Prevention of beta-cell dysfunction via targeting novel GPCRs in pancreatic islets

Rajesh Kumar

Research output: ThesisDoctoral Thesis (compilation)

Abstract

The primary aim of this thesis was to investigate the role of G protein coupled receptors (GPCRs) in insulin secretion and beta-cell survival. The second aim was to determine which pathway is involved in insulin release and beta-cell protection via GPCRs.
This has been investigated in three different studies, which concluded the
following:
Study 1) GPR30 is expressed in female mice pancreatic islets. G-1 (GPR30
agonist) and estrogen stimulate insulin secretion and protect cytokine induced apoptosis of beta-cells even in the presence of nuclear receptor (ERalpha and ERbeta ) antagonists.
Study 2) The activation of GPR30 mediates insulinotropic effects mainly via
cAMP/PKA pathway, anti-apoptotic effects via phosphorylation and activation of CREB, AKT and ERK pathways on female human pancreatic islets. In addition, we have shown here that estrogen and G-1 potentiate the effects of glibenclamide (sulfonylurea) and abolish the inhibitory effects of clonidine on insulin secretion from female human pancreatic islets.
Study 3) Protease-activated receptor 2 (PAR-2) belongs to a subfamily of G
protein-coupled receptors and is expressed in pancreatic islets. Several studies have suggested that the PAR-2 is an important mediator of inflammation. PAR-2 is highly expressed in diabetic vs normal subjects and induction of PAR-2 expression via PAR-2 agonists (SLIKGV or tryptase) mediates apoptosis and reduces the rate of cell proliferation.
In this study we have shown that treatment with alpha-1 antitrypsin protects
against PAR-2 specific peptide induced apoptosis in human pancreatic islets via a MAP kinase pathway. A1AT displayed PAR-2 antagonistic activities and
suppressed the PAR-2 pro-inflammatory effects. In addition we have shown that the alpha-1 antitrypsin stimulates insulin secretion in a dose-dependent manner. In view of these novel findings we suggest that drugs that can selectively inhibit the activity of PAR-2 and activate GPR30 receptor will be of great benefit in the treatment of diabetes mellitus.
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Advisors
  • Salehi, S Albert, Supervisor
Award date2011 Sep 23
Publisher
Print ISBNs1652-8220, 978-91-86871-17-8
Publication statusPublished - 2011

Bibliographical note

Defence details

Date: 2011-09-23
Time: 13:00
Place: Jubileumsaulan, Entrance 59, Malmö University Hospital

External reviewer(s)

Name: Nadal, Angel
Title: Professor
Affiliation: Miguel Hernandez University,Elche, Spain

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Subject classification (UKÄ)

  • Endocrinology and Diabetes

Keywords

  • Type II Diabetes
  • GPCR
  • Pancreatic islets
  • Estrogen
  • Alpha-1 antitrypsin.

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