Metformin ameliorates extreme insulin resistance in a patient with anti-insulin receptor antibodies: description of insulin receptor and postreceptor effects in vivo and in vitro.
The effect of metformin on insulin binding and insulin action in the presence of anti-insulin receptor antibodies was investigated in a case of type B extreme insulin resistance. Oral administration of metformin (1500 mg/d) for 10 days significantly decreased plasma blood glucose and insulin levels and enhanced the hypoglycemic response to exogenous insulin. In vitro preincubation of normal erythrocytes with insulin receptor antibody from the patient plus 4 x 10(-5) mol/l metformin markedly enhanced insulin binding to receptors, compared to cells incubated with antibody alone. This effect was apparent after 2 h, was maximal after 4 h and did not change up to 24 h. Closely similar results were found when human adipocytes were studied. Analysis of binding data confirmed the increase in both receptor number and affinity. One hour exposure of control adipocytes to metformin enhanced basal lipogenesis by more than 30%. Acute exposure of fat cells to the patient's receptor antibodies resulted in a stimulation of glucose transport and a state of severe insulin resistance. The addition of metformin to antibody in preincubation buffer strongly enhanced basal glucose incorporation into lipids, but did not prevent insulin unresponsiveness. It is suggested that metformin increases, possibly through a change in the spatial conformation of insulin receptor within the plasma membrane, the availability of pre-existing receptors to insulin binding and/or decreases the availability of specific epitopes to antibody anchoring. Further, in the model of insulin resistance described here, metformin enhanced the basal rate of glucose transport through a direct insulin-mimicking activity and/or a potentiation of the sensitivity of glucose transport to the antibody.
Di Paolo
S
S
Policlinico, Università di Bari, Italy.
D000273:Adipose Tissue / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology*; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008055:Lipids / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D011972:Receptor, Insulin / Q000276:immunology* / Q000378:metabolism
D001323:Autoantibodies; D007328:Insulin; D008055:Lipids; D008687:Metformin; D011972:Receptor, Insulin