Diabetes mellitus is one of the most important metabolic disorders and is characterized by chronic hyperglycaemia resulting from defects in insulin secretion, insulin action, or both. However, many aspects of insulin secretion remain elusive for the complex machinery involved, in particular the role of serotonin (5-HT) in endocrine pancreatic beta-cells. It is known for more than three decades that 5-HT is stored together with insulin in secretory beta-granules and it is co-released when pancreatic islets are stimulated with glucose. Nevertheless, the function of 5-HT in this context was not identified so far. 5-HT is a neurotransmitter of major importance as well as a peripheral hormone with multiple actions in primary haemostasis, the cardiovascular and immune system. It is synthesized independently by two rate-limiting tryptophan hydroxylase isoenzymes in peripheral tissues (TPH1) and neurons (TPH2). In addition to the classic signalling between cells via 5-HT surface receptors, the generation of Tph1-/- mice has recently allowed us to identify a receptor-independent signalling mechanism of 5-HT within thrombocytes, which we have termed "serotonylation". This transglutaminase-dependent mechanism bases on the constitutive activation of small GTPases by covalent binding of 5-HT to a highly conserved glutamine residue within their catalytic core, thereby triggering the exocytosis of alpha-granules of the thrombocytes.

In our present study we show that 5-HT regulates insulin secretion by serotonylation of GTPases within endocrine pancreatic beta-cells. These data suggest that intracellular 5-HT acts in various 5-HT containing tissues via this signalling mechanism.