title: Phosphatidylinositol 3-kinase activation is required for sulfonylurea stimulation of glucose transport in rat skeletal muscle.
abstract: Sulfonylureas are drugs widely used in the treatment of patients with type 2 diabetes mellitus. In addition to their pancreatic effect of stimulating insulin secretion, many studies suggest that sulfonylureas also have extrapancreatic actions. We have previously reported that gliclazide, a second-generation sulfonylurea, stimulates the glucose uptake by rat hindquarter skeletal muscle directly and immediately by promoting the translocation of glucose transporter 4 to the plasma membrane. The aim of our study was to approach the gliclazide intracellular signaling pathway. For this purpose, we incubated clamped and isolated soleus muscle from rat with gliclazide. The following results were obtained: 1) gliclazide stimulates insulin receptor substrate (IRS)-1-phosphatidylinositol 3 (PI3)-kinase-associated activity, and this activity is necessary for gliclazide-stimulated glucose transport; 2) gliclazide treatment produces a gradual translocation of the diacylglycerol (DAG)-dependent isoforms protein kinase C (PKC) alpha, theta, and epsilon from cytosolic to membrane fraction that is dependent on PI3-kinase and phospholipase C (PLC)-gamma activation; and 3) PKC and PLC-gamma activation is necessary for gliclazide-stimulated glucose transport. We propose a hypothetical signaling pathway by which gliclazide could stimulate IRS-1 that would allow its association with PI3-kinase, promoting its activation. PI3-kinase products could induce PLC-gamma activation, whose hydrolytic activity could activate the DAG-dependent isoforms PKC alpha, theta, and epsilon.
authors.affiliation: Department of Endocrinology, Fundación Jiménez Díaz, Avda. Reyes Católicos 2, 28040 Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Rodríguez
authors.forename: Nieves
authors.initials: N
authors.lastname: Pulido
authors.forename: Remedios
authors.initials: R
authors.lastname: Romero
authors.forename: Francisco
authors.initials: F
authors.lastname: Arrieta
authors.forename: Aranzazu
authors.initials: A
authors.lastname: Panadero
authors.forename: Adela
authors.initials: A
authors.lastname: Rovira
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D004075:Diglycerides / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005907:Gliclazide / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D004075:Diglycerides; D004791:Enzyme Inhibitors; D005907:Gliclazide; D005947:Glucose; D007004:Hypoglycemic Agents; D007211:Indoles; D055504:Insulin Receptor Substrate Proteins; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051966:Phospholipase C gamma; D010750:Phosphoproteins; D011493:Protein Kinase C; D010738:Type C Phospholipases; D000077191:Wortmannin; C526296:Irs1 protein, rat; C064758:Ro 31-8220