Effects Of Pioglitazone On β-Cell Function And Endothelial Function In Metabolic Syndrome Patients With Impaired Glucose Tolerance

Objective: We conducted the present study in patients with metabolic syndrome who have impaired glucose tolerance(IGT) to determine the potential effects of a thiazolidinedione (pioglitazone) on beta-cell function and endothelial function and sought to explore the possible mechanisms.Subjects and methods: 24 subjects (14 women and 10men, age: 52±10 yr, body mass index: 26.3±2.5 Kg/m~2) with IGT and metabolic syndrome were treated with pioglitazone 30mg once daily for 4 months. Ischeamic cardiovascular or cerebrovascular or peripheral vascular disease, taking medication known to alter glucose metabolism, hyperuricemia, significant liver or renal impairment were considered exclusion criteria. At baseline, each subject underwent an intravenous glucose tolerance test (IVGTT), the acute insulin response (AIR), glucose disappearance rates (coefficients K) and the ratio of incremental concentrations for insulin and glucose(AI/AG) were calculated according to IVGTT results. Hyperglycemic clamp was performed on 12 subjects to determine the second-phase insulin response (2ndIR), insulin sensitivity index(ISI) and glucose infusion rate (M), whereas euglycemic clamp was conducted on the other 12 subjects to measure glucose depositrate(GDR). Plasma glucose, insulin, C peptide, free fatty acid(FFA) and proinsulin levels were also monitored in all patients. On the other hand, high-resolution ultrasound images were used to assess the endothelium dependant or independent vasodilation in the brachial artery. And fasting blood samples were collected to measure the serum concentrations of malondialdehyde(MDA), tripeptide glutathione(GSH), high-sensitivity C-reactive protein(hs-CRP) and the activity of plasminogen activator inhibitor-l(PAI-l). The same protocol was repeated after therapy.Results: Acute insulin response was unchanged (500.2 + 308.5 u U min/ml vs. 559.7 + 230.7 u U. min/ml, P=0.25) after pioglitazone treatment, whereas the value of AI/AG increased significantly in the first 10 minutes of IVGTT (P<0.05). The second-phase insulin response and glucose infusion rate during the last hour of hyperglycemic clamp were both demonstrated marked increments(64.7 + 18.8uU/ml vs. 70.8 + 22.7 u U/ml, P<0.01 and 7.62 + 2.57mg/Kg.min vs. 9.41+2.08mg/Kg.min, PO.01 respectively). And a significant decrease in fasting proinsulin level was observed [14.2(7.2-19.9) pmol/Lv5.5.3(4.0-9.9) pmol/L,P<0.001]. Pioglitazone therapy also resulted in significant improvements of K and ISI values(1.75 + 0.58 vs.2.08 + 0.62, PO.01 and 12.0 + 3.5mg.mL/Kg.min. n U vs. 14.2 + 4.7mg.mL/Kg.min. y U, P<0.05, respectively). And the increment of glucose desposit rate was great too(8.32±2.31mg/Kg.m2 vs. 9.49 + 2.22mg/Kg.m2, P<0.01). At the same time, plasma glucose, insulin, C peptide and FFA levels reduced markedly. A highly significant relationship was observed between change in the second-phase insulin response and change in K value(r=0.682, P = 0.021). In addition, endothelium dependant vasodilation improved significantly(6.98±3.34% w.10.00±2.18%, P <0.01) and endothelium independant vasodilation was not changed after treatment. The level of MDA reduced markedly (4.51±1.27 nmol/mL vj.3.86±1.44 nmol/mL P<0.01), whereas serum GSH concentration had a moderate increase (216.32±29.36mg/mL vs. 228.3 l±29.13mg/mL, P=0.085). Both hs-CRP level and PAI-1 activity were significantly lower posttreatment compared to pretreatment[3.60mg/L (0.1-7.54mg/L)vs.0.48mg/L(0.1-4.07mg/L), PO.01 and 1.12±0.19AU/mL vs. 1.05 ± 0.18 AU/mL, P = 0.048, respectively]. We found that the improvement of endothelium independant vasodilation was strongly associated with the changes in GSH and CRP concentrations (r=0.469, P=0.032 and r=-0.581, P=0.011, respectively).Conclusions: In metabolic syndrome patients with IGT, short-term pioglitazone therapy improved beta-cell dysfunction, possibly by lowering insulin resistance. Furthermore, the treatment ameliorated endothelial dysfunction and this improvement was related to its antioxidant and anti-inflammatory properties. Our findings suggest thiazolidinedione mihgt be able to prevent or delay type 2 diabetes and its macrovascular complication, but long-term prospective studys are needed to verify this.