Role of poly(ADP-ribose) polymerase activation in the pathogenesis of diabetes mellitus and diabetic vascular dysfunction

Jon G. Mabley, László Virág, Csaba Szabo

Research output: Chapter in Book/Report/Conference proceedingChapter

3 Citations (Scopus)

Abstract

Insulin-dependent diabetes mellitus (type I) is an autoimmune disease occurring predominantly in children and young adults resulting in destruction of the pancreatic β-cells but not the other islet endocrine cells. Type I diabetes is characterized by prolonged periods of hyperglycemia, via reduced uptake of glucose and relative increase in glucagon secretion and gluconeogenesis. There is an increase in fat catabolism with production of ketone bodies and a fall in blood pH. If diabetic subjects do not receive insulin therapy, the metabolic effects can result in coma and death. The destruction of the islet β-cells is caused by an autoimmunological attack involving an initial hyperexpression of class I major histocompatability complex (MHC) molecules by all of the islet endocrine cells, which is followed by β-cell exclusive expression of MHC class II molecules. Expression of the MHC proteins induces an insulitis whereby the islet is infiltrated by mononuclear cells including lymphocytes, macrophages, and plasma cells. The actual trigger for the process of β-cell destruction is poorly characterized but is either an external factor (viral, chemical) or an internal stimulus (cytokines, free radical), which damages a proportion of the β-cells leading to release of specific β-cell proteins (insulin, GAD 65, etc.), which can be taken up by antigen presenting cells and processed to antigenic peptides. The antigen- presenting cell in association with the MHC class II molecules expressed on the β-cells carries this antigenic peptide to T-helper cells. The latter recognize the complex and become activated, resulting in transcription of cytokine genes including interferon- γ which can feed back onto the antigen-presenting cells to increase expression of interleukin-1B (IL-1β) and tumor necrosis factor-alpha (TNF-α). The Thelper cells also activate B lymphocytes that produce islet cell autoantibodies, which is followed by cytotoxicity by killer cell activation. In the serum of a large proportion of individuals with an increased risk of developing type I diabetes, (auto-) antibodies against specific β-cell antigens such as insulin,1 proinsulin,2 and glutamic acid decarboxylase3 have been detected. Cytotoxic T lymphocytes are also activated via the T-helper cells and are attracted to the increased MHC class II expression on the β-cells. The products of immune cell activation including cytokines and free radicals are the direct participants in inducing β-cell death. The final event in the autoimmune process is the removal of cell debris by macrophages.

Original languageEnglish (US)
Title of host publicationPARP as a Therapeutic Target
PublisherCRC Press
Pages277-319
Number of pages43
ISBN (Electronic)9781420042405
ISBN (Print)0849300738, 9780849300738
StatePublished - Jan 1 2002
Externally publishedYes

Fingerprint

Poly(ADP-ribose) Polymerases
Medical problems
Blood Vessels
Diabetes Mellitus
Chemical activation
Insulin
Lymphocytes
Macrophages
Cytokines
Molecules
Free Radicals
Cells
Proinsulin
Ketone Bodies
Peptides
Islets of Langerhans
T-cells
Interleukins
Cell death
Transcription

ASJC Scopus subject areas

  • Medicine(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Mabley, J. G., Virág, L., & Szabo, C. (2002). Role of poly(ADP-ribose) polymerase activation in the pathogenesis of diabetes mellitus and diabetic vascular dysfunction. In PARP as a Therapeutic Target (pp. 277-319). CRC Press.

Role of poly(ADP-ribose) polymerase activation in the pathogenesis of diabetes mellitus and diabetic vascular dysfunction. / Mabley, Jon G.; Virág, László; Szabo, Csaba.

PARP as a Therapeutic Target. CRC Press, 2002. p. 277-319.

Research output: Chapter in Book/Report/Conference proceedingChapter

Mabley, Jon G. ; Virág, László ; Szabo, Csaba. / Role of poly(ADP-ribose) polymerase activation in the pathogenesis of diabetes mellitus and diabetic vascular dysfunction. PARP as a Therapeutic Target. CRC Press, 2002. pp. 277-319
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