title: Proteomics reveals novel oxidative and glycolytic mechanisms in type 1 diabetic patients' skin which are normalized by kidney-pancreas transplantation.
abstract: BACKGROUND
  In type 1 diabetes (T1D) vascular complications such as accelerated atherosclerosis and diffused macro-/microangiopathy are linked to chronic hyperglycemia with a mechanism that is not yet well understood. End-stage renal disease (ESRD) worsens most diabetic complications, particularly, the risk of morbidity and mortality from cardiovascular disease is increased several fold.
  
  
  RESULTS
  We evaluated protein regulation and expression in skin biopsies obtained from T1D patients with and without ESRD, to identify pathways of persistent cellular changes linked to diabetic vascular disease. We therefore examined pathways that may be normalized by restoration of normoglycemia with kidney-pancreas (KP) transplantation. Using proteomic and ultrastructural approaches, multiple alterations in the expression of proteins involved in oxidative stress (catalase, superoxide dismutase 1, Hsp27, Hsp60, ATP synthase delta chain, and flavin reductase), aerobic and anaerobic glycolysis (ACBP, pyruvate kinase muscle isozyme, and phosphoglycerate kinase 1), and intracellular signaling (stratifin-14-3-3, S100-calcyclin, cathepsin, and PPI rotamase) as well as endothelial vascular abnormalities were identified in T1D and T1D+ESRD patients. These abnormalities were reversed after KP transplant. Increased plasma levels of malondialdehyde were observed in T1D and T1D+ESRD patients, confirming increased oxidative stress which was normalized after KP transplant.
  
  
  CONCLUSIONS
  Our data suggests persistent cellular changes of anti-oxidative machinery and of aerobic/anaerobic glycolysis are present in T1D and T1D+ESRD patients, and these abnormalities may play a key role in the pathogenesis of hyperglycemia-related vascular complications. Restoration of normoglycemia and removal of uremia with KP transplant can correct these abnormalities. Some of these identified pathways may become potential therapeutic targets for a new generation of drugs.
authors.affiliation: Diabetes Division, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Franco
authors.initials: F
authors.lastname: Folli
authors.forename: Valeria
authors.initials: V
authors.lastname: Guzzi
authors.forename: Lucia
authors.initials: L
authors.lastname: Perego
authors.forename: Dawn K
authors.initials: DK
authors.lastname: Coletta
authors.forename: Giovanna
authors.initials: G
authors.lastname: Finzi
authors.forename: Claudia
authors.initials: C
authors.lastname: Placidi
authors.forename: Stefano
authors.initials: S
authors.lastname: La Rosa
authors.forename: Carlo
authors.initials: C
authors.lastname: Capella
authors.forename: Carlo
authors.initials: C
authors.lastname: Socci
authors.forename: Davide
authors.initials: D
authors.lastname: Lauro
authors.forename: Devjit
authors.initials: D
authors.lastname: Tripathy
authors.forename: Christopher
authors.initials: C
authors.lastname: Jenkinson
authors.forename: Rita
authors.initials: R
authors.lastname: Paroni
authors.forename: Elena
authors.initials: E
authors.lastname: Orsenigo
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cighetti
authors.forename: Luisa
authors.initials: L
authors.lastname: Gregorini
authors.forename: Carlo
authors.initials: C
authors.lastname: Staudacher
authors.forename: Antonio
authors.initials: A
authors.lastname: Secchi
authors.forename: Angela
authors.initials: A
authors.lastname: Bachi
authors.forename: Michael
authors.initials: M
authors.lastname: Brownlee
authors.forename: Paolo
authors.initials: P
authors.lastname: Fiorina
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000628:therapy; D005260:Female; D005786:Gene Expression Regulation; D006019:Glycolysis; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D010100:Oxygen / Q000737:chemistry*; D016035:Pancreas Transplantation / Q000379:methods*; D040901:Proteomics / Q000379:methods*; D012867:Skin / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D010100:Oxygen