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Pioglitazone Acutely Reduces Insulin Secretion and Causes Metabolic Deceleration of the Pancreatic β-Cell at Submaximal Glucose Concentrations

Molecular Nutrition Unit and Montreal Diabetes Research Center (J.L., É.P., M.-L.P., É.J., S.R.M.M., M.P.), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), and Departments of Nutrition and Biochemistry, and Montreal Diabetes Research Center (V.P.), CRCHUM, and Department of Medicine, Université de Montréal, Montréal, Québec, Canada H1W 4A4; The Australian National University Medical School (C.J.N.), Canberra ACT 0200, Australia; and Departments of Medicine and Physiology and Biophysics (N.B.R.), Boston University School of Medicine and Diabetes Unit, Section of Endocrinology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: Dr. Marc Prentki, Montréal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, 2901 Rachel Street East, Room 401, Montréal, Québec, Canada H1W 4A4. E-mail: marc.prentki{at}umontreal.ca

Thiazolidinediones (TZDs) have beneficial effects on glucose homeostasis via enhancement of insulin sensitivity and preservation of β-cell function. How TZDs preserve β-cells is uncertain, but it might involve direct effects via both peroxisome proliferator-activated receptor--dependent and -independent pathways. To gain insight into the independent pathway(s), we assessed the effects of short-term (90 min) exposure to pioglitazone (Pio) (10 to 50 µM) on glucose-induced insulin secretion (GIIS), AMP-activated protein kinase (AMPK) activation, and β-cell metabolism in INS 832/13 β-cells and rat islets. Pio caused a right shift in the dose-dependence of GIIS, such that insulin release was reduced at intermediate glucose but unaffected at either basal or maximal glucose concentrations. This was associated in INS 832/13 cells with alterations in energy metabolism, characterized by reduced glucose oxidation, mitochondrial membrane polarization, and ATP levels. Pio caused AMPK phosphorylation and its action on GIIS was reversed by the AMPK inhibitor compound C. Pio also reduced palmitate esterification into complex lipids and inhibited lipolysis. As for insulin secretion, the alterations in β-cell metabolic processes were mostly alleviated at elevated glucose. Similarly, the antidiabetic agents and AMPK activators metformin and berberine caused a right shift in the dose dependence of GIIS. In conclusion, Pio acutely reduces glucose oxidation, energy metabolism, and glycerolipid/fatty acid cycling of the β-cell at intermediate glucose concentrations. We suggest that AMPK activation and the metabolic deceleration of the β-cell caused by Pio contribute to its known effects to reduce hyperinsulinemia and preserve β-cell function and act as an antidiabetic agent.