title: Impaired regulation of the TNF-alpha converting enzyme/tissue inhibitor of metalloproteinase 3 proteolytic system in skeletal muscle of obese type 2 diabetic patients: a new mechanism of insulin resistance in humans.
abstract: OBJECTIVE
  TNF-alpha levels are increased in obesity and type 2 diabetes. The regulation of TNF-alpha converting enzyme (TACE) and its inhibitor, tissue inhibitor of metalloproteinase 3 (TIMP3), in human type 2 diabetes is unknown.
  
  
  METHODS
  We examined TACE/TIMP3 regulation: (1) in lean and obese normal glucose tolerant (NGT) individuals and in type 2 diabetes patients; (2) following 6 h of lipid/saline infusion in NGT individuals; and (3) in cultured human myotubes from lean NGT individuals incubated with palmitate. Insulin sensitivity was assessed by a euglycaemic clamp and TACE/TIMP3 was evaluated by confocal microscopy, RT-PCR, western blotting and an in vitro activity assay. Circulating TNF-alpha, TNF-alpha-receptor 1 (TNFR1), TNF-alpha-receptor 2 (TNFR2), IL-6 receptor (IL-6R), vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) levels were evaluated.
  
  
  RESULTS
  TIMP3 levels were reduced and TACE enzymatic activity was increased in type 2 diabetes skeletal muscle. TACE expression, and TACE, TNF-alpha, TNFR1 and IL-6R levels were increased in type 2 diabetes, and positively correlated with insulin resistance. A 6 h lipid infusion into NGT individuals decreased insulin-stimulated glucose metabolism by 25% with increased TACE, decreased expression of the gene encoding TIMP3 and increased IL-6R release. Palmitate induced a dramatic reduction of TIMP3 and increased the TACE/TIMP3 ratio in cultured myotubes.
  
  
  CONCLUSIONS
  TACE activity was increased in skeletal muscle of obese type 2 diabetes patients and in lipid-induced insulin resistance. We propose that dysregulation of membrane proteolysis by TACE/TIMP3 of TNF-alpha and IL-6R is an important factor for the development of skeletal muscle insulin resistance in obese type 2 diabetes patients by a novel autocrine/paracrine mechanism.
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, 78229-3900, USA.
authors.forename: A
authors.initials: A
authors.lastname: Monroy
authors.forename: S
authors.initials: S
authors.lastname: Kamath
authors.forename: A O
authors.initials: AO
authors.lastname: Chavez
authors.forename: V E
authors.initials: VE
authors.lastname: Centonze
authors.forename: M
authors.initials: M
authors.lastname: Veerasamy
authors.forename: A
authors.initials: A
authors.lastname: Barrentine
authors.forename: J J
authors.initials: JJ
authors.lastname: Wewer
authors.forename: D K
authors.initials: DK
authors.lastname: Coletta
authors.forename: C
authors.initials: C
authors.lastname: Jenkinson
authors.forename: R M
authors.initials: RM
authors.lastname: Jhingan
authors.forename: D
authors.initials: D
authors.lastname: Smokler
authors.forename: S
authors.initials: S
authors.lastname: Reyna
authors.forename: N
authors.initials: N
authors.lastname: Musi
authors.forename: R
authors.initials: R
authors.lastname: Khokka
authors.forename: M
authors.initials: M
authors.lastname: Federici
authors.forename: D
authors.initials: D
authors.lastname: Tripathy
authors.forename: R A
authors.initials: RA
authors.lastname: DeFronzo
authors.forename: F
authors.initials: F
authors.lastname: Folli
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000328:Adult; D015153:Blotting, Western; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019947:Receptors, Interleukin-6; D019717:Tissue Inhibitor of Metalloproteinase-3; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human