Beta Cell Function: from Human Genetics to Animal Models
Author
Summary, in English
First, we tested whether single nucleotide polymorphisms (SNPs) of the human Free Fatty Acid Receptor 1 (FFAR1) are associated with T2D and insulin secretion. Another genetic study focused on FOXP3 association with T1D and the disease-related clinical parameters. The role of microRNAs (miRNAs) on beta cell function was studied in the third project using a novel genetically engineered mouse model. Subsequently, the effect of Alpha 1-Antitrypsin (AAT) on cytokine-induced apoptosis and on insulin secretion was studied in beta cells in vitro.
In Study I, we concluded that SNPs rs1978013 and rs1978014 in the upstream region of FFAR1 gene might contribute to impaired beta cell function in T2D. Study II showed that the minor A allele in the FOXP3 rs2232365 SNP might represent a protective factor in T1D pathogenesis and suggest a possible role of FOXP3 in the regulation of autoimmunity against pancreatic beta cells. We have demonstrated for the first time in Study III that targeted disruption of the Dicer1 gene specifically in beta cells leads to progressive impairment of insulin secretion and diabetes development. Our findings of Study IV show that AAT stimulates insulin secretion and protects beta cells against cytokine-induced apoptosis, and these effects of AAT seems to be mediated through the cAMP pathway.
Department/s
Publishing year
2009
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2009:61
Document type
Dissertation
Publisher
Lund University
Topic
- Endocrinology and Diabetes
Keywords
- animal model
- Dicer1
- genetics
- genetic association
- single nucleotide polymorphism
- SNP
- INS-1E
- AAT
- FOXP3
- beta cell function
- insulin secretion
- FFAR1
- insulin
- T2D
- glucose
- T1D
Status
Published
Research group
- Diabetes - Immunovirology
- Cellular Autoimmunity Unit
Supervisor
- Corrado Cilio
- Per Levéen
- Leif Groop
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-86253-49-3
Defence date
16 May 2009
Defence time
09:00
Defence place
Clinical Research Centre Aula, MAS, Malmö
Opponent
- Décio Eizirik (Ph.D.)