title: Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans.
abstract: Muscle insulin resistance is a key feature of obesity and type 2 diabetes and is strongly associated with increased intramyocellular lipid content and inflammation. However, the cellular and molecular mechanisms responsible for causing muscle insulin resistance in humans are still unclear. To address this question, we performed serial muscle biopsies in healthy, lean subjects before and during a lipid infusion to induce acute muscle insulin resistance and assessed lipid and inflammatory parameters that have been previously implicated in causing muscle insulin resistance. We found that acute induction of muscle insulin resistance was associated with a transient increase in total and cytosolic diacylglycerol (DAG) content that was temporally associated with protein kinase (PKC)θ activation, increased insulin receptor substrate (IRS)-1 serine 1101 phosphorylation, and inhibition of insulin-stimulated IRS-1 tyrosine phosphorylation and AKT2 phosphorylation. In contrast, there were no associations between insulin resistance and alterations in muscle ceramide, acylcarnitine content, or adipocytokines (interleukin-6, adiponectin, retinol-binding protein 4) or soluble intercellular adhesion molecule-1. Similar associations between muscle DAG content, PKCθ activation, and muscle insulin resistance were observed in healthy insulin-resistant obese subjects and obese type 2 diabetic subjects. Taken together, these data support a key role for DAG activation of PKCθ in the pathogenesis of lipid-induced muscle insulin resistance in obese and type 2 diabetic individuals.
authors: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany;German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany;Department of Endocrinology and Diabetology, University Hospital Düsseldorf, 40225 Düsseldorf, Germany; and.
authors: Julia
authors: J
authors: Szendroedi
authors: Howard Hughes Medical Institute andDepartment of Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06536.
authors: Toru
authors: T
authors: Yoshimura
authors: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany;German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany;
authors: Esther
authors: E
authors: Phielix
authors: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany;German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany;
authors: Chrysi
authors: C
authors: Koliaki
authors: Howard Hughes Medical Institute andDepartment of Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06536.
authors: Mellissa
authors: M
authors: Marcucci
authors: Howard Hughes Medical Institute andDepartment of Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06536.
authors: Dongyan
authors: D
authors: Zhang
authors: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany;German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany;
authors: Tomas
authors: T
authors: Jelenik
authors: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany;German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany;
authors: Janette
authors: J
authors: Müller
authors: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany;German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany;
authors: Christian
authors: C
authors: Herder
authors: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany;German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany;
authors: Peter
authors: P
authors: Nowotny
authors: Howard Hughes Medical Institute andDepartment of Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06536 gerald.shulman@yale.edu michael.roden@ddz.uni-duesseldorf.de.
authors: Gerald I
authors: GI
authors: Shulman
authors: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany;German Center for Diabetes Research, Partner Düsseldorf, Düsseldorf, Germany;Department of Endocrinology and Diabetology, University Hospital Düsseldorf, 40225 Düsseldorf, Germany; and gerald.shulman@yale.edu michael.roden@ddz.uni-duesseldorf.de.
authors: Michael
authors: M
authors: Roden
mesh_terms: D000704:Analysis of Variance; D001774:Blood Chemical Analysis; D002153:Calorimetry, Indirect; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004075:Diglycerides / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology*; D015309:Glucose Clamp Technique; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism*; D009132:Muscles / Q000378:metabolism / Q000503:physiopathology*; D011493:Protein Kinase C / Q000378:metabolism*; D000074121:Protein Kinase C-theta
chemical_list: D004075:Diglycerides; D007527:Isoenzymes; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta
keywords: insulin signaling; lipotoxicity