Functional Role of Serotonin in Insulin Secretion in a Diet-Induced Insulin-Resistant State

Abstract

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.

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

“…A previous report shows that tamoxifen-induced beta cell-specific knockout of 5htr2b results in mice remaining normoglycaemic during an intraperitoneal glucose tolerance test when challenged by a high-fat diet in vivo [36]. Such results infer that 5-HT 2B is unimportant for islet function.…”

“…5-HT 3 receptors are implicated in compensatory increase in insulin secretion during pregnancy [8] and global Htr3a knockout mice on a high-fat diet display a defective firstphase insulin release in vitro [36]. Additionally, beta cellspecific Tph1-knockout mice fed a high-fat diet become increasingly glucose intolerant in vivo, exhibiting an insulin secretory defect in vitro, suggesting that basal 5-HT production in beta cells is essential in GSIS.…”

Effect of mulberry leaf (Folium Mori) on insulin resistance via IRS-1/PI3K/Glut-4 signalling pathway in type 2 diabetes mellitus rats

“…In insulin resistant rats, the phosphorylation of IRS was drastically inhibited (Whelan et al 2010); which corresponded to our results, as represented in Figure 5. When there was a failure in the activation of insulin-related signalling pathway, this resulted in the resulting insulin resistance and glucose intolerance (Steppan et al 2001;Kim et al 2015). Following the phosphorylation of IRS, PI3K and PKB was activated, which activated glucose transport in skeletal tissue, and consequently, Glut-4 was translocated to the plasma membrane in order to improve glucose metabolism (Dutka et al 2006;Im et al 2007).…”

Increasing serotonin concentrations alter calcium and energy metabolism in dairy cows

“…Serotonin is known to induce hepatic regeneration (Lesurtel et al 2006), glucose secretion from the liver, and insulin secretion by the pancreas (Sugimoto et al 1990, Watanabe et al 2011 as well as liver glucose uptake mechanisms (Moore et al 2004(Moore et al , 2005 and glycogen metabolism (Papadimas et al 2012). Furthermore, serotonin has been shown to regulate glucose-stimulated insulin secretion by the b cells of the pancreas during pregnancy, and it is critical for glucosestimulated insulin secretion in an insulin-resistant state (Ohara-Imaizumi et al 2013, Kim et al 2015. Additionally, mice that were injected with increasing doses of serotonin were shown to have increased circulating leptin (Yamada et al 1989) and free fatty acid concentrations (Sumara et al 2012), which thus links serotonin with the regulation of fatty acid and energy metabolism.…”