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Comparison of the Effects of Pioglitazone and Metformin On Hepatic and Extra-Hepatic Insulin Action in People with Type 2 Diabetes

¹Division of Endocrinology, Diabetes, Metabolism & Nutrition, Mayo Clinic College of Medicine, Rochester, MN
² Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX
³ Division of Clinical and Molecular Endocrinology, Case Western Reserve University School of Medicine, Cleveland, OH
⁴ Chaim Sheba Medical Center, Tel-Hashomer, Israel

Objective: To determine mechanisms by which pioglitazone and metformin effect hepatic and extra-hepatic insulin action.

Design: 31 subjects with type 2 diabetes were randomly assigned to pioglitazone (45 mg) or metformin (2000 mg) for four 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/min) or metformin (22 ± 2 vs. 24 ± 3 µmol/kg/min). 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/min) and gluconeogenesis (n=11: 4.5 ± 0.9 vs.0.8 ± 1.2 µmol/kg/min). Metformin did not alter either suppression of glucose production (5.8 ± 1.0 vs. 5.0 ± 0.8 µmol/kg/min) or gluconeogenesis (n=9: 3.7 ± 0.8 vs. 2.6 ± 0.7 µmol/kg/min). Insulin induced suppression of free fatty acids was greater (p<0.05) following 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.

Key Words: gluconeogenesis • glycogenolysis • insulin resistance • free fatty acids

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