Abstract
BackgroundIn 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.Methods and FindingsWe 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 δ 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.ConclusionsOur 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.
Highlights
In type 1 diabetes mellitus (T1D), chronic hyperglycemia leads to the development of both microvascular and macrovascular complications [1,2]
Our data suggests persistent cellular changes of anti-oxidative machinery and of aerobic/anaerobic glycolysis are present in T1D and T1D+End-stage renal disease (ESRD) patients, and these abnormalities may play a key role in the pathogenesis of hyperglycemia-related vascular complications
The analysis with Image Master 2D Elite software emphasized that there were some spots differentially expressed in T1D+ESRD and T1D compared with the controls
Summary
In type 1 diabetes mellitus (T1D), chronic hyperglycemia leads to the development of both microvascular and macrovascular complications [1,2]. The four main mechanisms that may explain how chronic hyperglycemia may induce diabetic complications are: 1) an increase in polyol pathway flux; 2) an increase in advanced glycation end-product formation; 3) an activation of protein kinase C isoforms; and 4) an increase in hexosamine pathway flux [2,3,5]. It has been suggested that oxidative stress, which may induce protein modifications altering their activity or function, may accelerate the basic pathogenic processes of diabetic complications [5,6,7]. 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, the risk of morbidity and mortality from cardiovascular disease is increased several fold
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
