casein-kinase-ii and Diabetes-Mellitus--Type-1

Since diabetes is a global epidemic, the development of novel therapeutic strategies for the treatment of this disease is of major clinical interest. Diabetes is differentiated in two types: type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). T1DM arises from an autoimmune destruction of insulin-producing β-cells whereas T2DM is characterized by an insulin resistance, an impaired insulin reaction of the target cells, and/or dysregulated insulin secretion. In the past, a growing number of studies have reported on the important role of the protein kinase CK2 in the regulation of the survival and endocrine function of pancreatic β-cells. In fact, inhibition of CK2 is capable of reducing cytokine-induced loss of β-cells and increases insulin expression as well as secretion by various pathways that are regulated by reversible phosphorylation of proteins. Moreover, CK2 inhibition modulates pathways that are involved in the development of diabetes and prevents signal transduction, leading to late complications such as diabetic retinopathy. Hence, targeting CK2 may represent a novel therapeutic strategy for the treatment of diabetes.

Topics: Casein Kinase II; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Gene Expression Regulation; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin-Secreting Cells; Molecular Targeted Therapy; Signal Transduction

Diabetes is a chronic disease characterized by perturbed glucose and lipid metabolism, resulting in high blood glucose levels. Many complications induced by endothelial dysfunction can cause disability and even death of diabetic patients. Here, we found that the protein level of casein kinase 2α (CK2α) was increased in the endothelium of mice with type I diabetes (T1D) induced by streptozotocin (STZ) injection. Although a potential correlation between the protein level of CK2α and endothelial dysfunction in diabetes was established, the contribution of CK2α to the progression of endothelial dysfunction in diabetes remained largely unknown. By using CX4945 (a selective CK2α antagonist) and Si-csnk2a1 (small interfering RNA targeting CK2α), we found that inhibition of CK2α accelerated skin wound healing in T1D mice by promoting proliferation of endothelial cells. Administration of CX4945 or Si-csnk2a1 rescued the impaired Hedgehog signaling pathway in high glucose-treated human umbilical vein endothelial cells (HUVECs). Exploration of the underlying molecular mechanism revealed that the protective effect of CK2α inhibition on angiogenesis, which contributes to skin wound healing in diabetic mice, was blocked by administration of GANT61 (an inhibitor targeting the Hedgehog signaling pathway). Our findings establish CK2α as a regulator of endothelial dysfunction in diabetes and demonstrate that inhibition of CK2α accelerates skin wound healing in T1D mice by promoting endothelial cell proliferation via the Hedgehog signaling pathway.

Topics: Animals; Casein Kinase II; Cell Proliferation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Glucose; Hedgehog Proteins; Human Umbilical Vein Endothelial Cells; Humans; Mice; Wound Healing

Changes in cellular free Zn

Topics: Animals; Blotting, Western; Casein Kinase II; Cation Transport Proteins; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Heart Ventricles; Hyperglycemia; Immunoprecipitation; Myocytes, Cardiac; Phosphorylation; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sarcoplasmic Reticulum; Zinc