scholarly journals EphrinB1 modulates glutamatergic inputs into POMC-expressing progenitors and controls glucose homeostasis

PLoS Biology ◽  
2020 ◽  
Vol 18 (11) ◽  
pp. e3000680
Author(s):  
Manon Gervais ◽  
Gwenaël Labouèbe ◽  
Alexandre Picard ◽  
Bernard Thorens ◽  
Sophie Croizier
Keyword(s):  
Insulin Secretion ◽  
Nmda Receptor ◽  
Glucose Homeostasis ◽  
Synapse Formation ◽  
Brain Regions ◽  
Excitatory Input ◽  
Nerve Activity ◽  
Input Amount

Proopiomelanocortin (POMC) neurons are major regulators of energy balance and glucose homeostasis. In addition to being regulated by hormones and nutrients, POMC neurons are controlled by glutamatergic input originating from multiple brain regions. However, the factors involved in the formation of glutamatergic inputs and how they contribute to bodily functions remain largely unknown. Here, we show that during the development of glutamatergic inputs, POMC neurons exhibit enriched expression of the Efnb1 (EphrinB1) and Efnb2 (EphrinB2) genes, which are known to control excitatory synapse formation. In vivo loss of Efnb1 in POMC-expressing progenitors decreases the amount of glutamatergic inputs, associated with a reduced number of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits and excitability of these cells. We found that mice lacking Efnb1 in POMC-expressing progenitors display impaired glucose tolerance due to blunted vagus nerve activity and decreased insulin secretion. However, despite reduced excitatory inputs, mice lacking Efnb2 in POMC-expressing progenitors showed no deregulation of insulin secretion and only mild alterations in feeding behavior and gluconeogenesis. Collectively, our data demonstrate the role of ephrins in controlling excitatory input amount into POMC-expressing progenitors and show an isotype-specific role of ephrins on the regulation of glucose homeostasis and feeding.

scholarly journals EphrinB1 modulates glutamatergic inputs into POMC neurons and controls glucose homeostasis

2020 ◽  
Author(s):  
Manon Gervais ◽  
Alexandre Picard ◽  
Bernard Thorens ◽  
Sophie Croizier
Keyword(s):  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Synapse Formation ◽  
Brain Regions ◽  
Excitatory Input ◽  
Nerve Activity ◽  
Input Amount

AbstractProopiomelanocortin (POMC) neurons are major regulators of energy balance and glucose homeostasis. In addition to being regulated by hormones and nutrients, POMC neurons are controlled by glutamatergic input originating from multiple brain regions. However, the factors involved in the formation of glutamatergic inputs and how they contribute to bodily functions remain largely unknown. Here, we show that during the development of glutamatergic inputs, POMC neurons exhibit enriched expression of the Efnb1 (EphrinB1) and Efnb2 (EphrinB2) genes, which are known to control excitatory synapse formation. In vitro silencing and in vivo loss of Efnb1 or Efnb2 in POMC neurons decreases the amount of glutamatergic inputs into these neurons. We found that mice lacking Efnb1 in POMC neurons display impaired glucose tolerance due to blunted vagus nerve activity and decreased insulin secretion. However, mice lacking Efnb2 in POMC neurons showed no deregulation of insulin secretion and only mild alterations in feeding behavior and gluconeogenesis. Collectively, our data demonstrate the role of ephrins in controlling excitatory input amount into POMC neurons and show an isotype-specific role of ephrins on the regulation of glucose homeostasis and feeding.

scholarly journals Reduced expression of TCF7L2 in adipocyte impairs glucose tolerance associated with decreased insulin secretion, incretins levels and lipid metabolism dysregulation in male mice

2020 ◽  
Author(s):  
Marie-Sophie Nguyen-Tu ◽  
Aida Martinez-Sanchez ◽  
Isabelle Leclerc ◽  
Guy A. Rutter ◽  
Gabriela da Silva Xavier
Keyword(s):  
Insulin Secretion ◽  
Lipid Metabolism ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Knockout Mice ◽  
Male Mice ◽  
Glucose Stimulated Insulin Secretion

AbstractTranscription factor 7-like 2 (TCF7L2) is a downstream effector of the Wnt/beta-catenin signalling pathway and its expression is critical for adipocyte development. The precise role of TCF7L2 in glucose and lipid metabolism in adult adipocytes remains to be defined. Here, we aim to investigate how changes in TCF7L2 expression in mature adipocytes affect glucose homeostasis. Tcf7l2 was selectively ablated from mature adipocytes in C57BL/6J mice using an adiponectin promoter-driven Cre recombinase to recombine alleles floxed at exon 1 of the Tcf7l2 gene. Mice lacking Tcf7l2 in mature adipocytes displayed normal body weight. Male mice exhibited normal glucose homeostasis at eight weeks of age. Male heterozygote knockout mice (aTCF7L2het) exhibited impaired glucose tolerance (AUC increased 1.14 ± 0.04 -fold, p=0.03), as assessed by intraperitoneal glucose tolerance test, and changes in fat mass at 16 weeks (increased by 1.4 ± 0.09-fold, p=0.007). Homozygote knockout mice exhibited impaired oral glucose tolerance at 16 weeks of age (AUC increased 2.15 ± 0.15-fold, p=0.0001). Islets of Langerhans exhibited impaired glucose-stimulated insulin secretion in vitro (decreased 0.54 ± 0.13-fold aTCF7L2KO vs control, p=0.02), but no changes in in vivo glucose-stimulated insulin secretion. Female mice in which one or two alleles of the Tcf7l2 gene was knocked out in adipocytes displayed no changes in glucose tolerance, insulin sensitivity or insulin secretion. Plasma levels of glucagon-like peptide-1 and gastric inhibitory polypeptide were lowered in knockout mice (decreased 0.57 ± 0.03-fold and 0.41 ± 0.12-fold, p=0.04 and p=0.002, respectively), whilst plasma free fatty acids and Fatty Acid Binding Protein 4 circulating levels were increased by 1.27 ± 0.07 and 1.78 ± 0.32-fold, respectively (p=0.05 and p=0.03). Mice with biallelic Tcf7l2 deletion exposed to high fat diet for 9 weeks exhibited impaired glucose tolerance (p=0.003 at 15 min after glucose injection) which was associated with reduced in vivo glucose-stimulated insulin secretion (decreased 0.51 ± 0.03-fold, p=0.02). Thus, our data indicate that loss of Tcf7l2 gene expression in adipocytes leads to impairments on metabolic responses which are dependent on gender, age and nutritional status. Our findings further illuminate the role of TCF7L2 in the maintenance of glucose homeostasis.

scholarly journals Role of vesicular monoamine transporter type 2 in rodent insulin secretion and glucose metabolism revealed by its specific antagonist tetrabenazine

2008 ◽  
Vol 198 (1) ◽  
pp. 41-49 ◽  
Author(s):  
Anthony Raffo ◽  
Kolbe Hancock ◽  
Teresa Polito ◽  
Yuli Xie ◽  
Gordon Andan ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Glucose Homeostasis ◽  
Vesicular Monoamine Transporter ◽  
Β Cells ◽  
Monoamine Transporter ◽  
Specific Antagonist

AbstractDespite different embryological origins, islet β-cells and neurons share the expression of many genes and display multiple functional similarities. One shared gene product, vesicular monoamine transporter type 2 (VMAT2, also known as SLC18A2), is highly expressed in human β-cells relative to other cells in the endocrine and exocrine pancreas. Recent reports suggest that the monoamine dopamine is an important paracrine and/or autocrine regulator of insulin release by β-cells. Given the important role of VMAT2 in the economy of monoamines such as dopamine, we investigated the possible role of VMAT2 in insulin secretion and glucose metabolism. Using a VMAT2-specific antagonist, tetrabenazine (TBZ), we studied glucose homeostasis, insulin secretion both in vivo and ex vivo in cultures of purified rodent islets. During intraperitoneal glucose tolerance tests, control rats showed increased serum insulin concentrations and smaller glucose excursions relative to controls after a single intravenous dose of TBZ. One hour following TBZ administration we observed a significant depletion of total pancreas dopamine. Correspondingly, exogenous l-3,4-dihydroxyphenylalanine reversed the effects of TBZ on glucose clearance in vivo. In in vitro studies of rat islets, a significantly enhanced glucose-dependent insulin secretion was observed in the presence of dihydrotetrabenazine, the active metabolite of TBZ. Together, these data suggest that VMAT2 regulates in vivo glucose homeostasis and insulin production, most likely via its role in vesicular transport and storage of monoamines in β-cells.

The effect of melatonin on incretin hormones – results from experimental and randomized clinical studies

2021 ◽  
Author(s):  
Esben Stistrup Lauritzen ◽  
Julie Støy ◽  
Cecilie Bæch-Laursen ◽  
Niels Grarup ◽  
Niels Jessen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Tolerance Test ◽  
University Hospital ◽  
Oral Glucose ◽  
Incretin Hormones ◽  
Intravenous Glucose ◽  
In Situ Study

Abstract Context Glucose homeostasis is under circadian control through both endocrine and intracellular mechanisms with several lines of evidence suggesting that melatonin affects glucose homeostasis. Objective To evaluate the acute in-vivo and in-situ effects of melatonin on secretion of the incretin hormones, GLP-1 and GIP, and their impact on β-cell insulin secretion. Design A human randomized, double-blinded, placebo-controlled crossover study combined with a confirmatory in-situ study of perfused rat intestines. Setting Aarhus University Hospital. Methods: Fifteen healthy male participants were examined 2 x 2 times: An oral glucose tolerance test (OGTT) was performed on day one and an isoglycemic intravenous glucose infusion replicating the blood glucose profile of the OGTT day was performed on day two. These pairs of study days were repeated on treatment with melatonin and placebo, respectively. For the in-situ study, six rat intestines and four rat pancreases were perfused arterially with perfusion buffer ± melatonin. The intestines were concomitantly perfused with glucose through the luminal compartment. Results In humans, melatonin treatment resulted in reduced GIP secretion compared with placebo (ANOVA p=0.003), an effect also observed in the perfused rat intestines (ANOVA p=0.003) in which GLP-1 secretion also was impaired by arterial melatonin infusion (ANOVA p<0.001). Despite a decrease in GIP levels, the in-vivo glucose-stimulated insulin secretion was unaffected by melatonin (p=0.78). Conclusion Melatonin reduced GIP secretion during an oral glucose challenge in healthy young men but did not affect insulin secretion. Reduced GIP secretion was confirmed in an in-situ model of the rat intestine.

Specific Deletion of CASK in Pancreatic β Cells Affects Glucose Homeostasis and Improves Insulin Sensitivity in Obese Mice by Reducing Hyperinsulinemia Running Title: β Cell CASK Deletion Reduces Hyperinsulinemia

2021 ◽  
Author(s):  
Xingjing Liu ◽  
Peng Sun ◽  
Qingzhao Yuan ◽  
Jinyang Xie ◽  
Ting Xiao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Chow Diet ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Calcium Calmodulin Dependent ◽  
Normal Chow

Calcium/calmodulin-dependent serine protein kinase (CASK) is involved in the secretion of insulin vesicles in pancreatic β-cells. The present study revealed a new <i>in vivo </i>role of CASK in glucose homeostasis during the progression of type 2 diabetes mellitus (T2DM). A Cre-loxP system was used to specifically delete the <i>Cask </i>gene in mouse β-cells (βCASKKO), and the glucose metabolism was evaluated in <a>βCASKKO</a> mice fed a normal chow diet (ND) or a high-fat diet (HFD). ND-fed mice exhibited impaired insulin secretion in response to glucose stimulation. Transmission electron microscopy showed significantly reduced numbers of insulin granules at or near the cell membrane in the islets of βCASKKO mice. By contrast, HFD-fed βCASKKO mice showed reduced blood glucose and a partial relief of hyperinsulinemia and insulin resistance when compared to HFD-fed wildtype mice. The IRS1/PI3K/AKT signaling pathway was upregulated in the adipose tissue of HFD-βCASKKO mice. These results indicated that knockout of the <i>Cask</i> gene in β cells had a diverse effect on glucose homeostasis: reduced insulin secretion in ND-fed mice, but improves insulin sensitivity in HFD-fed mice. Therefore, CASK appears to function in the insulin secretion and contributes to hyperinsulinemia and insulin resistance during the development of obesity-related T2DM.

scholarly journals The Role of Physiological Afferent Nerve Activity during In Vivo Maturation of the Calyx of Held Synapse

2007 ◽  
Vol 27 (7) ◽  
pp. 1725-1737 ◽  
Author(s):  
E. Erazo-Fischer ◽  
J. Striessnig ◽  
H. Taschenberger
Keyword(s):  
Afferent Nerve ◽  
Calyx Of Held ◽  
Nerve Activity

scholarly journals A possible role of plasma glutathione in glucose-mediated insulin secretion: in vitro and in vivo studies in rats

Diabetologia ◽  
1989 ◽  
Vol 32 (11) ◽  
Author(s):  
H.P.T. Ammon ◽  
S. Klumpp ◽  
A. Fu� ◽  
E.J. Verspohl ◽  
H. Jaeschke ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
In Vivo Studies ◽  
Plasma Glutathione ◽  
Insulin Secretion In Vitro

scholarly journals GPR119 Regulates Murine Glucose Homeostasis Through Incretin Receptor-Dependent and Independent Mechanisms

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 374-383 ◽  
Author(s):  
Grace Flock ◽  
Dianne Holland ◽  
Yutaka Seino ◽  
Daniel J. Drucker
Keyword(s):  
Insulin Secretion ◽  
Gastric Emptying ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Peptide Yy ◽  
Cell Receptor ◽  
Dependent Manner ◽  
Glucagon Like Peptide 1

Abstract G protein-coupled receptor 119 (GPR119) was originally identified as a β-cell receptor. However, GPR119 activation also promotes incretin secretion and enhances peptide YY action. We examined whether GPR119-dependent control of glucose homeostasis requires preservation of peptidergic pathways in vivo. Insulin secretion was assessed directly in islets, and glucoregulation was examined in wild-type (WT), single incretin receptor (IR) and dual IR knockout (DIRKO) mice. Experimental endpoints included plasma glucose, insulin, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY. Gastric emptying was assessed in WT, Glp1r−/−, DIRKO, Glp2r−/−, and GPR119−/− mice treated with the GPR119 agonist AR231453. AR231453 stimulated insulin secretion from WT and DIRKO islets in a glucose-dependent manner, improved glucose homeostasis, and augmented plasma levels of GLP-1, GIP, and insulin in WT and Gipr−/−mice. In contrast, although AR231453 increased levels of GLP-1, GIP, and insulin, it failed to lower glucose in Glp1r−/− and DIRKO mice. Furthermore, AR231453 did not improve ip glucose tolerance and had no effect on insulin action in WT and DIRKO mice. Acute GPR119 activation with AR231453 inhibited gastric emptying in Glp1r−/−, DIRKO, Glp2r−/−, and in WT mice independent of the Y2 receptor (Y2R); however, AR231453 did not control gastric emptying in GPR119−/− mice. Our findings demonstrate that GPR119 activation directly stimulates insulin secretion from islets in vitro, yet requires intact IR signaling and enteral glucose exposure for optimal control of glucose tolerance in vivo. In contrast, AR231453 inhibits gastric emptying independent of incretin, Y2R, or Glp2 receptors through GPR119-dependent pathways. Hence, GPR119 engages multiple complementary pathways for control of glucose homeostasis.

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