Mechanism of Action of Metformin: Insulin Receptor and Postreceptor Effects in Vitro and in Vivo*

Abstract

Metformin (Met) is a biguanide oral hypogly-cemic agent used in the treatment of noninsulin-dependent diabetes mellitus (NIDDM). To define whether the glucose-lowering effects are mediated via alterations of insulin receptors, the effects of Met in vitro in rat adipocytes and in vivo in patients with poorly controlled NIDDM were studied. In vitro exposure of ratadipose tissue to metformin for 20 h resulted inasignificant increase ininsulin binding (mean±SEM percent specific [¹²⁵I]insulin bound per 10⁵ adipocytes: control, 1.35 ± 0.13; Met, 1.69± 0.18;P < 0.02). No change occurred after 2 h of exposure or less. In contrast, after only 1 hof preincubation, Met alone stimulated [U-¹⁴C]glucose oxidation by 58 ± 15.5% (P < 0.01). Met did not stimulate glucose oxidation inthe presence ofa high insulin concentration. For the in vivo studies, oral glucose tolerance tests and monocyte [¹²⁵I]insulin binding assays were performed before and after 7 days of Mettreatment (2 g/day) in 18 patients with poorly controlled NIDDM. All patients responded to Met with a decrease in fasting and postglucose plasma glucose concentra-tions, but no change ininsulin concentrations [pre-Met us. post-Met: fasting plasma glucose, 210± 10vs. 157± 11 mg/dl (P < 0.001); fasting plasma insulin, 20.3± 3.1 us. 18.4± 2.0μU/ml]. When insulin binding was examined, 8 patients with decreased binding each responded to Met with a 50%or greater increase (group 1), while 10 patients with normal binding had no increase after treatment (group 2). However, both groups had similar lowering of glucose concentrations [fasting plasma glucose: group 1,205± 19 us. 153± 20(P< 0.001); group 2,214± 11 us. 160 ± 13(P < 0.001)]. We conclude that 1) Met hasan acute insulin-like effect in vitro independent of its ability to increase insulin binding; 2) Met acts in vivo predominantly at a postre-ceptor site tolower plasma glucose; 3)theglucose-lowering effect i s independent ofpretreatment insulin binding status; and 4) the increase in insulin binding after Met treatment in patients with NIDDM andlow insulin binding occurs without changes n i insulin concentrations.