to the oral contraceptive pills.
Metformin should be considered as a therapy of choice prior to laparoscopic ovarian drilling or gonadotrophin injection therapy. On the other hand, more research is needed in order to define this agent's role in improving long term health outcomes for women with PCOS - including the prevention of diabetes and cardiovascular disease.
Various preclinical studies have shown reliable anti-tumor effects for metformin in different animal models. There is also a strong beneficial and antiproliferative effects on breast, ovarian, prostate, lung, pancreatic, colon and breast cancers, which was confirmed in clinical trials for the latter three malignancies.
It was observed that in the early stage breast cancer of non-diabetic women metformin reduced fasting insulin by 22% and improved several metabolic parameters. Large case-control studies showed that the risk of pancreatic cancer in group receiving metformin treatment is 62% lower than in placebo group.
Anticancer metabolic effects of metformin also occur through a direct modulation of metabolic genes and microRNAs (miRNAs). Currently, there are numerous trials underway with metformin as the potential drug in prostate cancer patients receiving androgen deprivation therapy, as well as in patients with small benign thyroid nodules and insulin resistance.
Metformin was also employed as an adjuvant therapy in cancer patients, and most of the cancer clinical trials of metformin use the doses which are typical for treating diabetes. Diabetes prevention and regulation of circadian clock represent future therapeutic perspectives for metformin.