Fibroblast growth factor-21 (FGF-21) is a recently discovered metabolic regulator. Here, we investigated the effects of FGF-21 in the pancreatic -cell. In rat islets and INS-1E cells, FGF-21 activated extracellular signal-regulated kinase 1/2 and Akt signaling pathways. In islets isolated from healthy rats, FGF-21 increased insulin mRNA and protein levels but did not potentiate glucose-induced insulin secretion. Islets and INS-1E cells treated with FGF-21 were partially protected from glucolipotoxicity and cytokineinduced apoptosis. In islets isolated from diabetic rodents, FGF-21 treatment increased islet insulin content and glucose-induced insulin secretion. Short-term treatment of normal or db/db mice with FGF-21 lowered plasma levels of insulin and improved glucose clearance compared with vehicle after oral glucose tolerance testing. Constant infusion of FGF-21 for 8 weeks in db/db mice nearly normalized fed blood glucose levels and increased plasma insulin levels. Immunohistochemistry of pancreata from db/db mice showed a substantial increase in the intensity of insulin staining in islets from FGF-21-treated animals as well as a higher number of islets per pancreas section and of insulin-positive cells per islet compared with control. No effect of FGF-21 was observed on islet cell proliferation. In conclusion, preservation of -cell function and survival by FGF-21 may contribute to the beneficial effects of this protein on glucose homeostasis observed in diabetic animals. Diabetes 55:2470 -2478, 2006 P ancreatic -cell dysfunction is a central component of the pathogenesis of all forms of diabetes. Type 1 diabetes manifests from the autoimmune destruction of -cells, whereas type 2 diabetes is characterized by reduced -cell mass and marked functional defects, including impaired first-phase insulin secretion, increased proinsulin-to-insulin ratio, and elevated rate of -cell apoptosis (1-3). The glucose-sensing and insulin-signaling pathways have been shown to play important roles in insulin secretion as well as -cell growth and survival. For example, mice lacking insulin receptors, insulin receptor substrate-2, or Akt (protein kinase B) display marked defects in glucose sensing, insulin secretion, and -cell mass (4 -6). The amount of secreted insulin is determined by the secretory activity of the -cell and the total number of -cells in the pancreas. Glucose plays an essential role in the control of secretory activity of -cells. Metabolism of glucose leads to an increase in the ATP-to-ADP ratio, membrane depolarization, Ca 2ϩ influx, and stimulation of insulin secretion (7). -Cell mass is governed by the balance between -cell growth and -cell death (apoptosis). Type 2 diabetic patients display a progressive loss of -cells caused by an increased rate of -cell apoptosis (8). However, the cause and mechanism(s) responsible for the increased apoptosis rate in type 2 diabetes are not well understood (9). Preventing -cell death and increasing survival of the -cell can be a valuable therapeutic approa...
By yeast two-hybrid screening we have identified interaction partners for the intracellular C-terminal tail of the human and rodent somatostatin receptor subtype 5 (SSTR5). Interactions with the PDZ domain-containing proteins PIST and PDZK1 are mediated by the PDZ ligand motif at the C terminus of the receptor; in case of the human and mouse (but not the rat) receptors, a slight sequence variation of this motif also allows for binding of the peroxisomal receptor PEX5. PIST is Golgi-associated and retains SSTR5 in the Golgi apparatus when coexpressed with the receptor; PDZK1 on the other hand associates with the SSTR5 at the plasma membrane. Endogenous SSTR5 in the neuroendocrine AtT-20 tumor cell line is colocalized with PIST in the Golgi apparatus. On a functional level, removal of the PDZ ligand motif of the receptor does not interfere with agonist-dependent internalization of the receptor or its targeting to a Golgi-associated compartment; however, recycling of the receptor to the plasma membrane after washout of the agonist is inhibited, suggesting that the PDZ-mediated interaction of SSTR5 is required for postendocytic sorting.In recent years it has been appreciated that the signaling and the subcellular distribution of G-protein-coupled receptors may be influenced by proteins that interact with the intracellular regions of the receptors, most notably the C termini (1, 2). Several interactions have been mapped to the membrane proximal domain of the C terminus, including the so-called helix 8, which encompasses the palmitoylation motifs found in most receptors of the rhodopsin-related type I family (3-5). These contacts especially involve proteins that act in the postendocytic, intracellular sorting of multiple receptors, i.e. the sorting nexin SNX1, N-ethylmaleimide sensitive factor and the G-protein-coupled receptor-associated sorting protein GASP. A second type of interactions involves the distal C termini of GPCRs, 4 which in many cases contain motifs for the interaction with PDZ domains. PDZ domain proteins frequently act as scaffold molecules because of their multiple protein interaction motifs (6). Thus this type of interaction has the potential to target a receptor to specific subcellular domains and into specific signaling complexes. Interaction of the  1 -adrenergic receptor with the third PDZ domain of PSD-95, for example, is believed to anchor this receptor at the postsynaptic density of excitatory synapses (7). The interaction of the parathyroid hormone receptor with Na ϩ /H ϩ exchanger regulatory factor/EBP-50 on the other hand physically links the receptor to phospholipase C, thereby shifting the second messenger response from adenylate cyclase activation to the hydrolysis of phospholipids (8).We have recently initiated a search for intracellular interaction partners for the various members of the somatostatin receptor (SSTR) family (9, 10). There are five SSTR subtypes in mammalian species, which form a rather homogeneous subfamily within the larger family of GPCRs, as they all preferential...
Liver X receptors (LXRs) form functional heterodimers with the retinoid X receptors (RXRs) and regulate cholesterol, lipid, and glucose metabolism. We demonstrated previously that activation of LXR modulates insulin secretion in MIN6 cells and pancreatic islets. In this study we investigated the effects of the LXR agonist T0901317 and the RXR agonist 9-cis-retinoic acid (9cRA) on cell proliferation and apoptosis in MIN6 cells. Whereas T0901317 showed no effect on proliferation of MIN6 cells, combination of T0901317 with 9cRA inhibited cell proliferation. Flow cytometry analysis of cell cycle demonstrated that activation of LXR/RXR prevented MIN6 cells from G1 to G2 phase progression. Combination of T0901317 and 9cRA increased apoptosis rate and caspase-3/7 activity in MIN6 cells. Moreover, T0901317 or its combination with 9cRA significantly increased the cell susceptibility to free fatty acid- and cytokine-induced apoptosis. Treatment of MIN6 cells with LXR and RXR agonists produced a strong increase in expression of mothers against decapentaplegic homolog 3, a protein known to inhibit cell cycle G1/S phase progression and induce apoptosis. In isolated rat islets, the effect of palmitic acid on caspase-3/7 activity was increased with T0901317 alone and even more with the combination of T0901317 and 9cRA. Thus, activation of LXR/RXR signaling inhibits cell proliferation and induces apoptosis in pancreatic beta-cells.
Liver X receptors (LXRalpha and LXRbeta) regulate glucose and lipid metabolism. Pancreatic beta-cells and INS-1E insulinoma cells express only the LXRbeta isoform. Activation of LXRbeta with the synthetic agonist T0901317 increased glucose-induced insulin secretion and insulin content, whereas deletion of the receptor in LXRbeta knockout mice severely blunted insulin secretion. Analysis of gene expression in LXR agonist-treated INS-1E cells and islets from LXRbeta-deficient mice revealed that LXRbeta positively regulated expression of ATP-binding cassette transporter A1 (ABCA1), sterol regulatory element-binding protein 1 (SREBP-1), insulin, PDX-1, glucokinase, and glucose transporter 2 (Glut2). Down-regulation of SREBP-1 expression with the specific small interfering RNA blocked basal and LXRbeta-induced expression of pancreatic duodenal homeobox 1 (PDX-1), insulin, and Glut2 genes. SREBP-1 small interfering RNA also prevented an increase in insulin secretion and insulin content induced by T0901317. Moreover, 5-(tetradecyloxy)-2-furoic acid, an inhibitor of the SREBP-1 target gene acetyl-coenzyme A carboxylase, blocked T0901317-induced stimulation of insulin secretion. In conclusion, activation of LXRbeta in pancreatic beta-cells increases insulin secretion and insulin mRNA expression via SREBP-1-regulated pathway. These data support the role of LXRbeta, SREBP-1, and cataplerosis/anaplerosis pathways in the control of insulin secretion in pancreatic beta-cells.
The multi-domain protein PIST (protein interacting specifically with Tc10) interacts with the SSTR5 (somatostatin receptor 5) and is responsible for its intracellular localization. Here, we show that PIST is expressed in pancreatic b-cells and interacts with SSTR5 in these cells. PIST expression in MIN6 insulinoma cells is reduced by somatostatin (SST). After stimulation with SST, SSTR5 undergoes internalization together with PIST. MIN6 cells over-expressing PIST display enhanced glucose-stimulated insulin secretion and a decreased sensitivity to SST-induced inhibition of insulin secretion. These data suggest that PIST plays an important role in insulin secretion by regulating SSTR5 availability at the plasma membrane.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.