Proteomics reveals novel oxidative and glycolytic mechanisms in type 1 diabetic patients' skin which are normalized by kidney-pancreas transplantation.
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.
Folli
Franco
F
Diabetes Division, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
Guzzi
Valeria
V
Perego
Lucia
L
Coletta
Dawn K
DK
Finzi
Giovanna
G
Placidi
Claudia
C
La Rosa
Stefano
S
Capella
Carlo
C
Socci
Carlo
C
Lauro
Davide
D
Tripathy
Devjit
D
Jenkinson
Christopher
C
Paroni
Rita
R
Orsenigo
Elena
E
Cighetti
Giuliana
G
Gregorini
Luisa
L
Staudacher
Carlo
C
Secchi
Antonio
A
Bachi
Angela
A
Brownlee
Michael
M
Fiorina
Paolo
P
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
D010100:Oxygen