Novel insights into the role of serotonin in control of beta-cell function
Inadequate insulin secretion is a central component in the development of Diabetes Mellitus, resulting from reduced pancreatic β-cell mass, as well as diminished β-cell function. Islet produced 5-hydroxy tryptamine (5-HT) is suggested to regulate insulin secretion and β-cell mass in rodents during pregnancy and in metabolically challenged states. However, the role of 5-HT in control of insulin release in humans is still controversial. Virtually all 5-HT receptors are coupled to G-proteins and activate different second messenger systems, with the exception of the 5-HT3-receptor family which are ligand-gated ion channels. In this thesis I have studied 5-HT signaling in human islets of Langerhans employing a number of physiological and biochemical techniques. Moreover, different pharmacological compounds targeting specific 5-HT receptors to improve insulin release are investigated.
A complete transcriptional mapping of 5-HT receptors in human islets of Langerhans revealed expression of fourteen 5-HT receptors, as well as the enzymes involved in the biosynthesis of 5-HT. Two 5-HT receptor genes (HTR1D and HTR2A) were over-expressed in type 2 diabetic (T2D) islet donors and while 5-HT inhibited both insulin and glucagon secretion in non-diabetic islet donors, 5-HT increased the release of insulin in response to glucose in diabetic T2D islet donors. When investigating the specific function of receptors 5-HT1d and 5-HT2a in non-diabetic islets, we found that a 5-HT1d receptor agonist inhibited insulin release, while a 5-HT1d antagonist potentiated insulin release. Similarly, a 5-HT2a receptor agonist significantly potentiated insulin release, and an antagonist blunted the response of insulin to glucose.
When stimulating human and mouse islets, as well as INS-1 (832/13) cells with a specific 5-HT2b receptor agonist GSIS was enhanced. Moreover, silencing Htr2b in INS-1 (832/13) cells resulted in a 30% reduction in GSIS. In addition, 5-HT2b receptor-activation produced robust, regular and sustained Ca2+ oscillations, paralleled with an increase in oxidative consumption rate in mouse islets.
In vivo studies showed that AMS significantly decreased the insulinogenic index in AMS treated HFD fed mice as compared to untreated mice. Moreover, isolated pancreatic islets from AMS-treated mice given a control diet secreted less insulin in response to glucose compared to islets from untreated control diet fed mice.
Taken together, we show that differential expression levels of 5-HT receptors have functional consequences on islet hormone secretion that may contribute to islet dysfunction as observed in T2D. Furthermore, we provide evidence for an important role of 5-HT2b receptor signaling in control of insulin secretion in vitro. In conclusion, our data suggests an important role for 5-HT signaling in control of islet hormone secretion.