casein-kinase-ii and Insulin-Resistance

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

Previous studies have demonstrated that a high-carbohydrate intake could induce metabolic syndrome (MetS) in male rats with marked cardiac functional abnormalities. In addition, studies mentioned some benefits of insulin application on these complications, but there are considerable disagreements among their findings. Therefore, we aimed to extend our knowledge on the in-vitro influence of insulin on left ventricular dysfunction and also in the isolated cardiomyocytes from MetS rats.. At the organ function level, an acute insulin application (100-nM) provided an important beneficial effect on the left ventricular developed pressure in MetS rats. Furthermore, to treat the freshly isolated cardiomyocytes from MetS rats with insulin provided marked recoveries in elevated resting intracellular Ca. We propose that restoring normal kinase activities and also increases in phospho-Akt by insulin can contribute marked recoveries in MetS heart function, indicating a promising approach to modulate titin-associated factors in heart dysfunction associated with type-2 diabetes mellitus. Graphical Abstract.

Topics: Action Potentials; Animals; Calcium Signaling; Casein Kinase II; Connectin; Disease Models, Animal; Hypoglycemic Agents; Insulin; Insulin Resistance; Isolated Heart Preparation; Male; Metabolic Syndrome; Myocytes, Cardiac; Oxidative Stress; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Wistar; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Pressure

The inositol pyrophosphate, diphosphoinositol pentakisphosphate, regulates p53 and protein kinase Akt signaling, and its aberrant increase in cells has been implicated in apoptosis and insulin resistance. Inositol hexakisphosphate kinase-2 (IP6K2), one of the major inositol pyrophosphate synthesizing enzymes, mediates p53-linked apoptotic cell death. Casein kinase-2 (CK2) promotes cell survival and is upregulated in tumors. We show that CK2 mediated cell survival involves IP6K2 destabilization. CK2 physiologically phosphorylates IP6K2 at amino acid residues S347 and S356 contained within a PEST sequence, a consensus site for ubiquitination. HCT116 cells depleted of IP6K2 are resistant to cell death elicited by CK2 inhibitors. CK2 phosphorylation at the degradation motif of IP6K2 enhances its ubiquitination and subsequent degradation. IP6K2 mutants at the CK2 sites that are resistant to CK2 phosphorylation are metabolically stable.

Topics: Amino Acid Motifs; Apoptosis; Casein Kinase II; Cell Survival; Enzyme Stability; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; HEK293 Cells; HeLa Cells; Humans; Insulin Resistance; Neoplasms; Phosphorylation; Phosphotransferases (Phosphate Group Acceptor); Proto-Oncogene Proteins c-akt; Signal Transduction; Tumor Suppressor Protein p53; Ubiquitination; Up-Regulation

Hepatic insulin receptor levels in 6-week-old obese (fa/fa) rats were about 2-fold lower than those from lean (Fa/-) rats, which agrees with their insulin-resistant state. Nuclear protein kinase CK2 activity and protein content in livers from obese (fa/fa) rats were similar to those of lean (Fa/-) animals but the cytosolic levels were reduced to half, due to a decrease in the 39-kD)a catalytic subunit. Marked increases in activity, due to rises in the 44-kDa and 39-kDa catalytic subunits, were seen in the 16000 x g sediments (M1) from insulin-resistant rats, with moderate changes in the 100000xg sediments (M2). The increase in CK2 binding to M1 did not require increases in the molecular chaperone grp94, which was unaltered in insulin-resistant rats.

Topics: Animals; Casein Kinase II; Chromatography, Affinity; Female; HSP70 Heat-Shock Proteins; Insulin Resistance; Lectins; Liver; Membrane Proteins; Obesity; Protein Serine-Threonine Kinases; Rats; Rats, Zucker; Receptor, Insulin; Sepharose; Subcellular Fractions