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Thiazolidinediones (TZDs) improve glycemic control and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). There is growing evidence from in vivo and in vitro studies that TZDs improve pancreatic β-cell function. The aim of this study was to determine whether TZD-induced improvement in glycemic control is associated with improved β-cell function. We studied 11 normal glucose-tolerant and 53 T2DM subjects [age 53 ± 2 yr; BMI 29.4 ± 0.8 kg/m² fasting plasma glucose (FPG) 10.3 ± 0.4 mM; Hb A1c 8.2 ± 0.3%]. Diabetic patients were randomized to receive placebo or TZD for 4 mo. Subjects received 1) 2-h OGTT with determination of plasma glucose, insulin, and C-peptide concentrations and 2) two-step euglycemic insulin (40 and 160 mU·m-2min-1) clamp with [3-³H]glucose. T2DM patients were then randomized to receive 4 mo of treatment with pioglitazone (45 mg/day), rosiglitazone (8 mg/day), or placebo. Pioglitazone and rosiglitazone similarly improved FPG, mean plasma glucose during OGTT, Hb A1c, and insulin-mediated total body glucose disposal (Rd) and decreased mean plasma FFA during OGTT (all P < 0.01, ANOVA). The insulin secretion/insulin resistance (disposition) index [ΔSR(AUC)/Δglucose(AUC) ÷ IR] was significantly improved in all TZD-treated groups: + 1.8 ± 0.7 (PlO + drug-naive diabetics), +0.7 ± 0.3 (PlO + sulfonylurea-treated diabetics), and 0.7 ± 0.2 (ROSI + sulfonylurea-withdrawn diabetics) vs. -0.2 ± 0.3 in the two placebo groups (P < 0.01, all TZDs vs. placebo, ANOVA). Improved insulin secretion correlated positively with increased body weight, fat mass, and Rd and inversely with decreased plasma glucose and FFA during the OGTT In T2DM patients, TZD treatment leads to improved β-cell function, which correlates strongly with improved glycemic control. [ABSTRACT FROM AUTHOR]

We determined the effect of 48-h elevation of plasma free fatty acids (FFA) on insulin secretion during hyperglycemic clamps in control female Wistar rats (group a) and in the following female rat models of progressive β-cell dysfunction: lean Zucker diabetic fatty (ZDF) rats, both wild-type (group b) and heterozygous for the fa mutation in the leptin receptor gene (group c); obese (fa/fa) Zucker rats (nonprediabetic; group d); obese prediabetic (fa/fa) ZDF rats (group e); and obese (fa/fa) diabetic ZDF rats (group f). FFA induced insulin resistance in all groups but increased C-peptide levels (index of absolute insulin secretion) only in obese prediabetic ZDF rats. Insulin secretion corrected for insulin sensitivity using a hyperbolic or power relationship (disposition index or compensation index, respectively, both indexes of β-cell function) was decreased by FFA. The decrease was greater in normoglycemic heterozygous lean ZDF rats than in Wistar controls. In obese "prediabetic" ZDF rats with mild hyperglycemia, the FFA-induced decrease in 3-cell function was no greater than that in obese Zucker rats. However, in overtly diabetic obese ZDF rats, FFA further impaired β-cell function. In conclusion, 1) the FFA-induced impairment in β-cell function is accentuated in the presence of a single copy of a mutated leptin receptor gene, independent of hyperglycemia. 2) In prediabetic ZDF rats with mild hyperglycemia, lipotoxicity is not accentuated, as the β-cell mounts a partial compensatory response for FFA-induced insulin resistance. 3) This compensation is lost in diabetic rats with more marked hyperglycemia and loss of glucose sensing. [ABSTRACT FROM AUTHOR]