Implication of the enzyme Glycogen Synthase Kinase 3 (GSK3) in the mediation of the diabetogenic effects of glucocorticoids

Les glucocorticoïdes (GCs) sont largement prescrits en clinique en raison de leurs propriétés anti-inflammatoires, anti-allergiques et immuno-modulatrices. Cependant, ces traitements entrainent de nombreux effets secondaires, notamment des perturbations du métabolisme glucidique, faisant des GCs la première cause de diabète iatrogène. Les GCs exercent des effets néfastes sur les cellules beta; pancréatiques, affectant leur fonctionnalité, leur survie ainsi que leur développement. Dans ce travail, nous nous sommes intéressés à une cible moléculaire, l'enzyme Glycogène Synthase Kinase 3 (GSK3), dont la modulation permettrait d'atténuer les effets diabétogènes des GCs. Dans un premier temps, nous avons exploré in vitro et ex vivo le rôle de GSK3 dans l'apoptose et le dysfonctionnement cortico-induit de la cellule beta; pancréatique, et nous avons élucidé les mécanismes sous-jacents. Nous avons montré l'existence d'un dialogue entre la signalisation des GCs et GSK3, et nous avons identifié l'isoforme GSK3 beta ; comme étant celle qui joue un rôle prépondérant dans ce processus. Par la suite, in vivo, chez le rat Wistar, nous avons étudié l'impact de l'inhibition pharmacologique de GSK3 sur la modulation des effets diabétogènes des GCs. Nous avons montré qu'un traitement au chlorure de lithium, un inhibiteur reconnu de GSK3, permet la correction partielle des dérégulations de l'homéostasie glucidique induites par le traitement aux GCs. Enfin, nous nous sommes intéressés au développement pancréatique dans des conditions d'excès de GCs et au rôle de GSK3, notamment dans le développement de la cellule beta; et alpha; pancréatique au cours du développement. En conclusion, l'ensemble de nos résultats suggère que GSK3 semble être une cible prometteuse dans le but de diminuer les effets diabétogènes des GCs.Glucocorticoids are widely prescribed in clinics for their anti-inflammatory, anti-allergic, and immunomodulatory properties. However, these treatments cause many side effects, including disturbances in glucose metabolism, making glucocorticoids the leading cause of iatrogenic diabetes. Glucocorticoids exert adverse effects on pancreatic beta; cells, affecting their functionality, survival and development. In this work, we focused on a molecular target, the enzyme Glycogen Synthase Kinase 3 (GSK3), whose modulation would reduce the diabetogenic effects of glucocorticoids. First, we explored in vitro and ex vivo, the role of GSK3 in corticoid-induced apoptosis and dysfunction of pancreatic beta; cells, and we elucidated the underlying mechanisms, notably the implication of GSK3 in Glucocorticoid Receptor expression and nuclear localization. We have shown the existence of a complex cross-talk between GSK3 and glucocorticoids signaling pathway, and showed that GSK3beta; is the main isoform involved in the glucocorticoid-induced beta; cell apoptosis. Subsequently, in vivo, in Wistar rats, we studied the impact of pharmacological inhibition of GSK3 on the modulation of diabetogenic effects of glucocorticoids. We have shown that treatment with lithium chloride, a recognized GSK3 inhibitor, widely used in clinic in other diseases, allows partial correction of the deregulations of glucose homeostasis induced by glucocorticoids treatment. Finally, we investigated the pancreatic development under conditions of glucocorticoids excess as well as the role of GSK3, in the development of pancreatic beta; and α cells.In conclusion, our results suggest that GSK3 is a promising target for reducing the diabetogenic effects of GCs

Hypothesis and Theory: Circulating Alzheimer's-Related Biomarkers in Type 2 Diabetes. Insight From the Goto-Kakizaki Rat

International audienceEpidemiological data suggest an increased risk of developing Alzheimer's disease (AD) in individuals with type 2 diabetes (T2D). AD is anatomically associated with an early progressive accumulation of A beta leading to a gradual Tau hyperphosphorylation, which constitute the main characteristics of damaged brain in AD. Apart from these processes, mounting evidence suggests that specific features of diabetes, namely impaired glucose metabolism and insulin signaling in the brain, play a key role in AD. Moreover, several studies report a potential role of A beta and Tau in peripheral tissues such as pancreatic beta cells. Thus, it appears that several biological pathways associated with diabetes overlap with AD. The link between peripheral insulin resistance and brain insulin resistance with concomitant cognitive impairment may also potentially be mediated by a liver/pancreatic/brain axis, through the excessive trafficking of neurotoxic molecules across the blood-brain barrier. Insulin resistance incites inflammation and pro-inflammatory cytokine activation modulates the homocysteine cycle in T2D patients. Elevated plasma homocysteine level is a risk factor for AD pathology and is also closely associated with metabolic syndrome. We previously demonstrated a strong association between homocysteine metabolism and insulin via cystathionine beta synthase (CBS) activity, the enzyme implicated in the first step of the trans-sulfuration pathway, in Goto-Kakizaki (GK) rats, a spontaneous model of T2D, with close similarities with human T2D. CBS activity is also correlated with DYRK1A, a serine/threonine kinase regulating brain-derived neurotrophic factor (BDNF) levels, and Tau phosphorylation, which are implicated in a wide range of disease such as T2D and AD. We hypothesized that DYRK1A, BDNF, and Tau, could be among molecular factors linking T2D to AD. In this focused review, we briefly examine the main mechanisms linking AD to T2D and provide the first evidence that certain circulating AD biomarkers are found in diabetic GK rats. We propose that the spontaneous model of T2D in GK rat could be a suitable model to investigate molecular mechanisms linking T2D to AD

Lithium treatment mitigates the diabetogenic effects of chronic cortico-therapy

Background and purpose: Glucocorticoids (GCs) are the main treatment for autoimmune and inflammatory disorders and are also used as immunosuppressive therapy for patients with organ transplantation. However, these treatments have several side effects, including metabolic disorders. Indeed, cortico-therapy may induce insulin resistance, glucose intolerance, disrupted insulin and glucagon secretion, excessive gluconeogenesis, leading to diabetes in susceptible individuals. Recently, lithium has been shown to alleviate deleterious effects of GCs in various diseased conditions. Experimental approach: In this study, using two rat models of GC-induced metabolic disorders, we investigated the effects of Lithium Chloride (LiCl) in the mitigation of deleterious effects of GCs. Rats were treated either with corticosterone or dexamethasone, and with or without LiCl. Animals were then assessed for glucose tolerance, insulin sensitivity, in vivo and ex vivo glucose-induced insulin secretion and hepatic gluconeogenesis. Key results: We showed that in rats chronically treated with corticosterone, lithium treatment markedly reduced insulin resistance. In addition, in rats treated with dexamethasone, lithium administration improved glucose tolerance, associated with enhanced insulin secretion in vivo. Moreover, liver gluconeogenesis was reduced upon LiCl treatment. The improvement of insulin secretion in vivo appeared to be due to an indirect regulation of β cell function, since the ex vivo assessment of insulin secretion and β cell mass in islets from animals treated with LiCl revealed no difference compared to untreated animals. Conclusion and Implications: Collectively, our data provide evidences for the beneficial effects of lithium to mitigate the adverse metabolic effects of chronic cortico-therapy

Endoplasmic reticulum stress in renal cell carcinoma

The endoplasmic reticulum is an organelle exerting crucial functions in protein production, metabolism homeostasis and cell signaling. Endoplasmic reticulum stress occurs when cells are damaged and the capacity of this organelle to perform its normal functions is reduced. Subsequently, specific signaling cascades, together forming the so-called unfolded protein response, are activated and deeply impact cell fate. In normal renal cells, these molecular pathways strive to either resolve cell injury or activate cell death, depending on the extent of cell damage. Therefore, the activation of the endoplasmic reticulum stress pathway was suggested as an interesting therapeutic strategy for pathologies such as cancer. However, renal cancer cells are known to hijack these stress mechanisms and exploit them to their advantage in order to promote their survival through rewiring of their metabolism, activation of oxidative stress responses, autophagy, inhibition of apoptosis and senescence. Recent data strongly suggest that a certain threshold of endoplasmic reticulum stress activation needs to be attained in cancer cells in order to shift endoplasmic reticulum stress responses from a pro-survival to a pro-apoptotic outcome. Several endoplasmic reticulum stress pharmacological modulators of interest for therapeutic purposes are already available, but only a handful were tested in the case of renal carcinoma, and their effects in an in vivo setting remain poorly known. This review discusses the relevance of endoplasmic reticulum stress activation or suppression in renal cancer cell progression and the therapeutic potential of targeting this cellular process for this cancer.</p

Type 2 Diabetes Mellitus and Alzheimer’s Disease: Shared Molecular Mechanisms and Potential Common Therapeutic Targets

The global prevalence of diabetes mellitus and Alzheimer’s disease is increasing alarmingly with the aging of the population. Numerous epidemiological data suggest that there is a strong association between type 2 diabetes and an increased risk of dementia. These diseases are both degenerative and progressive and share common risk factors. The amyloid cascade plays a key role in the pathophysiology of Alzheimer’s disease. The accumulation of amyloid beta peptides gradually leads to the hyperphosphorylation of tau proteins, which then form neurofibrillary tangles, resulting in neurodegeneration and cerebral atrophy. In Alzheimer’s disease, apart from these processes, the alteration of glucose metabolism and insulin signaling in the brain seems to induce early neuronal loss and the impairment of synaptic plasticity, years before the clinical manifestation of the disease. The large amount of evidence on the existence of insulin resistance in the brain during Alzheimer’s disease has led to the description of this disease as “type 3 diabetes”. Available animal models have been valuable in the understanding of the relationships between type 2 diabetes and Alzheimer’s disease, but to date, the mechanistical links are poorly understood. In this non-exhaustive review, we describe the main molecular mechanisms that may link these two diseases, with an emphasis on impaired insulin and IGF-1 signaling. We also focus on GSK3β and DYRK1A, markers of Alzheimer’s disease, which are also closely associated with pancreatic β-cell dysfunction and type 2 diabetes, and thus may represent common therapeutic targets for both diseases

S100 proteins in fatty liver disease and hepatocellular carcinoma

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent and slow progressing hepatic pathology characterized by different stages of increasing severity which can ultimately give rise to the development of hepatocellular carcinoma (HCC). Besides drastic lifestyle changes, few drugs are effective to some extent alleviate NAFLD and HCC remains a poorly curable cancer. Among the deregulated molecular mechanisms promoting NAFLD and HCC, several members of the S100 proteins family appear to play an important role in the development of hepatic steatosis, non-alcoholic steatohepatitis (NASH) and HCC. Specific members of this Ca2+-binding protein family are indeed significantly overexpressed in either parenchymal or non-parenchymal liver cells, where they exert pleiotropic pathological functions driving NAFLD/NASH to severe stages and/or cancer development. The aberrant activity of S100 specific isoforms has also been reported to drive malignancy in liver cancers. Herein, we discuss the implication of several key members of this family, e.g., S100A4, S100A6, S100A8, S100A9 and S100A11, in NAFLD and HCC, with a particular focus on their intracellular versus extracellular functions in different hepatic cell types. Their clinical relevance as non-invasive diagnostic/prognostic biomarkers for the different stages of NAFLD and HCC, or their pharmacological targeting for therapeutic purpose, is further debated.</p

Underlying mechanisms of glucocorticoid-induced beta-cell death and dysfunction: a new role for glycogen synthase kinase 3

International audienceGlucocorticoids (GCs) are widely prescribed for their anti-inflammatory and immunosuppressive properties as a treatment for a variety of diseases. The use of GCs is associated with important side effects, including diabetogenic effects. However, the underlying mechanisms of GC-mediated diabetogenic effects in beta-cells are not well understood. In this study we investigated the role of glycogen synthase kinase 3 (GSK3) in the mediation of beta-cell death and dysfunction induced by GCs. Using genetic and pharmacological approaches we showed that GSK3 is involved in GC-induced beta-cell death and impaired insulin secretion. Further, we unraveled the underlying mechanisms of GC-GSK3 crosstalk. We showed that GSK3 is marginally implicated in the nuclear localization of GC receptor (GR) upon ligand binding. Furthermore, we showed that GSK3 regulates the expression of GR at mRNA and protein levels. Finally, we dissected the proper contribution of each GSK3 isoform and showed that GSK3 beta isoform is sufficient to mediate the pro-apoptotic effects of GCs in beta-cells. Collectively, in this work we identified GSK3 as a viable target to mitigate GC deleterious effects in pancreatic beta-cells

MiR-22 deficiency fosters hepatocellular carcinoma development in fatty liver

MiR-22 is mostly considered as a hepatic tumor-suppressor microRNA based on in vitro analyses. Yet, whether miR-22 exerts a tumor-suppressive function in the liver has not been investigated in vivo. Herein, in silico analyses of miR-22 expression were performed in hepatocellular carcinomas from human patient cohorts and different mouse models. Diethylnitrosamine-induced hepatocellular carcinomas were then investigated in lean and diet-induced obese miR-22-deficient mice. The proteome of liver tissues from miR-22-deficient mice prior to hepatocellular carcinoma development was further analyzed to uncover miR-22 regulated factors that impact hepatocarcinogenesis with miR-22 deficiency. MiR-22 downregulation was consistently observed in hepatocellular carcinomas from all human cohorts and mouse models investigated. The time of appearance of the first tumors was decreased and the number of tumoral foci induced by diethylnitrosamine was significantly increased by miR-22-deficiency in vivo, two features which were further drastically exacerbated with diet-induced obesity. At the molecular level, we provide evidence that the loss of miR-22 significantly affects the energetic metabolism and mitochondrial functions of hepatocytes, and the expression of tumor-promoting factors such as thrombospondin-1. Our study demonstrates that miR-22 acts as a hepatic tumor suppressor in vivo by restraining pro-carcinogenic metabolic deregulations through pleiotropic mechanisms and the overexpression of relevant oncogenes.</p