Convergence of the Insulin and Serotonin Programs in the Pancreatic β-Cell

Abstract

OBJECTIVEDespite their origins in different germ layers, pancreatic islet cells share many common developmental features with neurons, especially serotonin-producing neurons in the hindbrain. Therefore, we tested whether these developmental parallels have functional consequences.RESEARCH DESIGN AND METHODSWe used transcriptional profiling, immunohistochemistry, DNA-binding analyses, and mouse genetic models to assess the expression and function of key serotonergic genes in the pancreas.RESULTSWe found that islet cells expressed the genes encoding all of the products necessary for synthesizing, packaging, and secreting serotonin, including both isoforms of the serotonin synthetic enzyme tryptophan hydroxylase and the archetypal serotonergic transcription factor Pet1. As in serotonergic neurons, Pet1 expression in islets required homeodomain transcription factor Nkx2.2 but not Nkx6.1. In β-cells, Pet1 bound to the serotonergic genes but also to a conserved insulin gene regulatory element. Mice lacking Pet1 displayed reduced insulin production and secretion and impaired glucose tolerance.CONCLUSIONSThese studies demonstrate that a common transcriptional cascade drives the differentiation of β-cells and serotonergic neurons and imparts the shared ability to produce serotonin. The interrelated biology of these two cell types has important implications for the pathology and treatment of diabetes.

Gα i/o -coupled receptor signaling restricts pancreatic β-cell expansion

“…Animals identified as sick by veterinary staff were not used for experiments. Note that the expression pattern of ePet transgenics including ePet-cre (18,19,54) compare favorably with many other commonly used pancreas-, islet-, and β-cell-specific transgenic mouse lines, which, like ePet, also express in serotonergic brainstem nuclei as well as in the pancreas. However, unlike ePet, when used as cre drivers other pancreatic promoters frequently cause recombination in other CNS locations including the hypothalamus (Fig.…”

“…First, we expressed a well-studied Gi-GPCR, serotonin receptor HTR1A, in developing islet cells under the control of the ePet1 enhancer from the Fev gene ( Fig. S1A) (18,19). The transgenic progeny of one ePet1-Htr1a transgenic founder displayed marked hyperglycemia (Fig.…”

Serotonin (5-HT) receptor 2b activation augments glucose-stimulated insulin secretion in human and mouse islets of Langerhans

“…Clinically, 5-HT systems in the central nervous system are targeted by antidepressants and long-term use of antidepressants is associated with an increased type 2 diabetes risk [38,39]. Since beta cells express multiple 5-HT receptors [10,11] and the serotonin transporter (SERT) [40], direct effects on insulin secretion are likely. Indeed, selective serotonin re-uptake inhibitors (SSRIs) inhibit insulin secretion in clonal beta cells [41,42], possibly through an increased 5-HT concentration in the extracellular space.…”

Positron Emission Tomography Ligand [11C]5-Hydroxy-Tryptophan Can Be Used as a Surrogate Marker for the Human Endocrine Pancreas

“…Despite originating from different germinal layers, pancreatic islet cells share many common developmental features with neurons, especially serotonin-producing neurons in the hindbrain (6,7). As shown in mice, a common transcriptional cascade drives the differentiation of b-cells and serotonergic neurons, which imparts the shared ability to produce serotonin (8). Several studies in mice and guinea pigs have also demonstrated the localization of serotonin to the islets of Langerhans, particularly to the granules or microvesicles of the b-cells (8)(9)(10)(11).…”