Search

26RFa (pyroglutamilated RFamide peptide [QRFP]) is a biologically active peptide that regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity at the periphery. 26RFa is also produced by a neuronal population localised in the hypothalamus. In this study we investigated whether 26RFa neurons are involved in the hypothalamic regulation of glucose homeostasis.26RfaOur data indicate that i.c.v.-injected 26RFa induces a robust antihyperglycaemic effect associated with an increase in insulin production by the pancreatic islets. In addition, we found that insulin strongly stimulates 26Rfa expression and secretion by the hypothalamus. RNAscope experiments revealed that neurons expressing 26Rfa are mainly localised in the lateral hypothalamic area, that they co-express the gene encoding the insulin receptor and that insulin induces the expression of 26Rfa in these neurons. Concurrently, the central antihyperglycaemic effect of insulin is abolished in the presence of a GPR103 antagonist and in 26RFa-deficient mice. Finally, our data indicate that the hypothalamic 26RFa neurons are not involved in the central inhibitory effect of insulin on hepatic glucose production, but mediate the central effects of the hormone on its own peripheral production.We have identified a novel mechanism in the hypothalamic regulation of glucose homeostasis, the 26RFa/GPR103 system, and we provide evidence that this neuronal peptidergic system is a key relay for the central regulation of glucose metabolism by insulin.

Introduction: The aim of the study is to investigate whether acute or chronic central administration of the hypothalamic neuropeptide 26RFa may ameliorate the glycemic control of obese/diabetic mice. Methods: Mice were treated for 4 months with a high-fat (HF) diet and received a single i.c.v. injection of 26RFa (3 µg) or a chronic i.c.v. administration of the peptide during 28 days via osmotic minipumps (25 µg/day). i.p. and oral glucose (GLU) tolerance tests, insulin (INS) tolerance test, glucose-stimulated insulin secretion (GSIS), food/water intake, horizontal/vertical activity, energy expenditure, meal pattern, and whole-body composition were monitored. In addition, 26RFa and GPR103 mRNA expressions as well as plasma 26RFa levels were evaluated by RT-QPCR and radioimmunoassay. Results: Acute administration of 26RFa in HF mice induced a robust antihyperglycemic effect by enhancing INS secretion, whereas chronic administration of the neuropeptide is unable to improve glucose homeostasis in these obese/diabetogenic conditions. By contrast, chronic 26RFa treatment induced an increase of the body weight accompanied with an enhanced food intake and a decreased energy expenditure. Finally, we show that the HF diet does not alter the hypothalamic expression of the 26RFa/GPR103 neuropeptidergic system nor the levels of circulating 26RFa. Conclusion: Our data indicate that the central beneficial effect of 26RFa on glucose homeostasis, by potentiating GSIS, is preserved in HF mice. However, chronic administration of the neuropeptide is unable to balance glycemia in these pathophysiological conditions, suggesting that the hypothalamic 26RFa/GPR103 neuropeptidergic system mainly affects short-term regulation of glucose metabolism.

International audience; The regulatory peptide 26RFa (QRFP) is involved in the control of glucose homeostasis at the periphery by acting as an incretin, and in the brain by mediating the central antihyperglycemic effect of insulin, indicating the occurrence of a close relationship between 26RFa and insulin in the regulation of glucose metabolism. Here, we investigated the physiological interactions between 26RFa and insulin in two complementary models i.e. a model of obese/hyperglycemic mice deficient for 26RFa and a model of diabetic mice deficient for insulin. For this, transgenic 26RFa-deficient mice were made obese and chronically hyperglycemic by a 3-month high fat diet (HFD) and second group of mice was made diabetic by destruction of the β cells of the pancreatic islets using a single injection of streptozotocin. Our data reveal that 26RFa deficiency does not impact significantly the “glycemic” phenotype of the HFD mice. The pancreatic islets, liver, white adipose tissue masses are not altered by the lack of 26RFa production but the brown adipose tissue (BAT) weight is significantly increased in these animals. In diabetic insulin-deficient mice, the injection of 26RFa does not exhibit any beneficial effect on the impaired glucose homeostasis characterizing this model. Finally, we show that streptozotocin diabetic mice display lowered plasma 26RFa levels as compared to untreated mice, whereas the expression of the peptide in the duodenum is not affected. Taken together, the present results indicate that dysregulation of glucose homeostasis in obese/hyperglycemic mice is not aggravated by the absence of 26RFa that may be compensated by the increase of BAT mass. In diabetic insulin-deficient mice, the antihypergycemic effect of 26RFa is totally blunted probably as a result of the impaired insulin production characterizing this model, avoiding therefore the action of the peptide.

Resume Le neuropeptide 26RFa, aussi denomme QRFP (pour pyroglutamilatedRfamide peptide) et son recepteur, le GPR103, sont impliques dans la regulation de la prise alimentaire et l’homeostasie du glucose. En complement de donnees deja rapportees (Prevost G et al., 2017), qui ont permis de decrire une activite orexigene et incretine du 26RFa, des resultats recents viennent renforcer l’implication de ce systeme peptidergique dans la regulation de la glycemie et, plus specifiquement, au cours du diabete de type 2.

During corticogenesis, projection neurons migrate along the radial glial axis to form cortical layers, the alteration of which is associated with functional deficits in adulthood. As byproducts of cell metabolism, reactive oxygen species act as second messengers to contribute to neurodevelopment; however, free radical excess may impede this process. SELENOT is a thioredoxin-like enzyme of the endoplasmic reticulum abundantly expressed during embryogenesis whose gene disruption in the brain leads to neuroblast cell demise due to increased free radical levels. To determine the potential contribution of SELENOT to the establishment of cortical networks, we analyzed first its expression profile in the neocortex at different stages of development. These studies revealed the widespread expression of SELENOT in all cortical layers, and its continous increase throughout mouse lifespan. In addition, we disrupted the SELENOT gene in the cortex using in utero electroporation and Nes-Cre/lox knockout. SELENOT deficiency altered neuroblast migration polarity, at the level of radial scaffolding, and projection neuron positionning. These results indicate that SELENOT plays a crucial role during neurodevelopment by sustaining projection neuron migration.

Introduction26RFa (QRFP) is a biologically active peptide that has been found to control feeding behaviour by stimulating food intake, and to regulate glucose homeostasis by acting as an incretin. The aim of the present study was thus to investigate the impact of 26RFa gene knockout on the regulation of energy and glucose metabolism.Research design and methods26RFa mutant mice were generated by homologous recombination, in which the entire coding region of prepro-26RFa was replaced by the iCre sequence. Energy and glucose metabolism was evaluated through measurement of complementary parameters. Morphological and physiological alterations of the pancreatic islets were also investigated.ResultsOur data do not reveal significant alteration of energy metabolism in the 26RFa-deficient mice except the occurrence of an increased basal metabolic rate. By contrast, 26RFa mutant mice exhibit an altered glycemic phenotype with an increased hyperglycemia after a glucose challenge associated with an impaired insulin production, and an elevated hepatic glucose production. 2D and 3D immunohistochemical experiments indicate that the insulin content of pancreatic β cells is much lower in the 26RFa-/- mice as compared to the wild-type littermates.ConclusionDisruption of the 26RFa gene induces substantial alteration in the regulation of glucose homeostasis with, in particular, a deficit in insulin production by the pancreatic islets. These findings further support the notion that 26RFa is an important regulator of glucose homeostasis.Significance of this studyWhat is already known about this subject?26RFa is a biologically active peptide produced in abundance in the gut and the pancreas. 26RFa has been found to regulate glucose homeostasis by acting as an incretin and by increasing insulin sensitivity.What are the new findings?Disruption of the 26RFa gene induces substantial alteration in the regulation of glucose homeostasis with, in particular, a deficit in insulin production by the pancreatic islets, assessing therefore the notion that 26RFa is an important regulator of glucose homeostasis.How might these results change the focus of research or clinical practice?Identification of a novel actor in the regulation of glucose homeostasis is crucial to better understand the general control of glucose metabolism in physiological and pathophysiological conditions, and opens new fields of investigation to develop innovative drugs to treat diabetes mellitus.

INTRODUCTION Urotensin II is a potent vasoactive peptide activating the the G protein-coupled urotensin II receptor UT, and is involved in systemic inflammation and cardiovascular functions. The aim of our work was to study the impact of the UT antagonist urantide on survival, systemic inflammation, and cardiac function during endotoxic shock. METHODS C57Bl/6 mice were intraperitoneally injected with lipopolysaccharide (LPS) and then randomized to be injected either by urantide or NaCl 0.9% 3, 6, and 9 h (H3, H6, H9) after LPS. The effect of urantide on the survival rate, the levels of cytokines in plasma at H6, H9, H12, the expression level of nuclear factor-kappa B (NF-κB-p65) in liver and kidney (at H12), and the cardiac function by trans-thoracic echocardiography from H0 to H9 was evaluated. RESULTS Urantide treatment improved survival (88.9% vs. 30% on day 6, P

Resident adrenal mast cells have been shown to activate aldosterone secretion in rat and man. Especially, mast cell proliferation has been observed in adrenal tissues from patients with aldosterone-producing adrenocortical adenoma. In the present study, we show that the activity of adrenal mast cells is stimulated by low-sodium diet and correlates with aldosterone synthesis in C57BL/6 and BALB/c mice. We have also investigated the regulation of aldosterone secretion in mast cell–deficient C57BL/6 Kit W-sh/W-sh mice in comparison with wild-type C57BL/6 mice. Kit W-sh/W-sh mice submitted to normal sodium diet had basal plasma aldosterone levels similar to those observed in wild-type animals. Conversely, low-sodium diet unexpectedly induced an exaggerated aldosterone response, which seemed to result from an increase in adrenal renin and angiotensin type 1 receptor expression. Severe hyperaldosteronism was associated with an increase in systolic blood pressure and marked hypokalemia, which favored polyuria. Adrenal renin and angiotensin type 1 receptor overexpression may represent a compensatory mechanism aimed at activating aldosterone production in the absence of mast cells. Finally, C57BL/6 Kit W-sh/W-sh mice represent an unexpected animal model of primary aldosteronism, which has the particularity to be triggered by sodium restriction.

International audience; Recent studies have shown that the hypothalamic neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin, and increasing insulin sensitivity. In this study, we further characterized the role of the 26RFa/GPR103 peptidergic system in the global regulation of glucose homeostasis using a 26RFa receptor antagonist, and also assessed whether a dysfunction of the 26RFa/GPR103 system occurs in obese hyperglycemic mice. Firstly, we demonstrate that administration of the GPR103 antagonist reduces the global glucose-induced incretin effect and insulin sensitivity whereas, conversely, administration of exogenous 26RFa attenuates glucose-induced hyperglycemia. Using a mouse model of high-fat diet-induced obesity and hyperglycemia, we found a loss of the anti-hyperglcemic effect and insulinotropic activity of 26RFa, accompanied with a marked reduction of its insulin-sensitive effect. Interestingly, this resistance to 26RFa is associated with a down-regulation of the 26RFa receptor in the pancreatic islets, and insulin target tissues. Finally, we observed that the production and release kinetics of 26RFa after an oral glucose challenge is profoundly altered in the high-fat mice. Altogether, the present findings support the view that 26RFa is a key regulator of glucose homeostasis whose activity is markedly altered under obese/hyperglycemic conditions.

Objective Recent studies performed in mice revealed that the neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity. However, in humans, an association between 26RFa and the regulation of glucose homeostasis is poorly documented. In this study, we have thus investigated in detail the distribution of 26RFa and its receptor, GPR103, in the gut and the pancreas, and determined the response of this peptidergic system to an oral glucose challenge in obese patients. Design and methods Distribution of 26RFa and GPR103 was examined by immunohistochemistry using gut and pancreas tissue sections. Circulating 26RFa was determined using a specific radioimmunoassay in plasma samples collected during an oral glucose tolerance test. Results 26RFa and GPR103 are present all along the gut but are more abundant in the stomach and duodenum. In the stomach, the peptide and its receptor are highly expressed in the gastric glands, whereas in the duodenum, ileum and colon they are present in the enterocytes and the goblet cells. In the pancreatic islets, the 26RFa/GPR103 system is mostly present in the β cells. During an oral glucose tolerance test, plasma 26RFa profile is different between obese patients and healthy volunteers, and we found strong positive correlations between 26RFa blood levels and the BMI, and with various parameters of insulin secretion and insulin resistance. Conclusion The present data suggest an involvement of the 26RFa/GPR103 peptidergic system in the control of human glucose homeostasis.

Resume Le neuropeptide 26RFa, aussi denomme QRFP (pour pyroglutamilated RFamide peptide ), est le dernier membre decrit de la famille des peptides RF-amides. Identifie comme ligand du recepteur GPR103, les travaux ont montre que, fortement exprime dans le noyau arque hypothalamique, ce systeme peptidergique exercait une activite orexigene. Des donnees plus recentes ont egalement isole le peptide au niveau de la paroi intestinale et ont permis de definir le 26RFa comme une nouvelle incretine.

International audience; Chez l’homme, les mastocytes surrénaliens activent la sécrétion d’aldostérone via un mécanisme paracrine. Les mastocytes sont également détectés dans la surrénale fœtale où leur présence est corrélée à l’expression des enzymes nécessaires à la production d’aldostérone, suggérant un rôle de ces cellules immunocompétentes dans la mise en place anténatale de la voie de synthèse des minéralocorticoïdes.Afin d’explorer cette hypothèse, nous avons étudié par RT-QPCR l’impact de l’absence de mastocytes sur l’expression des gènes impliqués dans la synthèse et la régulation d’aldostérone en comparant, à différents stades de développement périnatal (E18, E20, P0, P1, P7 et P14), un modèle de souris déficientes en mastocytes (KitW-sh/W-sh) à la souche sauvage C57BL/6.Nous avons observé une expression surrénalienne significativement plus faible de Cyp11b2 chez les souris KitW-sh/W-sh aux stades E18, E20, P0, P14 comparée aux souris sauvages. En revanche, il n’a pas été noté de différence d’expression pour les gènes Cyp21a1 et Hsd3b1. De manière surprenante, à P7, on constate une expression surrénalienne de Cyp11b2 plus élevée chez les souris KitW-sh/W-sh. De plus, on note à ce stade une expression rénale plus élevée du gène codant la rénine sans différence d’expression surrénalienne du gène codant le récepteur de type 1 de l’angiotensine.Au total, ces résultats montrent que les mastocytes contrôlent l’expression du gène codant l’aldostérone synthase durant le développement périnatal murin. Les mécanismes sous-jacents de l’interaction mastocytes/synthèse des minéralocorticoïdes et le retentissement fonctionnel de l’absence de mastocytes en période périnatale restent à déterminer.

International audience; EM66 is a conserved 66-amino acid peptide derived from secretogranin II (SgII), a member of the granin protein family. EM66 is widely distributed in secretory granules of endocrine and neuroendocrine cells, as well as in hypothalamic neurones. Although EM66 is abundant in the hypothalamus, its physiological function remains to be determined. The present study aimed to investigate a possible involvement of EM66 in the hypothalamic regulation of feeding behaviour. We show that i.c.v. administration of EM66 induces a drastic dose-dependent inhibition of food intake in mice deprived of food for 18 hours, which is associated with an increase of hypothalamic pro-opiomelanocortin (POMC) and melanocortin-3 receptor mRNA levels and c-Fos immunoreactivity in the POMC neurones of the arcuate nucleus. By contrast, i.c.v. injection of EM66 does not alter the hypothalamic expression of neuropeptide Y (NPY), or that of its Y1 and Y5 receptors. A 3-month high-fat diet (HFD) leads to an important decrease of POMC and SgII mRNA levels in the hypothalamus, whereas NPY gene expression is not affected. Finally, we show that a 48 hours of fasting in HFD mice decreases the expression of POMC and SgII mRNA, which is not observed in mice fed a standard chow. Taken together, the present findings support the view that EM66 is a novel anorexigenic neuropeptide regulating hypothalamic feeding behaviour, at least in part, by activating the POMC neurones of the arcuate nucleus.

Aim of this article is to illustrate the application of a multivariate approach known as t-pattern analysis in the study of rat behavior in elevated plus maze. By means of this multivariate approach, significant relationships among behavioral events in the course of time can be described. Both quantitative and t-pattern analyses were utilized to analyze data obtained from fifteen male Wistar rats following a trial 1 - trial 2 protocol. In trial 2, in comparison with the initial exposure, mean occurrences of behavioral elements performed in protected zones of the maze showed a significant increase counterbalanced by a significant decrease of mean occurrences of behavioral elements in unprotected zones. Multivariate t-pattern analysis, in trial 1, revealed the presence of 134 t-patterns of different composition. In trial 2, the temporal structure of behavior become more simple, being present only 32 different t-patterns. Behavioral strings and stripes (i.e. graphical representation of each t-pattern onset) of all t-patterns were presented both for trial 1 and trial 2 as well. Finally, percent distributions in the three zones of the maze show a clear-cut increase of t-patterns in closed arm and a significant reduction in the remaining zones. Results show that previous experience deeply modifies the temporal structure of rat behavior in the elevated plus maze. In addition, this article, by highlighting several conceptual, methodological and illustrative aspects on the utilization of t-pattern analysis, could represent a useful background to employ such a refined approach in the study of rat behavior in elevated plus maze.

Urotensin II (UII) and Urotensin II-related peptide (URP) are structurally related paralog peptides that exert peripheral and central effects. UII binding sites have been partly described in brain, and those of URP have never been reported. We exhaustively compared [125I]-UII and -URP binding site distributions in the adult rat brain, and found that they fully overlapped at the regional level. We observed UII/URP binding sites in structures lining ventricles, comprising the sphenoid nucleus and cell rafts scattered on a line joining the fourth ventricle and its lateral recess. After injection of UII and URP in the lateral ventricle, we observed c-Fos-positive cell nuclei in areas close to the fourth ventricle, indicating that these receptors are functional. Different c-Fos-containing cell populations were activated. They were all positive for vimentin and glial fibrillary acidic protein (GFAP), excluding the possibility of an ependymal nature. In conclusion, this study demonstrated that UII and URP binding sites are totally overlapping and that these sites were functional in regions bordering the fourth ventricle. These data support a role for UII/URP at the interface between brain parenchyma and cerebrospinal fluid. J. Comp. Neurol. 522:2634–2649, 2014. © 2014 Wiley Periodicals, Inc.

This mini-review deals with the neuropeptide 26RFa (or QRFP) which is a member of the RFamide peptide family discovered simultaneously by three groups in 2003. 26RFa (or its N-extended form 43RFa) was subsequently shown to be the endogenous ligand of the human orphan receptor GPR103. In the brain, 26RFa and GPR103mRNA are primarily expressed in hypothalamic nuclei involved in the control of feeding behavior, and at the periphery, the neuropeptide and its receptor are present in abundance in the gut and the pancreatic islets, suggesting that 26RFa is involved in the regulation of energy metabolism. Indeed, 26RFa stimulates food intake when injected centrally, and its orexigenic effect is even more pronounced in obese animals. The expression of 26RFa is up-regulated in the hypothalamus of obese animals, supporting that the 26RFa/GPR103 system may play a role in the development and/or maintenance of the obese status. Recent data indicate that 26RFa is also involved in the regulation of glucose homeostasis. 26RFa reduces glucose-induced hyperglycemia, increases insulin sensitivity and insulinemia. Furthermore, an oral ingestion of glucose strongly stimulates 26RFa release by the gut, indicating that 26RFa is a novel incretin. Finally, 26RFa is able to prevent pancreatic β cell death and apoptosis. This brief overview reveals that 26RFa is a key neuropeptide in the regulation of energy metabolism. Further fields of research are suggested including the pathophysiological implication of the 26RFa/GPR103 system.

Selenoprotein T (SelT) is a newly discovered thioredoxin-like protein, which is abundantly but transiently expressed in the neural lineage during brain ontogenesis. Because its physiological function in the brain remains unknown, we developed a conditional knockout mouse line (Nes-Cre/SelTfl/fl) in which SelT gene is specifically disrupted in nerve cells. At postnatal day 7 (P7), these mice exhibited reduced volume of different brain structures, including hippocampus, cerebellum, and cerebral cortex. This phenotype, which is observed early during the first postnatal week, culminated at P7 and was associated with increased loss of immature neurons but not glial cells, through apoptotic cell death. This phenomenon was accompanied by elevated levels of intracellular reactive oxygen species, which may explain the increased neuron demise and reduced brain structure volumes. At the second postnatal week, an increase in neurogenesis was observed in the cerebellum of Nes-Cre/SelTfl/fl mice, suggesting the occurrence of developmental compensatory mechanisms in the brain. In fact, the brain volume alterations observed at P7 were attenuated in adult mice. Nevertheless, SelT mutant mice exhibited a hyperactive behavior, suggesting that despite an apparent morphological compensation, SelT deficiency leads to cerebral malfunction in adulthood. Altogether, these results demonstrate that SelT exerts a neuroprotective role which is essential during brain development, and that its loss impairs mice behavior.

The neuropeptide 26RFa, also referred to as QRFP (for pyroglutamilated RFamide peptide), is the latest member of the RFamide peptide family to be discovered. 26RFa and its N-extended form, 43RFa, have been characterized in all vertebrate classes as the endogenous ligands of the human orphan receptor GPR103. In the brain, 26RFa and GPR103mRNA are primarily expressed in hypothalamic nuclei involved in the control of feeding behavior, and in the periphery, the neuropeptide and its receptor are present in abundance in the gut and the pancreatic islets, suggesting that 26RFa is involved in the regulation of energy metabolism. Indeed, 26RFa stimulates food intake when centrally injected, and its orexigenic effect is even more pronounced in obese animals. The expression of 26RFa is up-regulated in the hypothalamus of obese animals, supporting the view that 26RFa may play a role in the development and/or maintenance of the obese status. Recent data indicate that 26RFa is also involved in the regulation of glucose homeostasis. 26RFa reduces glucose-induced hyperglycemia, increases insulin sensitivity and insulinemia. Furthermore, an oral ingestion of glucose strongly stimulates 26RFa release by the gut, indicating that 26RFa is a novel incretin. Finally, 26RFa is able to prevent pancreatic β cell death and apoptosis. In conclusion, this overview of the literature reveals that 26RFa is a key neuropeptide in the regulation of energy metabolism. Further fields of research are suggested including the pathophysiological implication of the 26RFa/GPR103 system.

International audience; Selenoproteins are involved in the regulation of redox status, which affects several cellular processes, including cell survival and homeostasis. Considerable interest has arisen recently concerning the role of selenoproteins in the regulation of glucose metabolism. Here, we found that selenoprotein T (SelT), a new thioredoxin-like protein of the endoplasmic reticulum, is present at high levels in human and mouse pancreas as revealed by immunofluorescence and quantitative PCR. Confocal immunohistochemistry studies revealed that SelT is mostly confined to insulin- and somatostatin-producing cells in mouse and human islets. To elucidate the role of SelT in β-cells, we generated, using a Cre-Lox strategy, a conditional pancreatic β-cell SelT-knockout C57BL/6J mice (SelT-insKO) in which SelT gene disruption is under the control of the rat insulin promoter Cre gene. Glucose administration revealed that male SelT-insKO mice display impaired glucose tolerance. Although insulin sensitivity was not modified in the mutant mice, the ratio of glucose to insulin was significantly higher in the SelT-insKO mice compared with wild-type littermates, pointing to a deficit in insulin production/secretion in mutant mice. In addition, morphometric analysis showed that islets from SelT-insKO mice were smaller and that their number was significantly increased compared with islets from their wild-type littermates. Finally, we found that SelT is up-regulated by pituitary adenylate cyclase-activating polypeptide (PACAP) in β-pancreatic cells and that SelT could act by facilitating a feed-forward mechanism to potentiate insulin secretion induced by the neuropeptide. Our findings are the first to show that the PACAP-regulated SelT is localized in pancreatic β- and δ-cells and is involved in the control of glucose homeostasis.

Les lesions cerebrales survenant chez le nouveau ne premature s'accompagnent de troubles du developpement sensorimoteur et/ou cognitif. Les repercussions consequentes sur le plan personnel et societal justifient de mener des etudes systematiques, incluant notamment les facteurs de risques, les declencheurs, les mecanismes cellulaires et moleculaires, les traitements ou les modes de prevention possibles. La comprehension de ces aspects beneficie largement a ce jour de resultats obtenus chez des modeles animaux, notamment rongeurs. Ce travail presente l'apport de ces modeles dans l'etude des lesions cerebrales du premature, en s'attachant en particulier sur trois d'entre eux parmi les plus utilises. Il se focalise ensuite sur la question des mesures comportementales associees en exposant les methodes actuelles ainsi que les difficultes rencontrees et des perspectives possibles et necessaires.

In our laboratories we use T-pattern analysis to study rat behavior in different and well-known experimental assays widely employed as rodent models of anxiety: the open field, the hole board and the elevated plus maze. By using Theme software and T-pattern analysis, we have observed that numerous events, characterizing rodent behavior in each experimental model, occurred sequentially and with significant constraints on the interval lengths separating them. In this chapter, for each test, we highlight some key aspects of our behavioral analyses, with a twofold attempt: first to provide the researcher with useful information concerning the application of T-pattern analysis in the study of rodent behavior and, second, to present and discuss various results of our studies., peer-reviewed

Le neuropeptide 26RFa, aussi nomme QRFP (pour pyroglutamilated RFamide peptide ), est le dernier membre de la famille des peptides RFamide a avoir ete decouvert. Le 26RFa et sa forme allongee en N-terminal, le 43RFa, ont ete caracterises dans toutes les classes de vertebres et les deux peptides ont ete identifies comme ligands endogenes d’un recepteur humain orphelin, le GPR103. Dans le cerveau, les transcrits du 26RFa et du GPR103 sont essentiellement exprimes dans des noyaux de l’hypothalamus impliques dans le controle du comportement alimentaire, et a la peripherie, le neuropeptide et son recepteur sont presents en abondance dans le tractus gastro-intestinal et les ilots pancreatiques, suggerant une implication du 26RFa dans la regulation du metabolisme energetique. De fait, le 26RFa stimule la prise alimentaire lorsqu’il est injecte au niveau central, et son activite orexigene est renforcee chez les animaux obeses. De plus, l’expression du 26RFa est augmentee dans l’hypothalamus des animaux obeses, suggerant que le systeme peptidergique 26RFa/GPR103 pourrait etre implique dans l’etablissement et le developpement de l’obesite. Des donnees recentes indiquent que le 26RFa intervient aussi dans la regulation de l’homeostasie glucidique. En effet, le 26RFa reduit significativement l’hyperglycemie induite par le glucose, augmente la sensibilite`a l’insuline ainsi que l’insulinemie. De plus, l’ingestion orale de glucose stimule fortement la liberation de 26RFa par le tube digestif, revelant que le 26RFa est une nouvelle incretine. Enfin, le 26RFa previent la mort et l’apoptose des cellules β pancreatiques. En conclusion, cette revue de la litterature montre que le 26RFa est un neuropeptide cle dans le controle du metabolisme energetique et des pistes de recherche sont evoquees pour mieux comprendre l’implication physiopathologique du systeme 26RFa/GPR103.

International audience; RésuméObjectifLe neuropeptide 26RFa exerce une activité orexigène via l’activation de son récepteur le GPR103 présent sur les neurones hypothalamiques à NPY. Nous avons déjà rapporté une augmentation des concentrations plasmatiques du peptide chez les patients obèses et diabétiques. L’objectif du travail est de déterminer l’origine du 26RFa plasmatique et son implication dans la régulation glycémique.Matériel et méthodesLe 26RFA exerce une activité de type incrétine Un immunomarquage sur différents segments du tractus digestif humain et murin a été réalisé avec un anticorps dirigé contre le 26RFa et le GPR103. Les concentrations plasmatiques du 26RFa ont été déterminées (dosage RIA) chez la souris après charge orale ou IV de glucose. La sécrétion intestinale du 26RFA lors d’une exposition au glucose a été évaluée in vitro à partir de segments de tractus digestifs murins montés en chambre de Ussing. Enfin, l’effet du 26RFA sur la sécrétion d’insuline a été évalué chez la souris et sur une lignée de cellules MIN6.RésultatsL’ensemble du tractus digestif humain et murin exprime le 26RFA et son récepteur. Chez la souris, les concentrations plasmatiques de 26RFA, stables lors de la charge IV de glucose, sont significativement augmentées 30minutes après la charge orale. Parallèlement in vitro, le glucose induit une libération significative de 26RFa par l’intestin proximal. Enfin, le 26RFA augmente la sécrétion d’insuline chez la souris et sur les cellules MIN6.ConclusionL’ensemble de ces données suggère pour la première fois que le 26RFA est impliqué dans la régulation glycémique via une activité de type incrétine.

26RFa is a hypothalamic neuropeptide that promotes food intake. 26RFa is upregulated in obese animal models, and its orexigenic activity is accentuated in rodents fed a high-fat diet, suggesting that this neuropeptide might play a role in the development and maintenance of the obese status. As obesity is frequently associated with type 2 diabetes, we investigated whether 26RFa may be involved in the regulation of glucose homeostasis. In the current study, we show a moderate positive correlation between plasma 26RFa levels and plasma insulin in patients with diabetes. Plasma 26RFa concentration also increases in response to an oral glucose tolerance test. In addition, we found that 26RFa and its receptor GPR103 are present in human pancreatic β-cells as well as in the gut. In mice, 26RFa attenuates the hyperglycemia induced by a glucose load, potentiates insulin sensitivity, and increases plasma insulin concentrations. Consistent with these data, 26RFa stimulates insulin production by MIN6 insulinoma cells. Finally, we show, using in vivo and in vitro approaches, that a glucose load induces a massive secretion of 26RFa by the small intestine. Altogether, the present data indicate that 26RFa acts as an incretin to regulate glucose homeostasis.

Brain-reactive auto-antibodies appear as key elements in the progressive CNS disturbances associated with systemic lupus erythematosus. The BxSB lupus prone mice are a model of this pathology, in which a gene located on the Y chromosome provokes a sex specific morbidity in males. This study was aimed to establish and characterize the relationships between behavioral disorders, neurological deficiencies and the aged-related immunological perturbations in this murine model. For this purpose, spatial and motor abilities were evaluated in male and female mice at six and 26 weeks of age. The results showed that the older males were greatly altered in their spatial abilities while the young ones and the females, whatever their age, were not. None of the animals had motor skill and motor learning disabilities. These spatial alterations were associated with modifications of basal neuronal activity measured by the cytochrome oxidase histochemical method in several areas directly or indirectly involved in spatial behavior, such as the hippocampus, the amygdala, the parietal and perirhinal cortex. Immunological study allowed us to correlate the behavioral abnormalities to the appearance of antibodies reactivities against cellular and nuclear components.

International audience; The elevated plus-maze (EPM) is a very common rodent test of anxiety. It is based on an approach-avoidance conflict between secure closed arms and aversive open arms. However, discrepancies remain on the interpretation of animals' behavior in this assay. The purpose of our study was to get a better understanding of the mouse behavior in the EPM. We applied a minute-by-minute analysis to compare the behavior of mice forcibly exposed to the maze or set free to explore the maze from a familiar box. Three strains of mice (CD1, BALB/c, and C57Bl/6) were tested. The combination of our different conditions of the test with the minute-by-minute analysis showed that mice did not avoid open arms during the first 2 min of the test when they were forcibly exposed to the EPM. Conversely, free exploration of the EPM resulted in a pattern of behavior characterized by open arm avoidance from the outset, demonstrating that open arm avoidance in mice is unconditioned. These findings generalize across the 3 mouse strains. These data suggest that rodents enter the open arms to complete spatial information about the apparatus as a whole before their natural tendency to avoid them is expressed. Our data also indicate that a detailed behavioral analysis is needed whenever BALB/c mice are to be exposed by force to the EPM. Further studies are required to fully understand the behavior of rodents in the EPM and to avoid false interpretations in the fields of psychopharmacology and behavioral neuroscience.

International audience; Ca(V)3.1 T-type channels are abundant at the cerebellar synapse between parallel fibers and Purkinje cells where they contribute to synaptic depolarization. So far, no specific physiological function has been attributed to these channels neither as charge carriers nor more specifically as Ca2+ carriers. Here we analyze their incidence on synaptic plasticity, motor behavior, and cerebellar motor learning, comparing WT animals and mice where T-type channel function has been abolished either by gene deletion or by acute pharmacological blockade. At the cellular level, we show that Ca(V)3.1 channels are required for long-term potentiation at parallel fiber-Purkinje cell synapses. Moreover, basal simple spike discharge of the Purkinje cell in KO mice is modified. Acute or chronic T-type current blockade results in impaired motor performance in particular when a good body balance is required. Because motor behavior integrates reflexes and past memories of learned behavior, this suggests impaired learning. Indeed, subjecting the KO mice to a vestibulo-ocular reflex phase reversal test reveals impaired cerebellum-dependent motor learning. These data identify a role of low-voltage activated calcium channels in synaptic plasticity and establish a role for Ca(V)3.1 channels in cerebellar learning.

Introduction Le neuropeptide 26RFa exerce une activite orexigene, via l’activation de son recepteur le GPR103, en regulant le systeme NPY/POMC de l’hypothalamus. L’expression hypothalamique du 26RFa est augmentee chez le rongeur soumis a un regime High Fat et nous avons deja rapporte une augmentation des concentrations plasmatiques de ce peptide chez les patients obeses et diabetiques. L’objectif du present travail est de determiner l’origine du 26RFa plasmatique et son implication dans l’homeostasie du glucose. Materiels et methodes un immunomarquage sur differents segments du tractus digestif de souris a ete realise avec un anticorps dirige contre le 26RFa. Les concentrations plasmatiques du 26RFa ont ete determinees par dosage radio-immunologique chez la souris apres l’administration orale de glucose. La secretion intestinale du 26RFa lors d’une exposition au glucose a ete evaluee in vitro a partir des differents segments de tractus digestif montes en chambre de Ussing. Enfin, les profils glycemique et insulinemique apres administration de 26RFa (500 µg/kg) ont ete determines au decours d’une charge intraperitoneale en glucose (2 g/kg). Un test de tolerance a l’insuline avec le 26RFa a egalement ete realise Resultats Des cellules a 26RFA presentant un phenotype neuroendocrine sont observees dans l’ensemble du tractus digestif. Les concentrations plasmatiques de 26RFa chez la souris sont significativement augmentees 30 minutes apres l’administration orale de glucose. Parallelement, le glucose induit in vitro une liberation significative de 26RFa par l’intestin proximale. Enfin, le 26RFa diminue significativement l’hyperglycemie induite par une charge en glucose en augmentant la sensibilite a l’insuline et la secretion de l’insuline Conclusion L’ensemble de ces donnees suggere pour la premiere fois que le 26RFa d’origine digestive est implique dans la regulation glycemique via une activite de type incretine. Declaration d’interet Les auteurs declarent ne pas avoir d’interet direct ou indirect (financier ou en nature) avec un organisme prive, industriel ou commercial en relation avec le sujet presente.

Les travaux anterieurs de notre equipe ont montre que les mastocytes exercent un controle paracrine stimulant sur la secretion d’aldosterone par la glande surrenale humaine normale. Les mastocytes paraissent jouer egalement un role dans la physiopathologie de l’hyperaldosteronisme primaire, la forte densite mastocytaire observee dans les adenomes de Conn etant correlee a l’aldosteronemie des patients. Les mastocytes intra-surrenaliens seraient donc susceptibles de liberer des facteurs stimulant la production de mineralocorticoides. Notre etude vise a evaluer le role des mastocytes dans la regulation de la secretion d’aldosterone grâce a l’utilisation de souris transgeniques C57BL/6 Kit W-sh/W-sh depourvues de mastocytes, par comparaison a la souche sauvage. En regime hyposode, les souris deficientes en mastocytes presentent une elevation de l’aldosteronurie superieure a celle des animaux temoins, ainsi qu’une diminution de la kaliurese et une augmentation de la pression arterielle systolique. Ces souris developpent egalement un syndrome polyuro-polydipsique associee a une baisse de l’osmolalite urinaire. Un test de restriction hydrique permet de conclure a une polydipsie primaire. L’analyse par PCR quantitative revele que l’expression du gene CYP11B2, codant l’aldosterone synthase, est doublee dans les surrenales des souris Kit W?sh/W-sh par rapport a celle des animaux sauvages. L’immunoreactivite de l’aldosterone synthase est plus intense dans les glandes surrenales des souris transgeniques que dans celles des animaux controles. Ces resultats indiquent qu’en regime hyposode, l’absence de mastocyte entraine a la fois une polydipsie primaire et une production exacerbee d’aldosterone. Nos donnees montrent pour la premiere fois le role des mastocytes dans la regulation de l’homeostasie hydrominerale.

The aim of present research is to study the temporal structure of the behavior in two strains of rats with different basal level of emotionality. To this purpose, the temporal profile of the behavior in Wistar rat and in the spontaneously more anxious DA/Han strain was analyzed in the Elevated Plus Maze. Both quantitative and multivariate t-pattern analyses were carried out. In comparison with Wistar, DA/Han subjects showed a significant reduction of the permanence in open arm and a significant increase of the time spent in the central platform of the maze. Mean frequencies of each behavioral element showed significant modifications both in open and in closed arm. Multivariate t-pattern analyses demonstrated a very different temporal profile of behavior in the two strains: Wistar rats presented 197 t-patterns of different composition, whereas DA/Han rats only 26; as to the mean number of t-patterns, Wistar presented a value of 698.90, whereas DA/Han only 92.80. Similar clear-cut differences were detected for the mean number of t-patterns in the two arms and for the time course of such t-patterns. Present study has evidenced that the temporal organization of the bahavior in Elevated Plus Maze is differently structured in two strains of rats with different basal level of emotionality.

Aim of the research was to evaluate, by means of quantitative and multivariate temporal pattern analyses, the behavior of Wistar rat in elevated plus maze (EPM) test. On the basis of an ethogram encompassing 24 behavioral elements, quantitative results showed that 130.14 ± 8.01 behavioral elements occurred in central platform and in closed arms (protected zones), whereas 88.62 ± 6.04 occurred in open arms (unprotected zones). Percent distribution was characterized by a prevalence of sniffing, walking and vertical exploration. Analysis of minute-by-minute duration evidenced a decrease for time spent in open arms and central platform and an increase for time spent in closed arms. As to multivariate t-pattern analysis, 126 different temporal patterns were detected. Behavioral stripes, summarizing distribution of such t-patterns along time, showed that several t-patterns were not homogeneously distributed along the test observational period: t-patterns encompassing behavioral events occurring prevalently in central platform-open arms were observed during the first minutes, whereas t-patterns structured on the basis of events occurring mainly in central platform-closed arms were detected during the last minutes. Therefore, during the observation in elevated plus maze, rat's behavior undergoes significant rearrangements of its temporal features. Present research demonstrates, for the first time, the existence of complex and significantly timed behavioral sequences in the activity of Wistar rats tested in elevated plus maze. Application of t-pattern analysis can provide useful tools to characterize the behavioral dynamics of anxiety-related rodent behavior and differentiate the effect of various anxioselective substances.

Introduction Le 26RFa est un neuropeptide initialement decouvert dans l'hypothalamus mais qui est egalement present en abondance dans le tractus gastrointestinal et les ilots pancreatiques. Nous avons recemment montre que le 26RFa regule l'homeostasie glucidique en agissant comme une incretine et en augmentant l'insulino-sensibilite. L'objectif de la presente etude etait d'evaluer l'impact du 26RFa sur la regulation glycemique au cours de l'obesite associee au diabete de type 2. Materiels et Methodes Nous avons utilise un modele de souris obeses et diabetiques, en soumettant les animaux a un regime hypercalorique high fat (HF) pendant 3 mois. La glycemie et l'insulinemie ont ete mesurees au cours de differents tests fonctionnels in vivo. L'expression du recepteur du 26RFa dans les tissus cibles de l'insuline a ete mesuree par PCR quantitative. Nous avons egalement evalue l'effet du 26RFa sur la secretion d'insuline par les cellules β pancreatiques humaines EndoC-βH1, en condition native et dans un modele de lipotoxicite induit par le palmitate. Resultats Chez les souris obeses et diabetiques, nous avons observe une perte de l'effet antihyperglycemiant du 26RFa et une diminution de son effet insulinosensibilisateur. Le recepteur du 26RFa, le GPR103, est exprime dans le muscle et le tissu adipeux et son expression est diminuee chez les souris HF. Le 26RFa stimule significativement la secretion d'insuline gluco-induite par les cellules β pancreatiques humaines EndoC-βH1. L'exposition des cellules au palmitate pendant 4 jours diminue significativement la secretion d'insuline par les EndoC-βH1, et abolit totalement l'effet insulino-secretant du 26RFa. De plus, le traitement au palmitate induit une baisse d'expression du GPR103. Conclusions Chez les animaux obeses et diabetiques, le 26RFa perd ses proprietes antihyperglycemiantes. Les effets insulino-senbilisateurs et insulino-secretants du 26RFa sont alteres, ce qui pourrait s'expliquer en partie par une baisse d'expression de son recepteur dans les tissus cibles de l'insuline et dans les cellules β pancreatiques.

Spatial representation is an active process that requires complex multimodal integration from a large interacting network of cortical and subcortical structures. We sought to determine the role of cerebellar protein kinase C (PKC)-dependent plasticity in spatial navigation by recording the activity of hippocampal place cells in transgenic L7PKCI mice with selective disruption of PKC-dependent plasticity at parallel fiber-Purkinje cell synapses. Place cell properties were exclusively impaired when L7PKCI mice had to rely on self-motion cues. The behavioral consequence of such a deficit is evidenced here by selectively impaired navigation capabilities during a path integration task. Together, these results suggest that cerebellar PKC-dependent mechanisms are involved in processing self-motion signals essential to the shaping of hippocampal spatial representation.

International audience; RésuméCO-023L'activation du sytème rénine-angiotensine intrassurénalien est responsable d’un hyperaldostéronisme chez les souris déficientes en mastocyte en régime hyposodé.HG. Boyer*a (M.), J. Wilsb (Dr), A. Araboc (Dr), C. Duparca (Dr), I. Bouteleta (Dr), H. Lefebvred (Pr), E. Louiseta (Dr)a INSERM U982, Université de Rouen, Institut de Recherche et d’innovation Biomédicale, Université de Rouen, Mont Saint Aignan, FRANCE ; b Laboratoire de Biochimie Médicale, Institut de Biologie Clinique, CHU de Rouen, Rouen, FRANCE ; c UFR des Sciences et Techniques, Université de Rouen, Mont Saint Aignan, FRANCE ; d Service d'Endocrinologie, Diabète et Maladies Métaboliques, CHU de Rouen, Rouen, Rouen, FRANCE* hadrien.boyer@etu.univ-rouen.frLes mastocytes intrasurrénaliens seraient susceptibles de libérer des facteurs modulant la production de minéralocorticoïdes. Cette étude évalue le rôle des mastocytes dans la régulation de la sécrétion d’aldostérone grâce à l'utilisation de souris transgéniques C57BL/6 Kit W-sh/W-sh dépourvues de mastocyte. En régime normosodé, les souris ont un profil électrolytique normal toutefois associé à une expression plus forte du gène codant la rénine dans le rein. En régime hyposodé, les souris déficientes en mastocyte développent un syndrome polyuro-polydipsique associé à une réduction de leur osmolalité urinaire et kaliémie. De plus, les souris transgéniques présentent une élévation du taux d’aldostérone plasmatique et de la pression artérielle. L’expression du gène CYP11B2, codant l’aldostérone synthase, est doublée dans les surrénales des souris Kit W?sh/W-sh par rapport aux animaux sauvages. De même, l’immunoréactivité de l’aldostérone synthase est plus prononcée dans les surrénales des animaux transgéniques. Le régime hyposodé, qui stimule le système rénine angiotensine chez les animaux sauvages, n’a pas d’effet sur l’expression du gène codant la rénine dans les reins des animaux déficients en mastocyte. En revanche, la privation de sodium augmente l’expression des gènes codant la rénine et le récepteur de l’angiotensine II dans leurs surrénales. L’activation du système rénine-angiotensine intrassurrénalien est responsable de l’hypersécrétion d’aldostérone chez les souris déficientes en mastocyte. L’activation du système rénine-angiotensine local compenserait la perturbation de l’équilibre hydrominéral occasionnée par l’absence de mastocyte chez les souris Kit W?sh/W-sh. Nos données indiquent que les mastocytes sont impliqués dans la régulation de la production d’aldostérone et de l’homéostasie hydrominérale.L’auteur n’a pas transmis de déclaration de conflit d’intérêt.

Introduction Le 26RFa est un neuropeptide orexigene, ligand endogene du recepteur GPR103. Des travaux realises chez l’animal suggerent sa participation dans la physiopathologie de l’obesite. Notre travail evalue les concentrations plasmatiques du 26RFa chez des patients obeses et/ou diabetiques et l’implication du peptide dans la regulation glycemique. Patients et methodes Un dosage plasmatique du 26RFa a ete realise chez 161 sujets repartis en 4 groupes : controles, obeses non diabetiques, patients DT1, patients DT2. Le 26RFa plasmatique a egalement ete evalue lors d’une HGPO chez des sujets controles. La localisation du 26RFa et du GPR103 a ete recherchee sur des coupes pancreatiques humaines. Enfin, des tests de tolerance au glucose avec administration du 26RFa ont ete realises chez la souris. Resultats La concentration plasmatique a jeun du 26RFa est significativement plus elevee chez les patients obeses comparativement aux controles (352 ± 47 vs 224 ± 32 pg/mL ; p Conclusion Nous rapportons pour la premiere fois que le 26RFa est eleve chez les patients obeses et diabetiques et que ce peptide est implique dans l’homeostasie glucidique.

In the systemic autoimmune/inflammatory lupus erythematosus disease, the involvement of the central nervous system is well recognized and frequently includes deficits in neurological function, cognition, and affect. The (NZW x BXSB)F1 lupus-prone mice are model of this pathology, in which a gene located on the Y chromosome provokes a sex specific morbidity in males. The present study examines whether autoimmune (NZW x BXSB)F1 mice develop impairments in learning and memory that correlate with severity of lupus-like disease. For this purpose, spatial and motor abilities were evaluated in 6- and 20-week-old male and female mice, and the immune status of these behaviorally tested mice was assessed by the presence of anti-nuclear antibodies (ANAbs) in the serum. The results showed that none of the animals had motor skill and motor learning disabilities, but that the older males were greatly impaired in their spatial abilities while the young ones and the females, whatever their age, were not. Besides, the ANAbs levels were similar and low in the young males, the young females and the old females, and very much higher in the old males, showing that spatial alterations were correlated to the anti-nuclear antibodies level.

Introduction Le 26RFa est un neuropeptide orexigene, ligand endogene du recepteur GPR103. Des travaux realises chez l’animal suggerent sa participation dans la physiopathologie de l’obesite. Notre travail vise a evaluer les concentrations plasmatiques du 26RFa chez des patients obeses et/ou diabetiques et l’implication du peptide dans la regulation glycemique. Patients et methodes Un dosage plasmatique du 26RFa a ete realise chez 161 sujets repartis en 4 groupes : controles normoponderaux normoglycemiques (n = 37), obeses non diabetiques (n = 52), patients DT1 (n = 19), patients DT2 (n = 53). Le 26RFa plasmatique a egalement ete evalue au decours d’une hyperglycemie par voie orale (HGPO) chez des sujets controles. La localisation du 26RFa et du GPR103 a ete recherchee sur des coupes pancreatiques humaines. Enfin, des tests de tolerance au glucose avec administration du 26RFa ont ete realises chez la souris. Resultats La concentration plasmatique a jeun du 26RFa est significativement plus elevee chez les patients obeses comparativement aux controles (352 ± 47 vs 224 ± 32 pg/ml ; p Conclusion Nous rapportons pour la premiere fois que le 26RFa est eleve chez les patients obeses et diabetiques en lien avec la glycemie a jeun. De plus, nous montrons que le peptide est implique dans l’homeostasie glucidique en regulant la secretion d’insuline.

Introduction Il existe de nombreuses donnees dans la litterature qui rendent compte de l’importance du selenium et des selenoproteines dans la pathogenie du diabete. Des travaux recents dans notre laboratoire ont montre qu’une nouvelle selenoproteine, la selenoproteine T (SelT), dont le role est inconnu, etait exprimee par des cellules neuroendocrines (PC12) apres stimulation par le PACAP. L’invalidation de la SelT dans ce modele cellulaire altere les mouvements calciques et la liberation hormonale. L’objectif du present travail consiste a tester l’hypothese d’un role de la SelT dans le pancreas endocrine Materiels et methodes Des etudes immunohistochimiques avec un anticorps dirige contre la SelT ont ete realisees sur des coupes de pancreas humains et murins, analysees en microscopie confocale. L’expression de la SelT a egalement ete determinee par PCR quantitative. Sur un modele de souris transgeniques invalidees pour la SelT, le statut glycemique a ete analyse par tests de charge en glucose, dosages plasmatiques d’insuline et tests de sensibilite a l’insuline. Resultats Les etudes immunohistochimiques sur coupes de pancreas humains et murins ont montre un marquage de la SelT specifiquement dans les ilots de Langerhans. L’analyse en microscopie confocale a montre que la SelT etait exprimee dans les cellules beta et delta mais non dans les cellules alpha. L’expression de la SelT a ete confirmee par la technique de qPCR dans les ilots murins et humains et lignee MIN6. Les animaux dont le gene de la SelT est invalide a l’etat homozygote ne sont pas viables. Un profil hyperglycemique au cours du test de tolerance au glucose a ete observe chez des souris heterozygotes, sans difference significative des concentrations plasmatiques d’insuline ni de la sensibilite a l’insuline. Conclusion La SelT est fortement exprimee dans l’ilot de Langerhans et son invalidation est associee a un profil hyperglycemique. Des etudes complementaires in vitro sont en cours afin d’etablir les mecanismes impliques.