Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA.
Diabetes. 2024 Oct 1;73(10):1553-1562. doi: 10.2337/dbi24-0013.
The stress response protein regulated in development and DNA damage response 1 (REDD1) has emerged as a key player in the pathogenesis of diabetes. Diabetes upregulates REDD1 in a variety of insulin-sensitive tissues, where the protein acts to inhibit signal transduction downstream of the insulin receptor. REDD1 functions as a cytosolic redox sensor that suppresses Akt/mTORC1 signaling to reduce energy expenditure in response to cellular stress. Whereas a transient increase in REDD1 contributes to an adaptive cellular response, chronically elevated REDD1 levels are implicated in disease progression. Recent studies highlight the remarkable benefits of both whole-body and tissue-specific REDD1 deletion in preclinical models of type 1 and type 2 diabetes. In particular, REDD1 is necessary for the development of glucose intolerance and the consequent rise in oxidative stress and inflammation. Here, we review studies that support a role for chronically elevated REDD1 levels in the development of diabetes complications, reflect on limitations of prior therapeutic approaches targeting REDD1 in patients, and discuss potential opportunities for future interventions to improve the lives of people living with diabetes. This article is part of a series of Perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program.
发育和 DNA 损伤反应调节的应激反应蛋白 1（REDD1）已成为糖尿病发病机制中的关键因素。糖尿病在多种胰岛素敏感组织中上调 REDD1，该蛋白作用于抑制胰岛素受体下游的信号转导。REDD1 作为一种细胞溶质氧化还原传感器，可抑制 Akt/mTORC1 信号通路，以减少细胞应激时的能量消耗。虽然 REDD1 的短暂增加有助于适应性细胞反应，但慢性升高的 REDD1 水平与疾病进展有关。最近的研究强调了全身和组织特异性 REDD1 缺失在 1 型和 2 型糖尿病临床前模型中的显著益处。特别是，REDD1 对于葡萄糖耐量降低以及随之而来的氧化应激和炎症增加是必需的。在这里，我们回顾了支持慢性升高的 REDD1 水平在糖尿病并发症发展中的作用的研究，反思了先前针对患者 REDD1 的治疗方法的局限性，并讨论了未来改善糖尿病患者生活的干预措施的潜在机会。本文是一系列观点的一部分，这些观点报告了美国糖尿病协会“停止糖尿病途径”计划资助的研究。
