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RACking up ceramide-induced islet beta-cell dysfunction

机译：施用神经酰胺诱导的胰岛β细胞功能障碍

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The International Diabetes Federation predicts that by 2045 the number of individuals afflicted with diabetes will increase to 629 million. Furthermore, similar to 352 million individuals with impaired glucose tolerance are at increased risk for developing diabetes. Several mechanisms have been proposed for the onset of metabolic dysfunction and demise of the islet beta-cell leading to the pathogenesis of diabetes. It is widely accepted that the onset of type 2 diabetes is due to an intricate interplay between genetic expression of the disease and a multitude of factors including increased oxidative and endoplasmic reticulum stress consequential to glucolipotoxicity and inflammation. Compelling experimental evidence from in vitro and in vivo studies implicates intracellular generation of ceramide (CER), a biologically-active sphingolipid, as a trigger in the onset of beta-cell demise under above pathological conditions. Recent pharmacological and molecular biological evidence affirms regulatory roles for Ras related C3 botulinum toxin substrate 1 (Racl), a small G protein, in the islet beta-cell function in health and diabetes. In this Commentary, we overviewed the emerging evidence implicating potential cross-talk between Racl and ceramide signaling pathways in the onset of metabolic dysregulation of the islet beta-cell culminating in impaired physiological insulin secretion, loss of beta-cell mass and the onset of diabetes. Further, we propose a model depicting contributory roles of defective protein lipidation (prenylation) pathway in the in duction of metabolic defects in the beta-cell under metabolic stress conditions. Potential avenues for the identifi cation of novel therapeutic targets for the prevention/treatment of diabetes and its associated complications are highlighted.
机译：国际糖尿病联合会预测，到2045年，糖尿病患病的个体数量将增加到6.29亿。此外，类似于葡萄糖耐受性受损的3.52亿个，患糖尿病的风险增加。已经提出了几种机制，用于发作代谢功能障碍和胰岛β细胞的清除，导致糖尿病发病机制。众所周知，2型糖尿病的发作是由于疾病的遗传表达与多种因素之间的复杂相互作用，包括葡糖毒性和炎症的增加的氧化和内质网胁迫。来自体外和体内研究的令人信服的实验证据意味着在上述病理条件下，在β细胞消除的β-细胞中的发作中的细胞内产生氨酰胺（CER）的细胞内产生。最近的药理学和分子生物学证据肯定了RAS相关C3肉毒杆菌毒素基质1（RACL），小G蛋白，在健康和糖尿病中的胰岛β细胞功能中的调节作用。在这方面，我们概述了新兴的证据，暗示了RACL和神经酰胺信号传导途径之间的潜在串扰，即在胰岛胰岛素分泌受损的胰岛β细胞的代谢失调，β细胞损失和糖尿病发作中的胰岛β细胞的起搏中。此外，我们提出了一种模型，描绘了在代谢应激条件下β细胞中代谢缺陷中的缺陷蛋白脂质（戊烯化）途径的含量作用的模型。突出了用于预防/治疗糖尿病的新疗法靶标的潜在途径及其相关并发症的潜在途径。

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