title: PKC-theta knockout mice are protected from fat-induced insulin resistance.
abstract: Insulin resistance plays a primary role in the development of type 2 diabetes and may be related to alterations in fat metabolism. Recent studies have suggested that local accumulation of fat metabolites inside skeletal muscle may activate a serine kinase cascade involving protein kinase C-theta (PKC-theta), leading to defects in insulin signaling and glucose transport in skeletal muscle. To test this hypothesis, we examined whether mice with inactivation of PKC-theta are protected from fat-induced insulin resistance in skeletal muscle. Skeletal muscle and hepatic insulin action as assessed during hyperinsulinemic-euglycemic clamps did not differ between WT and PKC-theta KO mice following saline infusion. A 5-hour lipid infusion decreased insulin-stimulated skeletal muscle glucose uptake in the WT mice that was associated with 40-50% decreases in insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1-associated PI3K activity. In contrast, PKC-theta inactivation prevented fat-induced defects in insulin signaling and glucose transport in skeletal muscle. In conclusion, our findings demonstrate that PKC-theta is a crucial component mediating fat-induced insulin resistance in skeletal muscle and suggest that PKC-theta is a potential therapeutic target for the treatment of type 2 diabetes.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8020, USA. jason.k.kim@yale.edu
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Fillmore
authors.forename: Mary Jean
authors.initials: MJ
authors.lastname: Sunshine
authors.forename: Bjoern
authors.initials: B
authors.lastname: Albrecht
authors.forename: Takamasa
authors.initials: T
authors.lastname: Higashimori
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Zhen-Xiang
authors.initials: ZX
authors.lastname: Liu
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Soos
authors.forename: Gary W
authors.initials: GW
authors.lastname: Cline
authors.forename: William R
authors.initials: WR
authors.lastname: O'Brien
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D000273:Adipose Tissue / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000628:therapy; D005230:Fatty Acids, Nonesterified / Q000097:blood; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics*; D007527:Isoenzymes / Q000172:deficiency* / Q000235:genetics* / Q000627:therapeutic use; D008055:Lipids / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000172:deficiency* / Q000235:genetics* / Q000627:therapeutic use; D000074121:Protein Kinase C-theta; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D007527:Isoenzymes; D008055:Lipids; D010750:Phosphoproteins; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta