Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review

Abstract

Insulin resistance, which manifests itself as endogenous glucose overproduction and reduced insulin-mediated glucose uptake, is a core defect in type 2 diabetes. Metformin and the peroxisome proliferator-activated receptor-gamma agonists, the thiazolidinediones (TZDs), both lower glucose, although their mechanism of action is still subject to debate. This review analyses the evidence relevant to these mechanisms in vivo. A systematic search of MEDLINE identified a total of 42 clinical studies that investigated the effects of TZDs (n=23) and/or metformin (n=19) on endogenous glucose production (using tracer glucose techniques) and peripheral glucose disposal (using the euglycaemic-hyperinsulinaemic clamp) in patients with type 2 diabetes (n=549). The original variables assessed were converted into standardised units and their mean group values were listed separately for open and placebo-controlled studies. Statistical analysis was scarried out, treating mean group values as individual values and comparing results (both as absolute values and percentage changes from baseline) across study categories (open vs placebo-controlled, TZDs vs metformin). Both TZDs and metformin enhance insulin suppression of endogenous glucose production and fasting plasma glucose clearance. TZDs, but not metformin, also improve insulin-mediated glucose uptake at all insulin levels. In patients with type 2 diabetes, metformin improves fasting hepatic insulin sensitivity and glucose clearance; TZDs improve fasting hepatic insulin sensitivity and glucose clearance, and potentiate glucose disposal under insulinised conditions.