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1.
Proc Natl Acad Sci U S A ; 110(14): 5422-7, 2013 Apr 02.
Article in English | MEDLINE | ID: mdl-23513224

ABSTRACT

Facilitated pyruvate transport across the mitochondrial inner membrane is a critical step in carbohydrate, amino acid, and lipid metabolism. We report that clinically relevant concentrations of thiazolidinediones (TZDs), a widely used class of insulin sensitizers, acutely and specifically inhibit mitochondrial pyruvate carrier (MPC) activity in a variety of cell types. Respiratory inhibition was overcome with methyl pyruvate, localizing the effect to facilitated pyruvate transport, and knockdown of either paralog, MPC1 or MPC2, decreased the EC50 for respiratory inhibition by TZDs. Acute MPC inhibition significantly enhanced glucose uptake in human skeletal muscle myocytes after 2 h. These data (i) report that clinically used TZDs inhibit the MPC, (ii) validate that MPC1 and MPC2 are obligatory components of facilitated pyruvate transport in mammalian cells, (iii) indicate that the acute effect of TZDs may be related to insulin sensitization, and (iv) establish mitochondrial pyruvate uptake as a potential therapeutic target for diseases rooted in metabolic dysfunction.


Subject(s)
Cell Respiration/drug effects , Membrane Transport Proteins/metabolism , Metabolic Networks and Pathways/physiology , Mitochondrial Membranes/metabolism , Mitochondrial Proteins/antagonists & inhibitors , Thiazolidinediones/pharmacology , Acrylates/pharmacology , Analysis of Variance , Animals , Anion Transport Proteins , Blotting, Western , Cell Line , Cytochromes c/metabolism , Glucose/metabolism , Humans , Membrane Potential, Mitochondrial/physiology , Mice , Mitochondrial Membrane Transport Proteins , Mitochondrial Proteins/metabolism , Monocarboxylic Acid Transporters , Muscle, Skeletal/metabolism , Rats , Reverse Transcriptase Polymerase Chain Reaction , Solute Carrier Proteins , Thiazolidinediones/metabolism
2.
Diabetes ; 51(1): 30-6, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11756319

ABSTRACT

Type 2 diabetic subjects failing glyburide therapy were randomized to receive additional therapy with either metformin (2,550 mg/day) or troglitazone (600 mg/day) for 3-4 months. Biopsies of subcutaneous abdominal adipose tissue were obtained before and after therapy. Glycemic control was similar with both treatments. Metformin treatment increased insulin-stimulated whole-body glucose disposal rates by 20% (P < 0.05); the response to troglitazone was greater (44% increase, P < 0.01 vs. baseline, P < 0.05 vs. metformin). Troglitazone-treated subjects displayed a tendency toward weight gain (5 +/- 2 kg, P < 0.05), increased adipocyte size, and increased serum leptin levels. Metformin-treated subjects were weight-stable, with unchanged leptin levels and reduced adipocyte size (to 84 +/- 4% of control, P < 0.005). Glucose transport in isolated adipocytes from metformin-treated subjects was unaltered from pretreatment. Glucose transport in both the absence (321 +/- 134% of pre-Rx, P < 0.05) and presence of insulin (418 +/- 161%, P < 0.05) was elevated after troglitazone treatment. Metformin treatment had no effect on adipocyte content of GLUT1 or GLUT4 proteins. After troglitazone treatment, GLUT4 protein expression was increased twofold (202 +/- 42%, P < 0.05). Insulin-stimulated serine phosphorylation of Akt was augmented after troglitazone (170 +/- 34% of pre-Rx response, P < 0.05) treatment and unchanged by metformin. We conclude that the ability of troglitazone to upregulate adipocyte glucose transport, GLUT4 expression, and insulin signaling can contribute to its greater effect on whole-body glucose disposal.


Subject(s)
Adipocytes/metabolism , Adipose Tissue/physiopathology , Chromans/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Insulin/physiology , Metformin/therapeutic use , Signal Transduction/physiology , Thiazoles/therapeutic use , Thiazolidinediones , Adipose Tissue/metabolism , Adult , Aged , Body Composition , Cells, Cultured , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/physiopathology , Female , Humans , Male , Middle Aged , Troglitazone
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