CaM Kinase II-δ Is Required for Diabetic Hyperglycemia and Retinopathy but Not Nephropathy
CaM Kinase II-δ Is Required for Diabetic Hyperglycemia and Retinopathy but Not Nephropathy
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DOI：
10.2337/db19-0659
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发表时间：
2021-02-01
期刊：
影响因子：
7.7
通讯作者：
Backs, Johannes
中科院分区：
文献类型：
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作者：
Chen, Jessy;Fleming, Thomas;Backs, Johannes
2型糖尿病已成为一种流行病，并导致器官（包括肾脏和眼睛）的晚期糖尿病并发症。降低血糖是临床医学的典型治疗目标。然而，高血糖可能只是糖尿病的一种症状，但不是晚期糖尿病并发症的唯一原因;相反，其他糖尿病相关的改变可能是病因。在这里，我们研究了CaM激酶II-δ（CaMKII δ）的作用，已知其通过糖尿病代谢被激活。CaMKII δ广泛表达，因此可能影响几个不同的器官系统。我们在全球范围内将糖尿病瘦素受体突变小鼠与缺乏CaMKII δ的小鼠杂交。值得注意的是，CaMKII δ缺陷型糖尿病小鼠没有出现高血糖症。作为潜在的潜在机制，我们提供了证据，改善胰岛素敏感性，增加葡萄糖转运到骨骼肌，也减少肝脏葡萄糖的产生。尽管血糖正常，但CaMKII δ缺陷型糖尿病小鼠发展出糖尿病肾病的全貌，但糖尿病视网膜病变得到预防。我们还揭示了可能导致CaMKII依赖性视网膜糖尿病并发症的视网膜特异性基因表达特征。这些数据挑战了糖尿病高血糖正常化作为晚期糖尿病并发症病因治疗策略的临床概念，并要求对不同糖尿病器官中的细胞内代谢信号进行更详细的分析。
Type 2 diabetes has become a pandemic and leads to late diabetic complications of organs, including kidney and eye. Lowering hyperglycemia is the typical therapeutic goal in clinical medicine. However, hyperglycemia may only be a symptom of diabetes but not the sole cause of late diabetic complications; instead, other diabetes-related alterations could be causative. Here, we studied the role of CaM kinase II-delta (CaMKII delta), which is known to be activated through diabetic metabolism. CaMKII delta is expressed ubiquitously and might therefore affect several different organ systems. We crossed diabetic leptin receptor-mutant mice to mice lacking CaMKII delta globally. Remarkably, CaMKII delta-deficient diabetic mice did not develop hyperglycemia. As potential underlying mechanisms, we provide evidence for improved insulin sensing with increased glucose transport into skeletal muscle and also reduced hepatic glucose production. Despite normoglycemia, CaMKII delta-deficient diabetic mice developed the full picture of diabetic nephropathy, but diabetic retinopathy was prevented. We also unmasked a retina-specific gene expression signature that might contribute to CaMKII-dependent retinal diabetic complications. These data challenge the clinical concept of normalizing hyperglycemia in diabetes as a causative treatment strategy for late diabetic complications and call for a more detailed analysis of intracellular metabolic signals in different diabetic organs.