TY  - JOUR
AU  - Chen, Jessy
AU  - Fleming, Thomas
AU  - Katz, Sylvia
AU  - Dewenter, Matthias
AU  - Hofmann, Kai
AU  - Saadatmand, Alireza
AU  - Kronlage, Mariya
AU  - Werner, Moritz P
AU  - Pokrandt, Bianca
AU  - Schreiter, Friederike
AU  - Lin, Jihong
AU  - Katz, Daniel
AU  - Morgenstern, Jakob
AU  - Elwakiel, Ahmed
AU  - Sinn, Peter
AU  - Gröne, Hermann-Josef
AU  - Hammes, Hans-Peter
AU  - Nawroth, Peter P
AU  - Isermann, Berend
AU  - Sticht, Carsten
AU  - Brügger, Britta
AU  - Katus, Hugo A
AU  - Hagenmueller, Marco
AU  - Backs, Johannes
TI  - CaM Kinase II-δ is Required for Diabetic Hyperglycemia and Retinopathy but not Nephropathy.
JO  - Diabetes
VL  - 70
IS  - 2
SN  - 1939-327X
CY  - Alexandria, Va
PB  - Assoc.
M1  - DKFZ-2020-03022
SP  - 616-626
PY  - 2021
N1  - 2021 Feb;70(2):616-626
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:33239449
DO  - DOI:10.2337/db19-0659
UR  - https://inrepo02.dkfz.de/record/166579
ER  -