IN-VIVO METFORMIN TREATMENT AMELIORATES INSULIN-RESISTANCE - EVIDENCEFOR POTENTIATION OF INSULIN-INDUCED TRANSLOCATION AND INCREASED FUNCTIONAL-ACTIVITY OF GLUCOSE TRANSPORTERS IN OBESE (FA FA) ZUCKER RAT ADIPOCYTES/

To examine the cellular mechanism of the antihyperglycemic action of i n vivo metformin (M) we used an animal model of severe insulin resista nce, the genetically obese (fa/fa) Zucker rat. The animals were treate d with or without M (250 mg/kg . day) which was supplied with the drin king water. Three weeks of in vivo M-treatment had no effect on body w eight and several blood lipid parameters, but markedly reduced plasma insulin levels by 45% (-M: 2932 +/- 166 vs. +M: 1614 +/- 85 pmol/liter , P < 0.01); plasma glucose was slightly but significantly decreased b y 8.3% (-M: 7.2 +/- 0.2 vs. +M: 6.6 +/- 0.16 mmol/liter, P < 0.05). Ad ipocytes were isolated and incubated with or.without insulin. In vivo M-treatment had no effect on basal 3-O-methylglucose uptake. In contra st, in vivo M-treatment increased insulin-stimulated glucose transport by 2.6 +/- 0.6-fold (P < 0.01). Measurement of cell surface insulin r eceptors revealed no effect of M on neither specific [I-125]insulin bi nding nor on insulin receptor kinase activity. Insulin-mediated transl ocation of both GLUT1 and GLUT4 glucose transporters was enhanced by i n vivo M-treatment, GLUT1 by 26.1%, GLUT4 by 30.5%. To fully account f or the M-induced increment of insulin-stimulated glucose transport (2. 6-fold), these data suggest that M increased the functional activity o f glucose transporters. We conclude that amelioration of insulin resis tance in (fa/fa) Zucker rats after 3 weeks of in vivo M-treatment is a ssociated with 1) a marked reduction of in vivo hyperinsulinemia, 2) a n increase of insulin-stimulated glucose transport in adipocytes; 3) t his increase of insulin-stimulated glucose transport is accompanied wi th both a potentiation of insulin-induced translocation of GLUT1 and G LUT4 glucose transporters from an intracellular pool to the plasma mem brane as well as increased functional activity of plasma membrane gluc ose transporters. 4) This M-effect seems to be independent of de novo glucose transporter synthesis, since total cellular GLUT1 and GLUT4 gl ucose transporter number were uneffected by M. 5) These results strong ly suggest a direct action of M at the level of glucose transport, sin ce neither tracer insulin binding nor insulin receptor kinase activity were significantly altered by M.