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Serotonin regulates glucose-stimulated insulin secretion from pancreatic β cells during pregnancy
Ohara-Imaizumi, Mica,Kim, Hail,Yoshida, Masashi,Fujiwara, Tomonori,Aoyagi, Kyota,Toyofuku, Yukiko,Nakamichi, Yoko,Nishiwaki, Chiyono,Okamura, Tadashi,Uchida, Toyoyoshi,Fujitani, Yoshio,Akagawa, Kimio National Academy of Sciences 2013 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.110 No.48
<P>In preparation for the metabolic demands of pregnancy, beta cells in the maternal pancreatic islets increase both in number and in glucose-stimulated insulin secretion (GSIS) per cell. Mechanisms have been proposed for the increased beta cell mass, but not for the increased GSIS. Because serotonin production increases dramatically during pregnancy, we tested whether flux through the ionotropic 5-HT3 receptor (Htr3) affects GSIS during pregnancy. Pregnant Htr3a(-/-) mice exhibited impaired glucose tolerance despite normally increased cell mass, and their islets lacked the increase in GSIS seen in islets from pregnant wild-type mice. Electrophysiological studies showed that activation of Htr3 decreased the resting membrane potential in beta cells, which increased Ca2+ uptake and insulin exocytosis in response to glucose. Thus, our data indicate that serotonin, acting in a paracrine/autocrine manner through Htr3, lowers the beta cell threshold for glucose and plays an essential role in the increased GSIS of pregnancy.</P>
Functional role of serotonin in insulin secretion in a diet-induced insulin-resistant state.
Kim, Kyuho,Oh, Chang-Myung,Ohara-Imaizumi, Mica,Park, Sangkyu,Namkung, Jun,Yadav, Vijay K,Tamarina, Natalia A,Roe, Michael W,Philipson, Louis H,Karsenty, Gerard,Nagamatsu, Shinya,German, Michael S,Kim The Endocrine Society 2015 Endocrinology Vol.156 No.2
<P>The physiological role of serotonin, or 5-hydroxytryptamine (5-HT), in pancreatic β-cell function was previously elucidated using a pregnant mouse model. During pregnancy, 5-HT increases β-cell proliferation and glucose-stimulated insulin secretion (GSIS) through the Gαq-coupled 5-HT2b receptor (Htr2b) and the 5-HT3 receptor (Htr3), a ligand-gated cation channel, respectively. However, the role of 5-HT in β-cell function in an insulin-resistant state has yet to be elucidated. Here, we characterized the metabolic phenotypes of β-cell-specific Htr2b(-/-) (Htr2b βKO), Htr3a(-/-) (Htr3a knock-out [KO]), and β-cell-specific tryptophan hydroxylase 1 (Tph1)(-/-) (Tph1 βKO) mice on a high-fat diet (HFD). Htr2b βKO, Htr3a KO, and Tph1 βKO mice exhibited normal glucose tolerance on a standard chow diet. After 6 weeks on an HFD, beginning at 4 weeks of age, both Htr3a KO and Tph1 βKO mice developed glucose intolerance, but Htr2b βKO mice remained normoglycemic. Pancreas perfusion assays revealed defective first-phase insulin secretion in Htr3a KO mice. GSIS was impaired in islets isolated from HFD-fed Htr3a KO and Tph1 βKO mice, and 5-HT treatment improved insulin secretion from Tph1 βKO islets but not from Htr3a KO islets. Tph1 and Htr3a gene expression in pancreatic islets was not affected by an HFD, and immunostaining could not detect 5-HT in pancreatic islets from mice fed an HFD. Taken together, these results demonstrate that basal 5-HT levels in β-cells play a role in GSIS through Htr3, which becomes more evident in a diet-induced insulin-resistant state.</P>