Altered serotonin (5-HT) 1D and 2A receptor expression may contribute to defective insulin and glucagon secretion in human type 2 diabetes

Bennet, Hedvig; Balhuizen, Alexander; Medina, Anya; Nitert, Marloes Dekker; Laakso, Emilia Ottosson; Essén, Sofia; Sartipy, Peter; Storm, Petter; Krus, Ulrika; Wierup, Nils; Fex, Malin

doi:10.1016/j.peptides.2015.07.008

Cited by 84 publications

(83 citation statements)

References 43 publications

(76 reference statements)

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“…Here, we were unable to detect the transcript of 5-HT 2C in either human or mouse islets. Most studies suggest that 5-HT inhibits insulin secretion [11,15,17,18]. 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].…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…The amine 5-HT and activation of 5-HT 1D receptors in non-diabetic human islets inhibits GSIS while activation of 5-HT 2A receptors potentiates GSIS. Interestingly, islets from donors with type 2 diabetes lose the inhibitory effect of 5-HT on GSIS, suggesting that alterations in 5-HT production or 5-HT receptor expression may contribute to beta cell dysfunction [11].…”

Section: +mentioning

confidence: 99%

“…Serotonin (5-hydroxytryptamine ) receptors are expressed in rodent islets [6][7][8] and virtually all 5-HT receptors (5-HT 1-7 ) are G protein-coupled with the exception of 5-HT 3 receptors (ligand-gated K + and Na + ion channels) [9]. Recently, microarray and RNA sequencing analyses revealed transcripts of almost all 5-HT receptors in human islets [10,11]. The natural ligand binding to these receptors, 5-HT, is synthesised from the amino acid tryptophan, is a well-established neurotransmitter in the central nervous system and is involved in regulation of mood and behaviour [9].…”

Section: Introductionmentioning

confidence: 99%

“…The natural ligand binding to these receptors, 5-HT, is synthesised from the amino acid tryptophan, is a well-established neurotransmitter in the central nervous system and is involved in regulation of mood and behaviour [9]. 5-HT has also been detected in islets of Langerhans in several mammalian species [12], including human islets [11], and is suggested to be co-released with insulin and ATP from rodent beta cells [13][14][15][16]. However, rodent islet studies examining the effects of 5-HT on insulin secretion have produced contradictory results; an inhibition [17,18] or a stimulation [19] of glucose-stimulated insulin secretion (GSIS) has been observed.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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Aims/hypothesis The G q -coupled 5-hydroxytryptamine 2B (5-HT 2B ) receptor is known to regulate the proliferation of islet beta cells during pregnancy. However, the role of serotonin in the control of insulin release is still controversial. The aim of the present study was to explore the role of the 5-HT 2B receptor in the regulation of insulin secretion in mouse and human islets, as well as in clonal INS-1(832/13) cells. Methods Expression of HTR2B mRNA and 5-HT 2B protein was examined with quantitative real-time PCR, RNA sequencing and immunohistochemistry. α-Methyl serotonin maleate salt (AMS), a serotonin receptor agonist, was employed for robust 5-HT 2B receptor activation. Htr2b was silenced with small interfering RNA in INS-1(832/13) cells. Insulin secretion, Ca 2+ response and oxygen consumption rate were determined. Results Immunohistochemistry revealed that 5-HT 2B is expressed in human and mouse islet beta cells. Activation of 5-HT 2B receptors by AMS enhanced glucose-stimulated insulin secretion (GSIS) in human and mouse islets as well as in INS-1(832/13) cells. Silencing Htr2b in INS-1(832/13) cells led to a 30% reduction in GSIS. 5-HT 2B receptor activation produced robust, regular and sustained Ca 2+ oscillations in mouse islets with an increase in both peak distance (period) and time in the active phase as compared with control. Enhanced insulin secretion and Ca 2+ changes induced by AMS coincided with an increase in oxygen consumption in INS-1(832/13) cells. Conclusions/interpretation Activation of 5-HT 2B receptors stimulates GSIS in beta cells by triggering downstream changes in cellular Ca 2+ flux that enhance mitochondrial metabolism. Our findings suggest that serotonin and the 5-HT 2B receptor stimulate insulin release.

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