Melatonin receptors in pancreatic islets - Linking a genetic variant to functional phenotype
Sammanfattning: Defective insulin secretion and insulin resistance are the two hallmarks of Type 2 Diabetes (T2D). The pathophysiology of the disease is not fully understood but genetic susceptibility for the disease is a new major player in the understanding of the underlying mechanisms. T2D research has in recent years invested tremendous efforts in identifying new risk variants for the disease. It has proven to be a great success, with about 40 new risk loci identified. This thesis describes the discovery and functional phenotype of one of these risk variants: the melatonin receptor 2 (MT2; MTNR1B). The overall aim was to understand the link between this genetic variation and the functional phenotype. 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.
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