PMID- 33239449 OWN - NLM STAT- MEDLINE DCOM- 20210510 LR - 20210510 IS - 1939-327X (Electronic) IS - 0012-1797 (Linking) VI - 70 IP - 2 DP - 2021 Feb TI - CaM Kinase II-delta Is Required for Diabetic Hyperglycemia and Retinopathy but Not Nephropathy. PG - 616-626 LID - 10.2337/db19-0659 [doi] 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-delta (CaMKIIdelta), which is known to be 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 provide evidence for improved insulin sensing with increased glucose transport into skeletal muscle and also reduced hepatic glucose production. Despite normoglycemia, CaMKIIdelta-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. CI - (c) 2020 by the American Diabetes Association. FAU - Chen, Jessy AU - Chen J AD - Institute of Experimental Cardiology, Heidelberg University, Heidelberg, Germany. AD - German Center for Cardiovascular Research (partner site Heidelberg/Mannheim), Heidelberg, Germany. FAU - Fleming, Thomas AU - Fleming T AD - Department of Internal Medicine I and Clinical Chemistry, University Hospital of Heidelberg, Heidelberg, Germany. FAU - Katz, Sylvia AU - Katz S AD - Institute of Experimental Cardiology, Heidelberg University, Heidelberg, Germany. AD - German Center for Cardiovascular Research (partner site Heidelberg/Mannheim), Heidelberg, Germany. FAU - Dewenter, Matthias AU - Dewenter M AD - Institute of Experimental Cardiology, Heidelberg University, Heidelberg, Germany. AD - German Center for Cardiovascular Research (partner site Heidelberg/Mannheim), Heidelberg, Germany. FAU - Hofmann, Kai AU - Hofmann K AD - Institute of Experimental Cardiology, Heidelberg University, Heidelberg, Germany. AD - German Center for Cardiovascular Research (partner site Heidelberg/Mannheim), Heidelberg, Germany. FAU - Saadatmand, Alireza AU - Saadatmand A AD - Institute of Experimental Cardiology, Heidelberg University, Heidelberg, Germany. AD - German Center for Cardiovascular Research (partner site Heidelberg/Mannheim), Heidelberg, Germany. FAU - Kronlage, Mariya AU - Kronlage M AD - Institute of Experimental Cardiology, Heidelberg University, Heidelberg, Germany. AD - German Center for Cardiovascular Research (partner site Heidelberg/Mannheim), Heidelberg, Germany. AD - Department of Cardiology, University of Heidelberg, Heidelberg, Germany. FAU - Werner, Moritz P AU - Werner MP AD - Institute of Experimental Cardiology, Heidelberg University, Heidelberg, Germany. AD - German Center for Cardiovascular Research (partner site Heidelberg/Mannheim), Heidelberg, Germany. FAU - Pokrandt, Bianca AU - Pokrandt B AD - Heidelberg University Biochemistry Center, INF 328, Heidelberg, Germany. FAU - Schreiter, Friederike AU - Schreiter F AD - Institute of Experimental Cardiology, Heidelberg University, Heidelberg, Germany. AD - German Center for Cardiovascular Research (partner site Heidelberg/Mannheim), Heidelberg, Germany. FAU - Lin, Jihong AU - Lin J AD - 5th Medical Department, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. FAU - Katz, Daniel AU - Katz D AD - Institute of Experimental Cardiology, Heidelberg University, Heidelberg, Germany. AD - German Center for Cardiovascular Research (partner site Heidelberg/Mannheim), Heidelberg, Germany. FAU - Morgenstern, Jakob AU - Morgenstern J AD - Department of Internal Medicine I and Clinical Chemistry, University Hospital of Heidelberg, Heidelberg, Germany. FAU - Elwakiel, Ahmed AU - Elwakiel A AD - Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics (ILM), University of Leipzig, Leipzig, Germany. FAU - Sinn, Peter AU - Sinn P AD - Department of Pathology, Heidelberg University Hospital, Heidelberg, Germany. FAU - Grone, Hermann-Josef AU - Grone HJ AD - Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany. AD - Institute of Pathology, University of Marburg, Marburg, Germany. FAU - Hammes, Hans-Peter AU - Hammes HP AD - 5th Medical Department, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. FAU - Nawroth, Peter P AU - Nawroth PP AD - Department of Internal Medicine I and Clinical Chemistry, University Hospital of Heidelberg, Heidelberg, Germany. AD - German Center for Diabetes Research (DZD), Neuherberg, Germany. AD - Institute for Diabetes and Cancer (IDC) Helmholtz Center Munich, Neuherberg, Germany. AD - Joint Heidelberg-Institute for Diabetes and Cancer (IDC) Translational Diabetes Program, Neuherberg, Germany. FAU - Isermann, Berend AU - Isermann B AD - Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics (ILM), University of Leipzig, Leipzig, Germany. FAU - Sticht, Carsten AU - Sticht C AD - Medical Research Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. FAU - Brugger, Britta AU - Brugger B AD - Heidelberg University Biochemistry Center, INF 328, Heidelberg, Germany. FAU - Katus, Hugo A AU - Katus HA AD - German Center for Cardiovascular Research (partner site Heidelberg/Mannheim), Heidelberg, Germany. AD - Department of Cardiology, University of Heidelberg, Heidelberg, Germany. FAU - Hagenmueller, Marco AU - Hagenmueller M AD - Institute of Experimental Cardiology, Heidelberg University, Heidelberg, Germany. AD - German Center for Cardiovascular Research (partner site Heidelberg/Mannheim), Heidelberg, Germany. FAU - Backs, Johannes AU - Backs J AUID- ORCID: 0000-0002-2322-2699 AD - Institute of Experimental Cardiology, Heidelberg University, Heidelberg, Germany johannes.backs@med.uni-heidelberg.de. AD - German Center for Cardiovascular Research (partner site Heidelberg/Mannheim), Heidelberg, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201125 PL - United States TA - Diabetes JT - Diabetes JID - 0372763 RN - 0 (Receptors, Leptin) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2) SB - IM MH - Animals MH - Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics/*metabolism MH - Diabetes Mellitus, Type 2/genetics/*metabolism MH - Diabetic Nephropathies/genetics/*metabolism MH - Diabetic Retinopathy/genetics/*metabolism MH - Gene Expression MH - Hyperglycemia/genetics/*metabolism MH - Mice MH - Mice, Knockout MH - Receptors, Leptin/genetics/metabolism EDAT- 2020/11/27 06:00 MHDA- 2021/05/11 06:00 CRDT- 2020/11/26 05:37 PHST- 2019/07/03 00:00 [received] PHST- 2020/11/17 00:00 [accepted] PHST- 2020/11/27 06:00 [pubmed] PHST- 2021/05/11 06:00 [medline] PHST- 2020/11/26 05:37 [entrez] AID - db19-0659 [pii] AID - 10.2337/db19-0659 [doi] PST - ppublish SO - Diabetes. 2021 Feb;70(2):616-626. doi: 10.2337/db19-0659. Epub 2020 Nov 25.