We explored the mechanisms by which a 4‐month, placebo‐controlled pioglitazone treatment (45 mg/day) improves glycemic control in type II diabetic patients (T2D, n=27) using physiological testing (6‐h mixed meal) and a triple tracer technique ([6,6‐²H₂]glucose infusion, ²H₂O and [6‐³H]glucose ingestion) to measure endogenous glucose production (EGP), gluconeogenesis (GNG), insulin‐mediated glucose clearance and β‐cell glucose sensitivity (by c‐peptide modeling). Compared to sex/age/weight‐matched non‐diabetic controls, T2D patients showed inappropriately (for prevailing insulinemia) raised glucose production (1.05[0.53] vs 0.71[0.36]mmol min⁻¹ kg_ffm⁻¹ pM, P=0.03) because of enhanced GNG (73.1±2.4 vs 59.5±3.6%, P<0.01) persisting throughout the meal, reduced insulin‐mediated glucose clearance (6[5] vs 12[13]ml min⁻¹ kg_ffm⁻¹ nM⁻¹, P<0.005), and impaired β‐cell glucose‐sensitivity (27[38] vs 71[37]pmol min⁻¹ m⁻² mM⁻¹, P=0.002). Compared to placebo, pioglitazone improved glucose overproduction (P=0.0001), GNG and glucose underutilization (P=0.05) despite lower insulinemia. GNG improvement was quantitatively related to raised adiponectin. β‐cell glucose sensitivity was unchanged. In mild‐to‐moderate T2D, pioglitazone monotherapy decreased fasting and post‐prandial glycemia, principally via inhibition of gluconeogenesis, improved hepatic and peripheral insulin resistance.

Clinical Pharmacology & Therapeutics (2007) 81, 205–212. doi:10.1038/sj.clpt.6100034