CaM Kinase II-δ Is Required for Diabetic Hyperglycemia and Retinopathy but Not Nephropathy

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.

Automated summary

This study investigated the role of CaMKII δ in diabetes and found that diabetic mice lacking CaMKII δ did not develop hyperglycemia, but still exhibited diabetic nephropathy while diabetic retinopathy was prevented. This challenges the clinical concept of normalizing hyperglycemia in diabetes for late diabetic complications and emphasizes the need for detailed analysis of intracellular metabolic signals in different organs affected by diabetes.