Highlights d Glyoxalase 1 is phosphorylated by CamKIId in vitro and in vivo d Phosphorylated Glyoxalase 1 is more efficient and more stable d Phosphorylation status of Glyoxalase 1 is associated with cancer, aging, and diabetes
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 δ (CaMKIIδ) that is known to be activated through diabetic metabolism. CaMKIIδ is expressed ubiquitously and might therefore affect several different organ systems. We crossed diabetic leptin receptor mutant mice to mice lacking CaMKIIδ globally. Remarkably, CaMKIIδ-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 but also reduced hepatic glucose production. Despite normoglycemia, CaMKIIδ-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.
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 δ (CaMKIIδ) that is known to be activated through diabetic
metabolism. CaMKIIδ is expressed ubiquitously
and might therefore affect several different organ systems. We crossed diabetic
leptin receptor mutant mice to mice lacking CaMKIIδ globally. Remarkably, CaMKIIδ-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 but also
reduced hepatic glucose production. Despite normoglycemia, CaMKIIδ-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.
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