Metformin is a biguanide widely used in the treatment 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 treating diabetes, which may also be of importance in cardiovascular diseases and cancer.
METFORMIN MECHANISM OF ACTION MADE SIMPLE *ANIMATED*
Diabetes mellitus
Several different mechanisms are included in the reduction of serum glucose level by metformin without increasing insulin secretion, predominantly via non-pancreatic pathways. Metformin is often referred to as an insulin sensitizer, as it increases the effects of insulin. Metformin also suppresses endogenous glucose production in the liver by reducing the rate of gluconeogenesis with 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, metformin 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 has also demonstrated protective properties against diabetic complications, especially by reducing the diabetes-related death rate.
Polycystic ovarian syndrome
Women with the polycystic ovarian syndrome (PCOS) present with diverse phenotypic and clinical features that may guide therapeutic options for metabolic protection and ovulation induction. The eventual presence of hyperinsulinemia is an important parameter to decide whether or not to initiate metformin therapy for 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 ovulation, hyperandrogenism, 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 oral contraceptive pills.
Metformin has the potential to 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.
Cancer prevention
Various preclinical studies have shown reliable anti-tumor effects for metformin in different animal models. Metformin has also been associated with 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 has been observed that in 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 a group receiving metformin treatment was 62% lower than in the placebo group.
Anticancer metabolic effects of metformin also occur through 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 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.
References
Further Reading
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