Melatonin receptors in pancreatic islets - Linking a genetic variant to functional phenotype
Author
Summary, in English
The initial finding of the risk variant in the MTNR1B gene was associated with increased fasting plasma glucose, impaired early insulin secretion, and increased risk of T2D. Also, risk variant carriers displayed increased mRNA expression of MTNR1B in islets, suggesting a direct inhibitory effect of melatonin on β-cells.
The confirmation and further characterization of melatonin receptor expression in pancreatic islets was completed in study II. Here, we could show that murine pancreatic islets express MT2 in β-cells, whereas melatonin receptor 1 (MT1) is localized in α-cells.
After an intravenous glucose challenge, glucose elimination was unaltered in MT2 whole body knock out animals. In contrast, insulin secretion was elevated, particularly the first phase of secretion. This could in part be explained by an increased amount of pancreatic islets in these animals.
The two other knock out strains investigated – the MT1 knock out and the double knock out MT1/2 – displayed a more moderate phenotype. Whereas the MT1/2 mouse was very similar to wild type mice in all parameters of glucose homeostasis investigated, MT1 mice displayed a more diabetes-like phenotype, with elevated blood glucose levels after glucose challenge.
Taken together, findings in the MT2 knock out mice supported the model of a gain-of-function mutation in MT2/MTNR1B in humans in T2D. This results in increased expression of the receptor in β-cells, where it exhibits a direct inhibition of insulin release. With this, we have substantiated a possible link between the genetic risk variant and the functional phenotype of MTNR1B.
Publishing year
2012
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2012:72
Document type
Dissertation
Publisher
Unit of Molecular Metabolism, Department of Clinical Sciences, Malmö.
Topic
- Endocrinology and Diabetes
Keywords
- Melatonin receptor
- knock out mice
- IVGTT
- OGTT
- ITT
- Hyperinsulinemic clamp
- MTNR1B
- MT2
Status
Published
Research group
- Diabetes - Molecular Metabolism
Supervisor
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-87189-35-7
Defence date
14 September 2012
Defence time
13:00
Defence place
Tidskriften, Jan Waldenströmsgata 5, plan 1, Skånes Universitets Sjukhus i Malmö (SUS)
Opponent
- Shanta Persaud (Professor)