De la patogénesis al tratamiento de la diabetes tipo 2. El paradigma de la rata GK

Now that the reduction in beta-mass has been clearly established in humans with type 2 diabetes mellitus (T2D), the debate focuses on the possible mechanisms responsible for abnormal islet microenvironment, decreased beta-cell number and impaired beta-cell function, and their multifactorial aetiologies. The informations available in the Goto-Kakizaki (GK/Par line) rat, one of the best characterized animal models of spontaneous T2D, are reviewed in such a perspective. We propose that the defective beta-cell mass and function in the GK/Par model reflects the complex interactions of three pathogenic players: i) several independent loci containing genes responsible for some diabetic traits (but not decreased beta-cell mass); (ii) gestational metabolic impairment inducing a programming of endocrine pancreas (decreased beta-cell neogenesis) which is transmitted to the next generation; and (iii) secondary (acquired) loss of beta-cell differentiation due to chronic exposure to hyperglycaemia (glucotoxicity). An important message is that the «heritable» determinants of T2D do not simply rely on genetic factors, but probably involve transgenerational epigenetic responses. Finally, studies from our group have shown that pharmacological use of GLP-1 receptor agonist in vivo during the GK prediabetes period, induced beta-cell regeneration through activation of beta-cell replication and neogenesis, and doing so prevented the development of hyperglycaemia. This suggests a novel application of GLP-1 receptor agonists to the prevention of human diabetes by treatment of at risk individuals during the prediabetic period. Since we also demonstrated that GLP-1 acutely restores the glucose competence of the GK beta-cell, GLP-1 receptor agonists turn to be very attractive tools for the treatment of the decreased beta-cell functioning mass as encountered in T2D.Ahora que la reducción de la masa de la célula beta ha sido claramente establecida en humanos con diabetes mellitas tipo 2 (T2D), el debate se focaliza sobre los posibles mecanismos responsables de un microambiente anormal en el islote, del decrecido número de células beta, del alterado funcionamiento de ellas y de sus etiologías multifactoriales. Las eficaces informaciones proporcionadas por la rata Goto-Kakizaki (línea GK), uno de los mejor caracterizados modelos animales de T2D espontánea, están siendo revisadas para tales fines. Nosotros proponemos que la defectuosa masa y función de la célula beta en el modelo GK reflejan unas interacciones complejas de tres vertientes patogénicas: i) varios loci que contienen genes responsables de algunos indicios diabéticos (pero no de decrecida masa de célula beta); ii) daño metabólico gestacional que induce un programa de páncreas endocrino (decrecida neogénesis de célula beta), lo cual es transmitido a la próxima generación, y iii) secundaria (adquirida) pérdida de diferenciación de célula beta debida a una exposición crónica a hiperglucemia (glucotoxicidad). Un mensaje importante es que los determinantes «heredables» de T2D no descansan simplemente sobre factores genéticos, sino probablemente envuelven respuestas epigenéticas transgeneracionales. Finalmente, estudios de nuestro grupo han mostrado que el uso farmacológico de agonistas del receptor de GLP-1 in vivo, en el periodo de prediabetes de ratas GK, inducían regeneración de célula beta, a través de la activación de la replicación y neogénesis de célula beta y de esta forma prevenían el desarrollo de hiperglucemia. Esto sugiere una nueva aplicación del receptor agonista de GLP-1 para la prevención de diabetes humana por el tratamiento con éste, durante el periodo prediabético, a individuos de riesgo. Como nosotros mostramos, también, que el GLP-1 restaura de forma acusada la sensibilidad a la glucosa de la célula beta GK, los agonistas del receptor de GLP-1 vuelven a ser una herramienta atractiva para el tratamiento del decrecimiento de la masa funcionante de la célula beta lo cual es encontrada en T2D

Activation of the GLP-1 Receptor Signalling Pathway: A Relevant Strategy to Repair a Deficient Beta-Cell Mass

Recent preclinical studies in rodent models of diabetes suggest that exogenous GLP-1R agonists and DPP-4 inhibitors have the ability to increase islet mass and preserve beta-cell function, by immediate reactivation of beta-cell glucose competence, as well as enhanced beta-cell proliferation and neogenesis and promotion of beta-cell survival. These effects have tremendous implication in the treatment of T2D because they directly address one of the basic defects in T2D, that is, beta-cell failure. In human diabetes, however, evidence that the GLP-1-based drugs alter the course of beta-cell function remains to be found. Several questions surrounding the risks and benefits of GLP-1-based therapy for the diabetic beta-cell mass are discussed in this review and require further investigation

Fetal pancreatic b-cell growth and insulin-like growth factors relationship in undernourished rats

Resumen del trabajo presentado al 38th EASD Annual Meeting of the European Association for the Study of Diabetes, celebrado en Budapest (Humgria) del 1 al 5 de septiembre de 2002.[Background and Aims] We have previously shown that Wistar fetuses from protein- caloric undernourished pregnant rats (U) at 21 days post coitum (dpc) exhibit increased β cell-mass. This alteration is correlated with increased insulinemia and total pancreatic insulin content, a pattern reminiscent to that reported in infants of mild diabetic mothers. Both Insulinlike Growth Factor (IGF)-I and -2 are essential players for growth and development during the fetal period. The aim of the present study was to investigate in the U fetuses at 21 dpc: 1) serum IGFs levels, 2) IGFs gene expression in the liver and pancreas, and 3) in vitro mitogenic effect of IGFs in isolated fetal islets using BrdU labelling index (LI). All values were compared to those in Wi star control fetuses (C). [Methods] Serum concentrations of IGF-I and IGF-2 were measured by radioimmuno assay and radioreceptor assay respectively. RNase protection assay was performed using RNA from pancreas and liver to evaluate IGFs or IGFBPs gene expression in both tissues. [Results] Similar serum IGF-I and-2levels were observed in U and C. IGF-I and IGF-2 mRNAs were detected in liver and pancreas of both C and U fetuses. Despite being decreased in the liver, IGF-l mRNA level was increased in U pancreases as compared to C. Concerning IGF-2 gene expression it was diminished in U pancreas while being normal in the liver as compared to C. No difference in IGFBP-I, -2 and -3 mRNA levels was detected in U liver when compared to C. However, gene expression of IGFBP-2 was increased and that of IGFBP-3 was decreased in U pancreases. Finally, the in vitro study showed a normal BrdU LI in U isolated fetal islets under basal conditions while it was found significantly increased twice in response to both IGF-I and IGF-2 (lOOng/ml) as compared to fetal C islets. [Conclusion] Our data suggest that in U fetuses at 21 dpc: I) the increased β-cell mass can be related to the stimulation of replicative β-cell response due to locally increased IGF-I in the pancreas 2) such IGF-I action is perhaps favored by an enhanced IGFBP-2 gene expression in pancreas, and 3) at variance with previous reports in several models of decreased intrapancreatic IGF-2 expression in fetuses, the low IGF-2 mRNA level as it is observed in the present U model does not correlate with a decreased β-cell growth.Peer Reviewe

Diabetic β-Cells Can Achieve Self-Protection against Oxidative Stress through an Adaptive Up-Regulation of Their Antioxidant Defenses

Background Oxidative stress (OS), through excessive and/or chronic reactive oxygen species (ROS), is a mediator of diabetes-related damages in various tissues including pancreatic β-cells. Here, we have evaluated islet OS status and β-cell response to ROS using the GK/Par rat as a model of type 2 diabetes. Methodology/Principal Findings Localization of OS markers was performed on whole pancreases. Using islets isolated from 7-day-old or 2.5-month-old male GK/Par and Wistar control rats, 1) gene expression was analyzed by qRT-PCR; 2) insulin secretion rate was measured; 3) ROS accumulation and mitochondrial polarization were assessed by fluorescence methods; 4) antioxidant contents were quantified by HPLC. After diabetes onset, OS markers targeted mostly peri-islet vascular and inflammatory areas, and not islet cells. GK/Par islets revealed in fact protected against OS, because they maintained basal ROS accumulation similar or even lower than Wistar islets. Remarkably, GK/Par insulin secretion also exhibited strong resistance to the toxic effect of exogenous H2O2 or endogenous ROS exposure. Such adaptation was associated to both high glutathione content and overexpression (mRNA and/or protein levels) of a large set of genes encoding antioxidant proteins as well as UCP2. Finally, we showed that such a phenotype was not innate but spontaneously acquired after diabetes onset, as the result of an adaptive response to the diabetic environment. Conclusions The GK/Par model illustrates the effectiveness of adaptive response to OS by beta-cells to achieve self-tolerance. It remains to be determined to what extend such islet antioxidant defenses upregulation might contribute to GK/Par beta-cell secretory dysfunction

Islet Endothelial Activation and Oxidative Stress Gene Expression Is Reduced by IL-1Ra Treatment in the Type 2 Diabetic GK Rat

Inflammation followed by fibrosis is a component of islet dysfunction in both rodent and human type 2 diabetes. Because islet inflammation may originate from endothelial cells, we assessed the expression of selected genes involved in endothelial cell activation in islets from a spontaneous model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We also examined islet endotheliuml/oxidative stress (OS)/inflammation-related gene expression, islet vascularization and fibrosis after treatment with the interleukin-1 (IL-1) receptor antagonist (IL-1Ra)

4.3. Alimentation et diabète de type 2

Diabète et obésité 382 millions de terriens adultes vivent à l’heure actuelle avec un diabète de type 2* (DT2). L’explosion récente (20 ans) de la prévalence du DT2 est attribuée aux changements socio-économiques et environnementaux, en particulier ceux qui touchent à l’alimentation. Durant cette période, le poids moyen individuel s’est accru pour toute la population mondiale, du fait essentiellement de l’augmentation des apports caloriques et de la diminution d’activité physique. Cet..

Anomalies programmées de la sécrétion d’insuline dans le diabète de type 2: le paradigme du rat GK

La perte de fonction β-cellulaire joue un rôle central dans la physiopathologie des diabètes de type 2. Alors que dans les formes rares de la maladie, les MODY (maturity onset diabetes of the young), son étiologie est simple, monogénique et décryptée, dans les formes courantes de diabète de type 2, elle est certainement beaucoup plus complexe et demeure mystérieuse. Cet article établit le bilan des données actuellement disponibles relatives au déterminisme de l’atteinte β-cellulaire dans un modèle animal approprié, le rat GK, spontanément porteur d’un diabète de type 2.The pathways that control insulin release and regulate pancreatic β-cell mass are crucial on the development of type 2 diabetes mellitus. Maturity-onset diabetes of the young comprises a number of single-gene disorders affecting β-cell development and/or function. A genetic basis for the more common forms of type 2 diabetes which affect adults in developed as well as many developing countries is less clear cut. It is also characterized by abnormal β-cell function. Appropriate inbred rodent models are an essential tool for the identification of genes and environmental factors that increase the risk of type 2 diabetes. The informations available from studies in the Goto-Kakizaki (GK) rat are here reviewed in such a perspective. This model was obtained by selective breeding of individuals with mild glucose intolerance from a non-diabetic Wistar rat colony. Heritability of defective β-mass and β-cell function in GK model is proposed to reflect the complex interactions of three pathogenic players: (1) three independent loci containing genes causating impaired insulin secretion; (2) gestational metabolic (hyperglycaemic) impairment inducing a programming of endocrine pancreas (decreased β-cell mass) which is transmitted to the next generation; (3) secondary (acquired) loss of β-cell differentiation due to chronic exposure to hyperglycaemia (glucotoxicity). A better understanding of the mechanisms involved in the failure of β-cell function in the GK model will lead to identification of new therapeutic targets for both the prevention and treatment of type 2 diabetes

Perturbations des mécanismes d'amplification de l'exocytose dans la cellule b pancréatique au cours du diabète de type 2 (rôle central de la signalisation AMPc-dépendante)

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