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 mg) for 4 months. RESULTS -Glucose was clamped before and after therapy at ϳ5 mmol/l, insulin raised to ϳ180 pmol/l, C-peptide suppressed with somatostatin, glucagon replaced at ϳ75 pg/ml, and glycerol maintained at ϳ200 mmol/l to ensure
... /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 Ϯ 3 vs. 24 Ϯ 2 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) or metformin (22 Ϯ 2 vs. 24 Ϯ 3 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ). In contrast, pioglitazone enhanced (P Ͻ 0.01) insulin-induced suppression of both glucose production (6.0 Ϯ 1.0 vs. 0.2 Ϯ 1.6 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and gluconeogenesis (n ϭ 11; 4.5 Ϯ 0.9 vs. 0.8 Ϯ 1.2 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Metformin did not alter either suppression of glucose production (5.8 Ϯ 1.0 vs. 5.0 Ϯ 0.8 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) or gluconeogenesis (n ϭ 9; 3.7 Ϯ 0.8 vs. 2.6 Ϯ 0.7 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Insulin-induced suppression of free fatty acids was greater (P Ͻ 0.05) after treatment with pioglitazone (0.14 Ϯ 0.03 vs. 0.06 Ϯ 0.01 mmol/l) but unchanged with metformin (0.12 Ϯ 0.03 vs. 0.15 Ϯ 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.