Pioglitazone acutely reduces insulin secretion and causes metabolic deceleration of the pancreatic beta-cell at submaximal glucose concentrations.
Thiazolidinediones (TZDs) have beneficial effects on glucose homeostasis via enhancement of insulin sensitivity and preservation of beta-cell function. How TZDs preserve beta-cells is uncertain, but it might involve direct effects via both peroxisome proliferator-activated receptor-gamma-dependent and -independent pathways. To gain insight into the independent pathway(s), we assessed the effects of short-term (<or=90 min) exposure to pioglitazone (Pio) (10 to 50 microM) on glucose-induced insulin secretion (GIIS), AMP-activated protein kinase (AMPK) activation, and beta-cell metabolism in INS 832/13 beta-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 beta-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 beta-cell at intermediate glucose concentrations. We suggest that AMPK activation and the metabolic deceleration of the beta-cell caused by Pio contribute to its known effects to reduce hyperinsulinemia and preserve beta-cell function and act as an antidiabetic agent.
Lamontagne
Julien
J
Department of Nutrition and Biochemistry, Molecular Nutrition Unit and Montreal Diabetes Research Center, Université de Montréal, Montréal, Québec, Canada.
Pepin
Emilie
E
Peyot
Marie-Line
ML
Joly
Erik
E
Ruderman
Neil B
NB
Poitout
Vincent
V
Madiraju
S R Murthy
SR
Nolan
Christopher J
CJ
Prentki
Marc
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001599:Berberine / Q000494:pharmacology; D002460:Cell Line; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D015151:Immunoblotting; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology; D000077205:Pioglitazone; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D045162:Thiazolidinediones / Q000494:pharmacology*
D005227:Fatty Acids; D007004:Hypoglycemic Agents; D007328:Insulin; D011720:Pyrazoles; D011743:Pyrimidines; D045162:Thiazolidinediones; D001599:Berberine; C516138:dorsomorphin; D000255:Adenosine Triphosphate; D008687:Metformin; D005947:Glucose; D000077205:Pioglitazone