Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier.

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.

Regulation of glucose transport and insulin signaling by troglitazone or metformin in adipose tissue of type 2 diabetic subjects.

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.

Effects of intravenous and dietary lipid challenge on intramyocellular lipid content and the relation with insulin sensitivity in humans.

An increased intramyocellular lipid (IMCL) content, as quantified by (1)H-magnetic resonance spectroscopy ((1)H-MRS), is associated with reduced insulin sensitivity. At present, it is unclear which factors determine IMCL formation and how rapidly IMCL accumulation can be induced. We therefore studied the impact of hyperinsulinemia and elevated circulating nonesterified fatty acid (NEFA) levels on IMCL formation and insulin sensitivity.

Retinoid X receptor expression in skeletal muscle of nondiabetic, obese and type 2 diabetic individuals.

Retinoid X receptor (RXR) is a nuclear receptor that functions as an obligate heterodimeric partner of peroxisome proliferator-activator receptor (PPAR). Studies have shown that the alpha isoform of RXR and PPARgamma act synergistically to regulate gene expression and insulin action. The aim of the current study was to compare the expression and regulation of RXR in the primary insulin-sensitive tissue, skeletal muscle, of various degrees of insulin-resistant states including obese type 2 diabetic (T2D), obese nondiabetic (OND), and lean nondiabetic (LND) subjects.

Distribution of peroxisome proliferator-activated receptors (PPARs) in human skeletal muscle and adipose tissue: relation to insulin action.

Aims/hypothesis: To evaluate the tissue distribution and possible role of the peroxisome proliferator-activated receptors (PPARs) in insulin action in fat and muscle biopsy specimens from lean, obese and subjects with Type II (non-insulin-dependent) diabetes mellitus.

Methods: We measured PPAR alpha, PPAR beta (delta) and PPAR gamma protein expression by western blot analysis. The PPAR gamma protein was also measured in muscle before and after 3-h hyperinsulinaemic (300 mU.