CaMKIIdelta is required for diabetic hyperglycemia but not nephropathy

Type 2 diabetes is an increasing pandemic health problem and leads to several late diabetic complications of organs including kidney and eye. Lowering elevated blood glucose levels is the typical therapeutic goal in clinical medicine. However, it is possible that hyperglycemia is only a symptom of diabetes but not the correct target to monitor, in order to prevent late diabetic complications. Instead, other diabetes-related alterations could be primary causes for late diabetic complications. Here, we studied the role of CaM Kinase II delta (CaMKIIdelta) that is activated through diabetic metabolism. CaMKIIdelta is expressed ubiquitously and might therefore affect several different organ systems. We crossed diabetic leptin receptor mutant mice to mice lacking CaMKIIdelta globally. Remarkably, CaMKIIdelta-deficient diabetic mice did not develop hyperglycemia. As potential underlying mechanisms, we found evidence for improved insulin sensing and increased glucose transport into skeletal muscle. Despite normoglycemia CaMKIIdelta-deficient diabetic mice developed the full picture of diabetic nephropathy. In contrast, diabetic retinopathy was prevented. These data challenge the clinical concept of normalizing elevated high glucose levels in diabetes as a causative treatment strategy for late diabetic complications and call for a more detailed analysis of intracellular metabolites in different organs. Retinal ("R") and renal ("K") mRNA profiles of 16 week old Lepr(+/+) or Lepr(db/db) with a global CAMK2D knockout (4 groups per organ: WT_ndb; WT_db; KO_ndb; KO_db2型糖尿病是一种日益严峻的大流行健康问题，可引发肾脏、眼部等多个器官的糖尿病晚期并发症。降低升高的血糖水平是临床医学中典型的治疗目标。然而，高血糖或许只是糖尿病的一种症状，而非监测预防糖尿病晚期并发症的正确靶点。反之，其他与糖尿病相关的病理改变或许才是糖尿病晚期并发症的核心诱因。本研究聚焦于经糖尿病代谢通路激活的钙/钙调蛋白依赖性蛋白激酶IIδ（CaM Kinase II delta, CaMKIIdelta）的作用。CaMKIIdelta广泛表达，因此可能影响多个不同的器官系统。我们将糖尿病性瘦素受体突变小鼠与全身敲除CaMKIIdelta的小鼠进行杂交。值得注意的是，CaMKIIdelta缺陷型糖尿病小鼠未出现高血糖症。作为潜在的核心机制，我们发现了胰岛素敏感性提升以及葡萄糖向骨骼肌转运增强的相关证据。尽管血糖维持正常，CaMKIIdelta缺陷型糖尿病小鼠仍出现了糖尿病肾病的全部病理特征；与之相反，糖尿病视网膜病变则得到了有效预防。上述研究结果对"将糖尿病患者的高血糖水平恢复至正常范围，以此作为治疗糖尿病晚期并发症的核心策略"这一临床理念提出了挑战，并呼吁对不同器官内的细胞内代谢物开展更为细致的分析。本数据集包含16周龄Lepr(+/+)或Lepr(db/db)小鼠在全局CAMK2D敲除背景下的视网膜（缩写为"R"）与肾脏（缩写为"K"）mRNA表达谱（每个器官分4组：WT_ndb; WT_db; KO_ndb; KO_db