Comparison of the Effects of Pioglitazone and Metformin on Hepatic and Extra-Hepatic Insulin Action in People With Type 2 Diabetes.

OBJECTIVE--To determine mechanisms by which pioglitazone and metformin effect hepatic and extra-hepatic insulin action. RESEARCH DESIGN AND METHODS--Thirty-one subjects with type 2 diabetes were randomly assigned to pioglitazone (45 mg) or metformin (2,000 rag) for 4 months. RESULTS--Glucose was clamped before and after therapy at ∼5 mmol/l, insulin raised to ∼180 pmol/l, C-peptide suppressed with somatostatin, glucagon replaced at ∼75 pg/ml, and glycerol maintained at ∼200 mmol/l to ensure comparable and equal portal concentrations on all occasions. Insulin-induced stimulation of glucose disappearance did not differ before and after treatment with either pioglitazone (23 ± 3 vs. 24 ± 2 µmol ⋅ kg-1 ⋅ min-1) or metformin (22 ± 2 vs. 24 ± 3 µmol ⋅ kg-1 ⋅ min-1). In contrast, pioglitazone enhanced (P < 0.01) insulin-induced suppression of both glucose production (6.0 ± 1.0 vs. 0.2 ± 1.6 µmol ⋅ kg-1 ⋅ min-1) and gluconeogenesis (n = 11; 4.5 ± 0.9 vs. 0.8 ± 1.2 µmol ⋅ kg-1 ⋅ min-1. Metformin did not alter either suppression of glucose production (5.8 ± 1.0 vs. 5.0 ± 0.8 µmol ⋅ kg-1 ⋅ min-1) or gluconeogenesis (n = 9; 3.7 ± 0.8 vs. 2.6 ± 0.7 µmol ⋅ kg-1 ⋅ min-1). Insulin-induced suppression of free fatty acids was greater (P < 0.05) after treatment with pioglitazone (0.14 ± 0.03 vs. 0.06 ± 0.01 mmol/l) but unchanged with metformin (0.12 ± 0.03 vs. 0.15 ± 0.07 mmol/l). CONCLUSIONS--Thus, relative to metformin, pioglitazone improves hepatic insulin action in people with type 2 diabetes, partly by enhancing insulin-induced suppression of gluconeogenesis. On the other hand, both drugs have comparable effects on insulin-induced stimulation of glucose uptake. Diabetes 57: 24-31, 2008 [ABSTRACT FROM AUTHOR]