Effect of metformin on hepatocyte insulin receptor binding in normal, streptozotocin diabetic and genetically obese diabetic (ob/ob) mice.

The effect of metformin on hepatocyte insulin receptor binding was examined in normal, streptozotocin diabetic and genetically obese diabetic (ob/ob) mice. In normal mice, chronic administration of metformin (60 mg X kg-1 X day-1 for 50 weeks) increased the number of low affinity receptors by 148%. During acute studies, metformin increased (30%) the number of low affinity receptors after 24 h. When metformin was withdrawn after treatment for 96 h, the number of low affinity receptors decreased, approaching control values by 48 h. In severely insulin resistant ob/ob mice, the concentrations of high and low affinity receptors were reduced by 60% and 27%, respectively. A high dose of metformin (240 mg X kg-1 X day-1 for 4 weeks) increased the concentration of high and low affinity receptors in ob/ob mice by 63% and 86%, respectively. However, the hypoglycaemic response to exogenous insulin was not altered. In streptozotocin-diabetic mice, the number of low affinity receptors was increased by 68% compared with normal mice. Metformin (60 mg X kg-1 X day-1 for 10 weeks) did not significantly alter the number of insulin receptors in streptozotocin-diabetic mice, but the hypoglycaemic response to exogenous insulin was improved by 94%. The results raise the possibility that metformin might affect post-receptor sites of insulin action independently of effects at the receptor level.