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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

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

Address correspondence and reprint requests to Robert A. Rizza, MD, Mayo Clinic, 200 1st St. SW, Room 5-194 Joseph, Rochester, MN 55905. E-mail: rizza.robert{at}mayo.edu

Key Words: HMW, high molecular weight

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.

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