Effects of Metformin and Rosiglitazone Treatment on Insulin Signaling and Glucose Uptake in Patients With Newly Diagnosed Type 2 Diabetes
A Randomized Controlled Study
Article Figures & Tables
Figures
- FIG. 1.
Schematic representation of the study protocol. A euglycemic-hyperinsulinemic clamp procedure was performed before and after 26 weeks of treatment with metformin, rosiglitazone, or placebo. Euglycemic-hyperinsulinemic conditions consisted of a 160-min insulin infusion. Leg muscle glucose uptake was assessed using PET. The arrow represents the time at which muscle biopsies were obtained. One biopsy was obtained under basal conditions, and two biopsies were obtained after insulin infusion (from rested and exercised leg, respectively).
- FIG. 2.
Whole-body and leg muscle glucose uptake rates. Whole-body glucose uptake (A) and leg muscle glucose uptake over the rested (B) and exercised (C) legs were determined during the euglycemic-hyperinsulinemic clamp procedure before (□) and after (▪) treatment. Leg glucose uptake was assessed across a portion of the vastus lateralis skeletal muscle using PET. Data are means ± SE for 9–11 subjects per group. *P < 0.05, **P < 0.01 for post- vs. pretreatment value. Met, metformin, Rosi, rosiglitazone; Plac, placebo.
- FIG. 3.
IRS-1–associated PI 3-kinase activity in skeletal muscle. Muscle biopsies were obtained under basal (□) or insulin-stimulated conditions in rested (▪) or exercised (
) legs before and after treatment with metformin (A), rosiglitazone (B), or placebo (C). PI 3-kinase activity was measured in IRS-1 immunoprecipitates. Results were quantitated using a PhosphorImager. Data are means ± SE arbitrary units for six to nine subjects per group. *P < 0.05 vs. basal; †P < 0.05 for post- vs. pretreatment for the insulin-stimulated condition. - FIG. 4.
Phosphorylation of Akt in skeletal muscle. Muscle biopsies were obtained under basal (□) or insulin-stimulated conditions in rested (▪) or exercised (
) legs before and after treatment with metformin (A), rosiglitazone (B), or placebo (C). Phosphorylation of Akt kinase was measured by immunoblot analysis using an anti–phospho-Ser473 Akt antibody. Results were quantitated using densitometry. Data are means ± SE arbitrary units for 7–11 subjects per group. *P < 0.05 vs. basal value. - FIG. 5.
Phosphorylation of AS160 in skeletal muscle. Muscle biopsies were obtained under basal (□) or insulin-stimulated conditions in rested (▪) or exercised (
) legs before and after treatment with metformin (A), rosiglitazone (B), or placebo (C). Phosphorylation of AS160 was measured by immunoblot analysis using an anti–phospho-Akt substrate antibody. Results were quantitated using densitometry. Data are means ± SE arbitrary units for seven to nine subjects per group. *P < 0.05 vs. basal, †P < 0.05 for post- vs. pretreatment for the insulin-stimulated condition. - FIG. 6.
Correlation analysis. A: Correlation between insulin-stimulated whole-body glucose uptake (GU) and insulin-stimulated leg muscle glucose uptake in the rested leg in the entire study cohort before pharmacological intervention (r = 0.88, P < 0.001, n = 30). B: Correlation between insulin-stimulated IRS-1–associated PI 3-kinase activity and insulin-stimulated leg muscle glucose uptake in the rested leg before pharmacological intervention (r = 0.57, P < 0.01, n = 21). C: Correlation between insulin-stimulated Akt phosphorylation and insulin-stimulated leg muscle glucose uptake in the rested leg before pharmacological intervention (r = 0.51, P < 0.05, n = 24).
Tables
- TABLE 1
Clinical and metabolic characteristics of the patients
Metformin Rosiglitazone Placebo Pretreatment Posttreatment Pretreatment Posttreatment Pretreatment Posttreatment n (M/F) 9 (6/3) 10 (8/2) 11 (9/2) Age (years) 57.7 ± 2.9 — 58.2 ± 2.1 — 58.6 ± 2.5 — BMI (kg/m²) 28.8 ± 1.3 28.0 ± 1.1* 28.2 ± 1.0 28.2 ± 1.2 29.4 ± 1.3 29.5 ± 1.3 HbA1c (%) 7.1 ± 0.3 6.4 ± 0.3‡ 6.8 ± 0.3 6.4 ± 0.2 6.3 ± 0.1 6.2 ± 0.1 Glucose (mmol/l) 8.3 ± 0.6 7.1 ± 0.4* 7.0 ± 0.3 6.8 ± 0.3 7.2 ± 0.3 7.5 ± 0.3 Insulin (mU/l) 10.8 ± 2.4 8.4 ± 1.3 6.8 ± 0.5 6.4 ± 0.4 10.2 ± 1.8 9.8 ± 1.2 C-peptide (nmol/l) 0.89 ± 0.12 0.61 ± 0.07* 0.72 ± 0.06 0.57 ± 0.05* 0.83 ± 0.09 0.71 ± 0.05* Fasting FFA (μmol/l) 458 ± 71 496 ± 63 596 ± 59 552 ± 86 598 ± 70 511 ± 58 Clamp FFA (μmol/l) 145 ± 26 102 ± 16* 110 ± 14 57 ± 5† 100 ± 20 93 ± 19 Total cholesterol (mmol/l) 4.2 ± 0.2 4.4 ± 0.2 4.9 ± 0.3 5.5 ± 0.4* 4.5 ± 0.3 4.4 ± 0.3 HDL cholesterol (mmol/l) 1.0 ± 0.1 1.1 ± 0.1† 1.1 ± 0.1 1.1 ± 0.1 1.3 ± 0.1 1.3 ± 0.1 LDL cholesterol (mmol/l) 2.6 ± 0.2 2.5 ± 0.2 2.9 ± 0.3 3.7 ± 0.3† 2.7 ± 0.3 2.7 ± 0.3 Triglycerides (mmol/l) 1.4 ± 0.1 1.5 ± 0.2 1.8 ± 0.3 1.5 ± 0.2 1.1 ± 0.1 1.0 ± 0.1 Plasma lactate (mmol/l) 1.0 ± 0.1 1.0 ± 0.1 0.9 ± 0.1 0.8 ± 0.1 0.8 ± 0.1 0.8 ± 0.1 Data are means ± SE.
- *
* P < 0.05,
- †
† P < 0.01,
- ‡
‡ P < 0.001 vs. pretreatment.
- TABLE 2
mRNA expression in skeletal muscle posttreatment
Metformin Rosiglitazone Placebo P value n 9 10 10 Lipid transport and metabolism CD36 1060 ± 186 1027 ± 133 1000 ± 161 NS FAT4 10.5 ± 2.3 10.5 ± 2.3 12.3 ± 4.4 NS ACC-α 2.7 ± 0.6 3.3 ± 0.6 3.4 ± 0.9 NS ACC-β 61 ± 13 65 ± 13 68 ± 12 NS LPL 104 ± 25 253 ± 88 144 ± 28 NS SCD 0.7 ± 0.3 1.4 ± 0.4 0.9 ± 0.2 NS UCP3 420 ± 87 285 ± 46 480 ± 114 NS DGK δ 36 ± 10 30 ± 4 38 ± 14 NS Glucose transport and metabolism GLUT4 145 ± 40 151 ± 35 193 ± 47 NS Hexokinase 2 25 ± 11 28 ± 9 22 ± 8 NS CAP 265 ± 40 281 ± 39 224 ± 33 NS Adiponectin receptor 1 322 ± 49 277 ± 42 244 ± 40 NS Transcription factors PPAR-γ 3.4 ± 0.8 4.2 ± 0.6 5.1 ± 2.0 NS PGC1-α 148 ± 16 169 ± 29 126 ± 15 NS PGC1-β 11.8 ± 2.2 14.4 ± 2.9 17.6 ± 5.6 NS PRC 7.3 ± 1.6 7.3 ± 1.6 7.6 ± 1.9 NS NRF-1 52 ± 14 47 ± 8 70 ± 33 NS FOXO1A 30 ± 5 24 ± 3 28 ± 3 NS SREBP1 33.6 ± 7.7 27.7 ± 4.2 32.3 ± 8.8 NS Data are mean ± SE arbitrary units normalized to GAPDH.
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