MicroARN et diabète

Rapidement après leur découverte, les microARN (miARN) ont acquis leurs lettres de noblesse en tant que régulateurs naturels de l’expression génique. Bien que les mécanismes complexes d’action et l’impact des miARN sur le développement, la physiologie et les maladies ne soient pas élucidés, des progrès notables ont été réalisés dans le décryptage du rôle de certains d’entre eux dans la sécrétion et l’action de l’insuline. Nous examinons ici la relation intime qui existe entre les miARN et le métabolisme glucidique. Nous discutons également le rôle potentiel des miARN dans la physiopathologie du diabète, ainsi que leur utilité éventuelle comme biomarqueurs de cette maladie

Rôle des acides aminés dans la signalisation de l'insuline et dans l'insulino-résistance du tissu adipeux

Les acides aminés sont les nutriments capables de réguler la protéine mTOR (mammalian Target Of Rapamycin) dans les cellules de mammifères. La protéine mTOR est principalement connue pour son rôle dans la régulation de la taille des cellules, notamment via la synthèse protéique. En plus d'être activée par les acides aminés, mTOR est régulée par l'insuline via une voie dépendante de la PI3K (Phosphatidylinositol 3-kinase). mTOR est un point de convergence entre les voies de signalisation des acides aminés et de l'insuline. mTOR a été peu étudié dans le tissu adipeux, un tissu cible majeur de l'insuline. Au cours de ma thèse, je me suis intéressée au rôle des acides aminés et de la protéine mTOR dans l'action de l'insuline dans ce tissu. Nous avons montré, dans les adipocytes fraîchement isolés de rat, que l'insuline et les acides aminés phosphorylent mTOR sur le résidu sérine 2448 et que ces deux agents activent indépendamment la voie de signalisation de mTOR. De manière intéressante, nous avons mis en évidence que les acides aminés permettent à l'insuline d'activer la voie PKB (protein kinase B)/mTOR via PDK-1 (phosphoinositide-dependent protein kinase-1), spécifiquement dans les adipocytes ou le tissu adipeux, quand l'activité de la PI3K est inhibée. Enfin, nous avons montré que les acides aminés améliorent la signalisation insulinique des adipocytes dans deux modèles d'insulino-résistance. Ainsi, les acides aminés, des molécules physiologiques, pourraient être utilisés comme des agents favorables pour le traitement et/ou la prévention de l'insulino-résistance chez l'homme.NICE-BU Sciences (060882101) / SudocSudocFranceF

The Adipose Tissue at the Crosstalk Between EDCs and Cancer Development

International audienceObesity is a major public health concern at the origin of many pathologies, including cancers. Among them, the incidence of gastro-intestinal tract cancers is significantly increased, as well as the one of hormone-dependent cancers. The metabolic changes caused by overweight mainly with the development of adipose tissue (AT), insulin resistance and chronic inflammation induce hormonal and/or growth factor imbalances, which impact cell proliferation and differentiation. AT is now considered as the main internal source of endocrine disrupting chemicals (EDCs) representing a low level systemic chronic exposure. Some EDCs are non-metabolizable and can accumulate in AT for a long time. We are chronically exposed to low doses of EDCs able to interfere with the endocrine metabolism of the body. Importantly, several EDCs have been involved in the genesis of obesity affecting profoundly the physiology of AT. In parallel, EDCs have been implicated in the development of cancers, in particular hormone-dependent cancers (prostate, testis, breast, endometrium, thyroid). While it is now well established that AT secretes adipocytokines that promote tumor progression, it is less clear whether they can initiate cancer. Therefore, it is important to better understand the effects of EDCs, and to investigate the buffering effect of AT in the context of progression but also initiation of cancer cells using adequate models recommended to uncover and validate these mechanisms for humans. We will review and argument here the potential role of AT as a crosstalk between EDCs and hormone-dependent cancer development, and how to assess it

Fast urinary screening of oligosaccharidoses by MALDI-TOF/TOF mass spectrometry.

International audienceBACKGROUND: Oligosaccharidoses, which belong to the lysosomal storage diseases, are inherited metabolic disorders due to the absence or the loss of function of one of the enzymes involved in the catabolic pathway of glycoproteins and indirectly of glycosphingolipids. This enzymatic deficiency typically results in the abnormal accumulation of uncompletely degraded oligosaccharides in the urine. Since the clinical features of many of these disorders are not specific for a single enzyme deficiency, unambiguous screening is critical to limit the number of costly enzyme assays which otherwise must be performed. METHODS: Here we provide evidence for the advantages of using a MALDI-TOF/TOF (matrix-assisted laser desorption ionization time-of-flight) mass spectrometric (MS) method for screening oligosaccharidoses. Urine samples from previously diagnosed patients or from unaffected subjects were randomly divided into a training set and a blind testing set. Samples were directly analyzed without prior treatment. RESULTS: The characteristic MS and MS/MS molecular profiles obtained allowed us to identify fucosidosis, aspartylglucosaminuria, GM1 gangliosidosis, Sandhoff disease, α-mannosidosis, sialidosis and mucolipidoses type II and III. CONCLUSIONS: This method, which is easily run in less than 30 minutes, is performed in a single step, and is sensitive and specific. Invaluable for clinical chemistry purposes this MALDI-TOF/TOF mass spectrometry procedure is semi-automatizable and suitable for the urinary screening of oligosacharidoses

Argonaute-2 is associated to brown adipose tissue activation

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Low Doses of PFOA Promote Prostate and Breast Cancer Cells Growth through Different Pathways

Endocrine Disrupting Compounds (EDCs) are found in everyday products. Widely distributed throughout the environment, persistent organic pollutants (POPs) are a specific class of EDCs that can accumulate in adipose tissue. Many of them induce adverse effects on human health—such as obesity, fertility disorders and cancers—by perturbing hormone effects. We previously identified many compounds with EDC activity in the circulation of obese patients who underwent bariatric surgery. Herein, we analyzed the effects of four of them (aldrin, BDE28, PFOA and PCB153) on two cancer cell lines of hormone-sensitive organs (prostate and breast). Each cell line was exposed to serial dilutions of EDCs from 10−6 M to 10−12 M; cytotoxicity and proliferation were monitored using the IncuCyte® technology. We showed that none of these EDCs induce cytotoxicity and that PFOA and PCB153, only at very low doses (10−12 M), increase the proliferation of DU145 (prostate cancer) and MCF7 (breast cancer) cells, while the same effects are observed with high concentrations (10−6 M) for aldrin or BDE28. Regarding the mechanistic aspects, PFOA uses two different signaling pathways between the two lines (the Akt/mTORC1 and PlexinD1 in MCF7 and DU145, respectively). Thus, our study demonstrates that even at picomolar (10−12 M) concentrations PFOA and PCB153 increase the proliferation of prostate and breast cancer cell lines and can be considered possible carcinogens

Cyclin D2 is Essential for the Compensatory Beta-Cell Hyperplastic Response to Insulin Resistance in Rodents

OBJECTIVE: A major determinant of the progression from insulin resistance to the development of overt type 2 diabetes is a failure to mount an appropriate compensatory β-cell hyperplastic response to maintain normoglycemia. We undertook the present study to directly explore the significance of the cell cycle protein cyclin D2 in the expansion of β-cell mass in two different models of insulin resistance. RESEARCH DESIGN AND METHODS: We created compound knockouts by crossing mice deficient in cyclin D2 (D2KO) with either the insulin receptor substrate 1 knockout (IRS1KO) mice or the insulin receptor liver-specific knockout mice (LIRKO), neither of which develops overt diabetes on its own because of robust compensatory β-cell hyperplasia. We phenotyped the double knockouts and used RT-qPCR and immunohistochemistry to examine β-cell mass. RESULTS: Both compound knockouts, D2KO/LIRKO and D2KO/IRS1KO, exhibited insulin resistance and hyperinsulinemia and an absence of compensatory β-cell hyperplasia. However, the diabetic D2KO/LIRKO group rapidly succumbed early compared with a relatively normal lifespan in the glucose-intolerant D2KO/IRS1KO mice. CONCLUSIONS: This study provides direct genetic evidence that cyclin D2 is essential for the expansion of β-cell mass in response to a spectrum of insulin resistance and points to the cell-cycle protein as a potential therapeutic target that can be harnessed for preventing and curing type 2 diabetes

Organoids as a model to study the impact of EDCs on the prostate gland.

info:eu-repo/semantics/publishe

microRNA-375 regulates glucose metabolism-related signaling for insulin secretion

International audienceEnhanced beta cell glycolytic and oxidative metabolism are necessary for glucose-induced insulin secretion. While several microRNAs modulate beta cell homeostasis, miR-375 stands out as it is highly expressed in beta cells where it regulates beta cell function, proliferation and differentiation. As glucose metabolism is central in all aspects of beta cell functioning, we investigated the role of miR-375 in this process using human and rat islets; the latter being an appropriate model for in-depth investigation. We used forced expression and repression of mR-375 in rat and human primary islet cells followed by analysis of insulin secretion and metabolism. Additionally, miR-375 expression and glucose-induced insulin secretion were compared in islets from rats at different developmental ages. We found that overexpressing of miR-375 in rat and human islet cells blunted insulin secretion in response to glucose but not to α-ketoisocaproate or KCl. Further, miR-375 reduced O2 consumption related to glycolysis and pyruvate metabolism, but not in response to α-ketoisocaproate. Concomitantly, lactate production was augmented suggesting that glucose-derived pyruvate is shifted away from mitochondria. Forced miR-375 expression in rat or human islets increased mRNA levels of pyruvate dehydrogenase kinase-4, but decreased those of pyruvate carboxylase and malate dehydrogenase1. Finally, reduced miR-375 expression was associated with maturation of fetal rat beta cells and acquisition of glucose-induced insulin secretion function. Altogether our findings identify miR-375 as an efficacious regulator of beta cell glucose metabolism and of insulin secretion, and could be determinant to functional beta cell developmental maturation