Abstract

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 mg) 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.