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Type 2 diabetes mellitus [T2DM] is a progressive metabolic disease which requires multiple and frequent treatment plan adjustments during the course of the disease. Conventional therapeutic strategy usually starts with lifestyle interventions supported by prescription of one glucose-lowering drug. When insulin resistance progresses and the monotherapy option becomes insufficient to control plasma glucose, patients are usually switched to a double drug regimen. In the worst case scenario further progression of insulin resistance and decline in endogenous insulin production require administration of exogenous insulin which becomes an unavoidable therapeutic imperative for many T2DM patients [1]. Metformin is the oldest and most widely prescribed first choice anti-diabetic drug representing the group of guanidinebased hypoglycemic agents. Most newly diagnosed T2DM patients are placed on metformin monotherapy which is later supplemented or often substituted by sulphonylureas, thiazolidinediones and dipeptidyl peptidase-4 inhibitors [2]. The antidiabetic properties of guanidine-related compounds were acknowledged for many centuries by the widespread use of G. officinalis (also known as French lilac, Goat’s rue or Italian Fitch) in diabetes care. However, in scientific terms, the hypoglycemic effect of guanidines, in particular the effect of isoamylene guanidine, was first demonstrated by C.K.Watanabe in 1918 [3]. The toxicity of guanidines imposed a significant limit on their pharmacological exploration, until a less toxic biguanidine analog – N,N-dimethylimidodicarbonimidic diamide (metformin) was synthesized in 1922. The discovery of insulin, whose hypoglycemic activity remains unsurpassed as well as the identification of other glucose-lowering compounds, weakened interest towards clinical use of guanidine-related compounds, including metformin, for decades. Therefore, it was not until 1979 that metformin was introduced in Europe and approved for T2DM use by the FDA in 1994. The moderate hypoglycemic activity of metformin resulting in low risk of hypoglycemia is complemented by the wide spectrum of pharmacological activity of the drug. Besides controlling blood glucose, metformin is known to have some “pleiotropic effects” such as reduction of plasma free fatty acids, LDL and VLDL, promotion of body weight loss, decrease in cardiovascular mortality and morbidity, prevention of hepatosteatosis and some anti-neoplastic effect [ 4]. Despite significant clinical research on metformin use in T2DM patients, the molecular mechanisms underlying the anti-diabetic properties of the drug remain surprisingly obscure. It is believed though that hypoglycemic action of metformin reflects its direct effect on the hepatic gluconeogenic pathway and on glucose utilization in peripheral tissues. While most of the hepatic effects of metformin develop due to induction of AMP-activated protein kinase (AMPK) and/or changes in CREBP-binding protein phosphorylation, the effect of metformin on glucose uptake is rather related to enhanced expression of glucose transporters [5,6]. Recent reports have unveiled a variety of new molecular mechanisms to explain the anti-diabetic activity of metformin. Among exciting scientific findings there are newly emerging reports suggesting that metformin can mediate its anti-diabetic activity through the family of proteins called sirtuins. This piece of information comes from the report of Caton PW et al . [7] who described increased levels of SIRT1 protein and its activity in the livers of metformin-treated db/db mice and HepG2 cells, a hepatocyte