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CaMKIIdelta is required for diabetic hyperglycemia but not nephropathy

ABSTRACT: 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 δ (CaMKIIδ) that is 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 found evidence for improved insulin sensing and increased glucose transport into skeletal muscle. Despite normoglycemia CaMKIIδ-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.

ORGANISM(S): Mus musculus

PROVIDER: GSE157739 | GEO | 2021/09/06

REPOSITORIES: GEO

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Project description:Patients with long-duration diabetes develop cardiovascular complications resulting in highly increased mortality and complications which affect the kidneys, eyes and peripheral nerves associated with high morbidity. Among the diabetic complications, damage in the eye, diabetic retinopathy, is the most common microvascular complication of diabetes. Diabetic retinopathy is a leading cause of vision-loss globally. It is characterized by a number of different patho-mechanisms including changes in vascular permeability, capillary degeneration, and finally at a late stage overshooting formation of new blood vessels. This expression analysis focused on the use of different experimental models for Diabetes Mellitus and its complications (for a review see 1: Al-Awar et al: Experimental Diabetes Mellitus in Different Animal Models. J Diabetes Res. 2016; doi: 10.1155/2016/9051426). By that, we wanted to uncover the relative contributions of systemic hyperinsulinaemia and/or hyperglycemia to molecular regulations. The following models have been used: As insulinopenic, hyperglycemic model reflecting Type 1 diabetes, male STZ-Wistar rats (60mg/kg BW; i.p.) were used. Wistar rats without STZ injection served as non-diabetic controls. Male obese ZDF rats (Fa/Fa) were used as type-2 diabetes model characterized by persisting hyperglycemia and transient hyperinsulinemia. Male lean ZDF rats (Fa/-) served as non-diabetic controls. Male obese ZF rats (Fa/Fa) hyperglycemia were used reflecting euglycemia and severe insulin resistance. Male lean ZF rats (Fa/-) served as controls. ZDF and ZF rats were obtained in two genotypes, obese (genotype fa/fa) and lean littermates (genotype Fa/?). All rats were housed in standard cages under a normal light-dark cycle for 16 weeks. All animals had free access to food and water. ZF and Wistar rats received a standard chow (Ssniff R/M) and ZDF rats received Purina 5008 chow. A group size of n=8 were used for all study groups. Wistar rats were rendered type-1 like hyperglycemic and hypoinsulinemic via a single injection of streptocotocin (STZ, 60mg/kg; i.p.) at 7 weeks of age. Obese ZDF rats (fa/fa) develop spontaneously a type-2 diabetes phenotype with persisting hyperglycemia and transient hyperinsulinemia (hyperglycemic, hypoinsulinemic). Obese ZF rats (fa/fa) develop insulin resistance with permanent hyperinsulinemia without concomitant hyperglycemia and no overt diabetes phenotype. Non STZ treated Wistar rats, lean ZDF littermates (Fa/?), and lean ZF littermates (Fa/?) served as controls. All groups were kept for 12 weeks on respective conditions together with appropriate age-matched controls. Unbiased gene expression analysis was performed per group using Affymetrix gene arrays.

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CaMKIIdelta is required for diabetic hyperglycemia but not nephropathy

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