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Anti-inflammatory properties of C-peptide. A new therapeutic strategy for reducing vascular damage in type 1 diabetes patients

Cifarelli, Vincenza (2011) Anti-inflammatory properties of C-peptide. A new therapeutic strategy for reducing vascular damage in type 1 diabetes patients. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

C-peptide, historically considered a biologically inactive peptide, has been shown to exert insulin-independent biological effects on a number of cells proving itself as a bioactive peptide with anti-inflammatory properties. Type 1 diabetes (T1D) patients typically lack physiological levels of insulin and C-peptide and are at increased risk of developing complications affecting the vessels of the eye, the kidneys, and the peripheral nerves. Inflammation is an important factor for the development of diabetes-associated vascular complications, and there is increasing evidence that T1D patients, even at a young age and after short duration of T1D, have circulating activated monocytes and increased plasma levels of inflammatory cytokines. It has been hypothesized that lack of circulating C-peptide might contribute to the development of diabetes-associated vascular complications by reducing the inflammatory response associated with T1D. In this study, we investigated the direct effect of C-peptide on several inflammatory processes of vascular damage, such as endothelial dysfunction and monocyte activation. In an hyperglycaemia-induced model of vascular dysfunction, we found that C-peptide exerted its beneficial effect on a variety of inflammatory events such as cytokines secretions, adhesion molecules expression, oxidative stress generation, and cellular proliferation. Finally, to gain insights on the cell biology of C-peptide, we investigated its process of from the cell surface and its sub-cellular localization in target cells. Our findings indicate that C-peptide internalization from the cell surface within membrane-bound organelles of the endocytic pathway and excluded direct translocation across the plasma membrane. The importance of this finding is that endosomes represent intracellular sites from which C-peptide affects key signaling pathways in target cell. The present evidences favor the view that replacement therapy with C-peptide in T1D patients has a critical public health impact for decreasing diabetic complications. In fact C-peptide therapy replacement offers an approach to retard the development of diabetes-associated vascular complications, for which no causal therapy is available today. Much of the burden of diabetes is due to the development of microvascular complications including retinopathy, nephropathy and neuropathy. The prevention and treatment of microvascular complications are of critical importance to decrease the associated mortality and morbidity.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Cifarelli, Vincenzacifarelli.v@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFerrell, Robertrferrell@pitt.eduRFERRELL
Committee MemberFinegold, Daviddnf@pitt.eduDNF
Committee MemberTrucco, Massimomnt@pitt.eduMNT
Committee MemberBarmada, Michael barmada@pitt.eduBARMADA
Committee MemberLuppi, Patrizialuppip@yahoo.com
Date: 23 September 2011
Date Type: Completion
Defense Date: 5 May 2011
Approval Date: 23 September 2011
Submission Date: 25 July 2011
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: c-peptide; confocal; diabetes; monocytes; reactive oxygen species
Other ID: http://etd.library.pitt.edu/ETD/available/etd-07252011-154415/, etd-07252011-154415
Date Deposited: 10 Nov 2011 19:53
Last Modified: 15 Nov 2016 13:46
URI: http://d-scholarship.pitt.edu/id/eprint/8601

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