Effects of Metformin and Rosiglitazone Treatment on Insulin Signaling and Glucose Uptake in Patients With Newly Diagnosed Type 2 Diabetes

Abstract

The effect of metformin or rosiglitazone monotherapy versus placebo on insulin signaling and gene expression in skeletal muscle of patients with newly diagnosed type 2 diabetes was determined. A euglycemic-hyperinsulinemic clamp, combined with skeletal muscle biopsies and glucose uptake measurements over rested and exercised muscle, was performed before and after 26 weeks of metformin (n ‫؍‬ 9), rosiglitazone (n ‫؍‬ 10), or placebo (n ‫؍‬ 11) treatment. Insulin-mediated whole-body and leg muscle glucose uptake was enhanced 36 and 32%, respectively, after rosiglitazone (P < 0.01) but not after metformin or placebo treatment. Insulin increased insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation, IRS-1-associated phosphatidylinositol (PI) 3-kinase activity, and phosphorylation of Akt Ser 473 and AS160, a newly described Akt substrate that plays a role in GLUT4 exocytosis, ϳ2.3 fold before treatment. These insulin signaling parameters were unaltered after metformin, rosiglitazone, or placebo treatment. Expression of selected genes involved in glucose and fatty acid metabolism in skeletal muscle was unchanged between the treatment groups. Low-intensity acute exercise increased insulin-mediated glucose uptake but was without effect on insulin signaling. In conclusion, the insulin-sensitizing effects of rosiglitazone are independent of enhanced signaling of IRS-1/PI 3-kinase/Akt/ AS160 in patients with newly diagnosed type 2 diabetes.

Exercise training increases insulin-stimulated glucose disposal and GLUT4 (SLC2A4) protein content in patients with type 2 diabetes

“…Taken together, these results suggest that AS160 phosphorylation is differentially regulated by insulin and exercise. In type 2 diabetic subjects, AS160 phosphorylation in skeletal muscle is lower during insulin infusion [46] and was unresponsive to low-intensity exercise or rosiglitazone treatment, despite increased insulin-mediated glucose disposal [47]. Here we report that after moderate/highintensity exercise, insulin-stimulated AS160 phosphorylation is unchanged in obese non-diabetic or obese type 2 diabetic subjects.…”

AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3

“…Treatment with metformin increased insulin-induced Akt phosphorylation in cultured HepG2 cells [52] and HGL5 cells [53], as well as in vivo in rat heart [54]. In contrast, metformin reduced Akt phosphorylation stimulated by interleukin-1b or by high glucose [55], whereas Akt phosphorylation was unaltered by metformin treatment in H4IIE cells [56] and in vivo in diabetic muscle [57][58][59]. These mixed results with metformin indicate that context (i.e., cell type and stimulus) as well as possible multiple targets of metformin cause this diversity of effects on Akt phosphorylation.…”

Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats

“…either exercise training in lean or obese animals [43], or rosiglitazone treatment [44,45]. However, these changes were observed after many weeks of treatment, whereas Pgc-1α transfection induced changes within 2 weeks.…”