The glutamate receptor GluK2 contributes to the regulation of glucose homeostasis and its deterioration during aging

OBJECTIVE: Islets secrete neurotransmitters including glutamate which participate in fine regulation of islet function. The excitatory ionotropic glutamate receptor GluK2 of the kainate receptor family is widely expressed in brain and also found in islets, mainly in alpha and gamma cells. alpha cells co-release glucagon and glutamate and the latter increases glucagon release via ionotropic glutamate receptors. However, neither the precise nature of the ionotropic glutamate receptor involved nor its role in glucose homeostasis is known. As isoform specific pharmacology is not available, we investigated this question in constitutive GluK2 knock-out mice (GluK2-/-) using adult and middle-aged animals to also gain insight in a potential role during aging. METHODS: We compared wild-type GluK2+/+ and knock-out GluK2-/- mice using adult (14-20 weeks) and middle-aged animals (40-52 weeks). Glucose (oral OGTT and intraperitoneal IPGTT) and insulin tolerance as well as pyruvate challenge tests were performed according to standard procedures. Parasympathetic activity, which stimulates hormones secretion, was measured by electrophysiology invivo. Isolated islets were used invitro to determine islet beta-cell electrical activity on multi-electrode arrays and dynamic secretion of insulin as well as glucagon was determined by ELISA. RESULTS: Adult GluK2-/- mice exhibit an improved glucose tolerance (OGTT and IPGTT), and this was also apparent in middle-aged mice, whereas the outcome of pyruvate challenge was slightly improved only in middle-aged GluK2-/- mice. Similarly, insulin sensitivity was markedly enhanced in middle-aged GluK2-/- animals. Basal and glucose-induced insulin secretion invivo was slightly lower in GluK2-/- mice, whereas fasting glucagonemia was strongly reduced. Invivo recordings of parasympathetic activity showed an increase in basal activity in GluK2-/- mice which represents most likely an adaptive mechanism to counteract hypoglucagonemia rather than altered neuronal mechanism. Invitro recording demonstrated an improvement of glucose-induced electrical activity of beta-cells in islets obtained from GluK2-/- mice at both ages. Finally, glucose-induced insulin secretion invitro was increased in GluK2-/- islets, whereas glucagon secretion at 2mmol/l of glucose was considerably reduced. CONCLUSIONS: These observations indicate a general role for kainate receptors in glucose homeostasis and specifically suggest a negative effect of GluK2 on glucose homeostasis and preservation of islet function during aging. Our observations raise the possibility that blockade of GluK2 may provide benefits in glucose homeostasis especially during aging.Transistors multimodaux sensibles aux ions à polymères ambivalents pour biocapteurs hybridesIdentification de biomarqueurs du stress et de l'inflammation des cellules B pancréatiques en explorant les communications inter-organes dans des modèles précliniques d'obésité et de diabète de type

Regenerating islet-derived protein 3α : A promising therapy for diabetes. Preliminary data in rodents and in humans

Publisher Copyright: © 2022The aim of our study was to test the hypothesis that administration of Regenerating islet-derived protein 3α (Reg3α), a protein described as having protective effects against oxidative stress and anti-inflammatory activity, could participate in the control of glucose homeostasis and potentially be a new target of interest in the treatment of type 2 diabetes. To that end the recombinant human Reg3α protein was administered for one month in insulin-resistant mice fed high fat diet. We performed glucose and insulin tolerance tests, assayed circulating chemokines in plasma and measured glucose uptake in insulin sensitive tissues. We evidenced an increase in insulin sensitivity during an oral glucose tolerance test in ALF-5755 treated mice vs controls and decreased the pro-inflammatory cytokine C-X-C Motif Chemokine Ligand 5 (CXCL5). We also demonstrated an increase in glucose uptake in skeletal muscle. Finally, correlation studies using human and mouse muscle biopsies showed negative correlation between intramuscular Reg3α mRNA expression (or its murine isoform Reg3γ) and insulin resistance. Thus, we have established the proof of concept that Reg3α could be a novel molecule of interest in the treatment of T2D by increasing insulin sensitivity via a skeletal muscle effect.Peer reviewe

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

L’exposition des populations des atolls de Rangiroa et de Tikehau (Polynésie française) au risque de submersion marine

Cet article représente l’une des rares études scientifiques cherchant à dépasser le discours général sur l’exposition des populations des atolls face aux risques liés à la mer, en l’occurrence ici à la submersion marine, en mesurant concrètement le degré réel d’exposition actuelle des populations et en observant les stratégies locales de protection/prévention de risques. Il s’applique à deux atolls de l’archipel des Tuamotu (Polynésie française) et croise deux types de données : les niveaux de submersion d’événements de référence passés, et les modes d’aménagement du territoire actuel (type d’habitat et dispositifs de défense des côtes). Les résultats reposent sur 106 entretiens semi-directifs et la caractérisation de 931 habitations. Ils indiquent d’abord que plus de 61 % des habitations sont aujourd’hui localisées dans une zone ayant connu au moins un épisode de submersion depuis les années 1980. Ensuite, que la stratégie de réponse des habitants face au risque de submersion marine passe moins par la mise en place de dispositifs de protection (murs, cordons d’enrochement, plantation de végétation, etc.) que par une surélévation de l’habitat. Celle-ci reste néanmoins limitée, puisque respectivement 52 % et 23 % des habitations sont surélevées de moins de 50 cm et 20 cm par rapport au niveau du sol et 23, et donc au mieux à quelques mètres au-dessus du niveau de la mer. Cela démontre un fort degré d’exposition à l’aléa submersion marine. Cet article analyse également les grands facteurs explicatifs de cette situation, à savoir une forte croissance démographique associée à un régime foncier contraignant qui, ensemble, expliquent la densification de l’habitat et des bâtiments publics dans des zones naturellement exposées. Des pistes concrètes de réduction de cette exposition sont discutées.This paper characterizes the current exposure of people leaving on the low-lying atoll reef islands to the risk of marine inundation induced by various sea-related hazards (i.e. cyclones, distant swells and local storms). It offers one of the rare scientific studies that go beyond the general assertion on atoll populations’ exposure to sea-related hazards, by bringing empirically based and detailed evidence on real exposure today. The paper builds on case studies in the Tuamotu Archipelago in French Polynesia, and combines two main types of data, i.e. the inundation levels of past events, and the management practices implemented by both inhabitants and public authorities (type of housing and coastal protection devices). The total sample is composed of 106 interviews and 931 studied houses. The results show first, that more than 61% of houses are located in an area that experienced at least one substantial marine inundation event since the 1980s. Second, that when inhabitants implement options to face coastal risks, they rather target coastal erosion (seawalls, rip-raps, vegetation plantation, etc.) than marine inundation. They only address the risk of marine inundation through housing standard, i.e. buildings’ elevation. This option however remains limited as 52% and 23% of houses have floor elevations less than 50 cm and 20 cm high, respectively. As a result, the population exhibits a high level of exposure to marine flooding. Exploring the root causes of such a situation, the paper emphasises the contributions of both the population growth that occurred over the past three decades and the constraining land tenure system to the increase in houses and public buildings density in flood-prone areas. Then the paper discusses pragmatic and realistic ways to decrease population exposure in the near future

L’exposition des populations des atolls de Rangiroa et de Tikehau (Polynésie française) au risque de submersion marine

Cet article représente l’une des rares études scientifiques cherchant à dépasser le discours général sur l’exposition des populations des atolls face aux risques liés à la mer, en l’occurrence ici à la submersion marine, en mesurant concrètement le degré réel d’exposition actuelle des populations et en observant les stratégies locales de protection/prévention de risques. Il s’applique à deux atolls de l’archipel des Tuamotu (Polynésie française) et croise deux types de données : les niveaux de submersion d’événements de référence passés, et les modes d’aménagement du territoire actuel (type d’habitat et dispositifs de défense des côtes). Les résultats reposent sur 106 entretiens semi-directifs et la caractérisation de 931 habitations. Ils indiquent d’abord que plus de 61 % des habitations sont aujourd’hui localisées dans une zone ayant connu au moins un épisode de submersion depuis les années 1980. Ensuite, que la stratégie de réponse des habitants face au risque de submersion marine passe moins par la mise en place de dispositifs de protection (murs, cordons d’enrochement, plantation de végétation, etc.) que par une surélévation de l’habitat. Celle-ci reste néanmoins limitée, puisque respectivement 52 % et 23 % des habitations sont surélevées de moins de 50 cm et 20 cm par rapport au niveau du sol et 23, et donc au mieux à quelques mètres au-dessus du niveau de la mer. Cela démontre un fort degré d’exposition à l’aléa submersion marine. Cet article analyse également les grands facteurs explicatifs de cette situation, à savoir une forte croissance démographique associée à un régime foncier contraignant qui, ensemble, expliquent la densification de l’habitat et des bâtiments publics dans des zones naturellement exposées. Des pistes concrètes de réduction de cette exposition sont discutées.This paper characterizes the current exposure of people leaving on the low-lying atoll reef islands to the risk of marine inundation induced by various sea-related hazards (i.e. cyclones, distant swells and local storms). It offers one of the rare scientific studies that go beyond the general assertion on atoll populations’ exposure to sea-related hazards, by bringing empirically based and detailed evidence on real exposure today. The paper builds on case studies in the Tuamotu Archipelago in French Polynesia, and combines two main types of data, i.e. the inundation levels of past events, and the management practices implemented by both inhabitants and public authorities (type of housing and coastal protection devices). The total sample is composed of 106 interviews and 931 studied houses. The results show first, that more than 61% of houses are located in an area that experienced at least one substantial marine inundation event since the 1980s. Second, that when inhabitants implement options to face coastal risks, they rather target coastal erosion (seawalls, rip-raps, vegetation plantation, etc.) than marine inundation. They only address the risk of marine inundation through housing standard, i.e. buildings’ elevation. This option however remains limited as 52% and 23% of houses have floor elevations less than 50 cm and 20 cm high, respectively. As a result, the population exhibits a high level of exposure to marine flooding. Exploring the root causes of such a situation, the paper emphasises the contributions of both the population growth that occurred over the past three decades and the constraining land tenure system to the increase in houses and public buildings density in flood-prone areas. Then the paper discusses pragmatic and realistic ways to decrease population exposure in the near future

The importance of on-site genetic counseling for prospective assisted reproductive technology patients

International audiencePurpose: To assess the value of having an onsite genetic counseling service integrated into an assisted reproductive technology (ART) center.Methods: Since January 2021, we have offered genetic counseling at our ART center for couples whose medical history suggests risk of transmission of a genetic disorder. The percentage of couples referred for genetic counseling, the distribution of couples according to reasons for consultation, the mode of transmission in cases of Mendelian disorders, and the frequency of mutations for those with identified genetic disorders were determined.Results: In an 18-month period, 150 of 1340 couples (11.2%) enrolled for ART treatment were referred to the genetic counseling unit. Two-thirds (99/150, 66.0%) were referred for a known genetic risk, a family history of a genetic disorder or chromosomal abnormality, a serious condition of unknown cause, or consanguinity. The remaining couples had a putative genetic risk (diminished ovarian reserve, high incidence of oocyte immaturity, recurrent abortion, or severe male infertility). Of the 99 with known genetic risk, 62 (62.7%), were approved for ART treatment, 23 (23.2%) were recommended prenatal or preimplantation testing, and 14 (14.1%) were referred for further testing before undergoing ART.Conclusions: Our findings reveal great value in having an on-site genetic counseling unit for referral of ART patients. Such a unit makes the ART process smoother and safer for couples, and it lightens the burden of ART staff by removing responsibilities for which they are neither trained, nor should they have to assume

[Erratum for] "Palatability Can Drive Feeding Independent of AgRP Neurons"

Erratum for "Palatability Can Drive Feeding Independent of AgRP Neurons." [Cell Metab. 2015] hal-02067347International audienc

Palatability Can Drive Feeding Independent of AgRP Neurons

International audienceFeeding behavior is exquisitely regulated by homeostatic and hedonic neural substrates that integrate energy demand as well as the reinforcing and rewarding aspects of food. Understanding the net contribution of homeostatic and reward-driven feeding has become critical because of the ubiquitous source of energy-dense foods and the consequent obesity epidemic. Hypothalamic agouti-related peptide-secreting neurons (AgRP neurons) provide the primary orexigenic drive of homeostatic feeding. Using models of neuronal inhibition or ablation, we demonstrate that the feeding response to a fast ghrelin or serotonin receptor agonist relies on AgRP neurons. However, when palatable food is provided, AgRP neurons are dispensable for an appropriate feeding response. In addition, AgRP-ablated mice present exacerbated stress-induced anorexia and palatable food intake--a hallmark of comfort feeding. These results suggest that, when AgRP neuron activity is impaired, neural circuits sensitive to emotion and stress are engaged and modulated by food palatability and dopamine signaling