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AuthorAshour, Amal
AuthorXue, Mingzhan
AuthorAl-Motawa, Maryam
AuthorThornalley, Paul J.
AuthorRabbani, Naila
Available date2023-09-06T05:27:58Z
Publication Date2020
Publication NameBMJ Open Diabetes Research and Care
ResourceScopus
ISSN20524897
URIhttp://dx.doi.org/10.1136/bmjdrc-2020-001458
URIhttp://hdl.handle.net/10576/47264
AbstractIntroduction Patients with diabetes have increased risk of periodontal disease, with increased risk of weakening of periodontal ligament and tooth loss. Periodontal ligament is produced and maintained by periodontal ligament fibroblasts (PDLFs). We hypothesized that metabolic dysfunction of PDLFs in hyperglycemia produces an accumulation of the reactive glycating agent, methylglyoxal (MG), leading to increased formation of the major advanced glycation endproduct, MG-H1 and PDLF dysfunction. The aim of this study was to assess if there is dicarbonyl stress and functional impairment of human PDLFs in primary culture in high glucose concentration-a model of hyperglycemia, to characterize the metabolic drivers of it and explore remedial intervention by the glyoxalase 1 inducer dietary supplement, trans-resveratrol and hesperetin combination (tRES-HESP). Research design and methods Human PDLFs were incubated in low and high glucose concentration in vitro. Metabolic and enzymatic markers of MG and glucose control were quantified and related changes in the cytoplasmic proteome and cell function-binding to collagen-I, assessed. Reversal of PDLF dysfunction by tRES-HESP was explored. Results In high glucose concentration cultures, there was a ca. twofold increase in cellular MG, cellular protein MG-H1 content and decreased attachment of PDLFs to collagen-I. This was driven by increased hexokinase-2 linked glucose metabolism and related increased MG formation. Proteomics analysis revealed increased abundance of chaperonins, heat shock proteins (HSPs), Golgi-to-endoplasmic reticulum transport and ubiquitin E3 ligases involved in misfolded protein degradation in high glucose concentration, consistent with activation of the unfolded protein response by increased misfolded MG-modified proteins. PDLF dysfunction was corrected by tRES-HESP. Conclusions Increased hexokinase-2 linked glucose metabolism produces dicarbonyl stress, increased MG-modified protein, activation of the unfolded protein response and functional impairment of PDLFs in high glucose concentration. tRES-HESP resolves this at source by correcting increased glucose metabolism and may be of benefit in prevention of diabetic periodontal disease.
SponsorFunding This study was funded by the Ministry of Education, Saudi Arabia, for a PhD studentship to AA, Qatar Foundation for a PhD studentship to MA-M and funding for PJT's research and Qatar University for funding research to NR.
Languageen
PublisherBMJ Publishing Group
Subjectfibroblasts
glycolysis
periodontal diseases
proteomics
TitleGlycolytic overload-driven dysfunction of periodontal ligament fibroblasts in high glucose concentration, corrected by glyoxalase 1 inducer
TypeArticle
Issue Number2
Volume Number8


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