Historical Aspects And Introduction

The glucose-lowering potential of guanides was first described in medieval times when extracts of Galega officinalis (goat's rue or French lilac) were used as treatment of diabetes in Europe (1). In 1957, metformin, a dimethylated biguanide, and phenformin, a phenetylated biguanide were introduced for the therapy of type 2 diabetes mellitus (Fig. 1). Because of the strong association with lactic acidosis, phenformin was withdrawn in the 1970s in most countries including the United States (2). In contrast, metformin continued to be used in Europe, Canada, and many other countries but was not approved by the U.S. Food and Drug Administration until 1995 (3). There is now a large body of data documenting the clinical efficacy of metformin in the treatment of type 2 diabetes (4) and most of its clinical, pharmacological, and basic cellular aspects have been addressed in several excellent reviews published during the past 20 years (5-12). Recently, the U.K. Prospective Diabetes Study (UKPDS) showed that metformin is particularly effective in type 2 diabetic subjects with obesity, a condition commonly associated with insulin resistance (13). Moreover, in essentially all clinical studies the improvement of hyperglycemia with metformin occurred in the presence of unaltered or reduced plasma insulin concentrations, e.g. (14,15). Taken collectively, these findings indicate the potential of metformin as an insulin-sensitizing drug and form the basis for metformin's current role in the treatment of type 2 diabetes (Fig. 2) (16).

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