Antidiabetic and Cardioprotective Effects of Pharmacological Inhibition of GRK2 in db/db Mice.

Abstract

Despite the availability of several therapies for the management of blood glucose in diabetic patients, most of the treatments do not show benefits on diabetic cardiomyopathy, while others even favor the progression of the disease. New pharmacological targets are needed that might help the management of diabetes and its cardiovascular complications at the same time. GRK2 appears a promising target, given its established role in insulin resistance and in systolic heart failure. Using a custom peptide inhibitor of GRK2, we assessed in vitro in L6 myoblasts the effects of GRK2 inhibition on glucose extraction and insulin signaling. Afterwards, we treated diabetic male mice (db/db) for 2 weeks. Glucose tolerance (IGTT) and insulin sensitivity (ITT) were ameliorated, as was skeletal muscle glucose uptake and insulin signaling. In the heart, at the same time, the GRK2 inhibitor ameliorated inflammatory and cytokine responses, reduced oxidative stress, and corrected patterns of fetal gene expression, typical of diabetic cardiomyopathy. GRK2 inhibition represents a promising therapeutic target for diabetes and its cardiovascular complications.

• Authors: Ersilia Cipolletta, Jessica Gambardella, Antonella Fiordelisi, Carmine Del Giudice, Eugenio Di Vaia, Michele Ciccarelli, Marina Sala, Pietro Campiglia, Enrico Coscioni, Bruno Trimarco, Daniela Sorriento, Guido Iaccarino
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 20 Issue 6 (Mar 25 2019) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 30934608 (Publication Type: Journal Article)

Chemical References

• Cardiotonic Agents
• Hypoglycemic Agents
• Insulin
• Protein Kinase Inhibitors
• GRK2 protein, mouse
• G-Protein-Coupled Receptor Kinase 2
• Glucose

Topics

• Animals
• Biological Transport (drug effects)
• Cardiomegaly (complications, drug therapy, pathology)
• Cardiotonic Agents (pharmacology, therapeutic use)
• Cell Line
• Diabetes Mellitus, Experimental (complications, drug therapy, pathology)
• G-Protein-Coupled Receptor Kinase 2 (antagonists & inhibitors, metabolism)
• Glucose (metabolism)
• Hypoglycemic Agents (pharmacology, therapeutic use)
• Inflammation (pathology)
• Insulin (metabolism)
• Insulin Resistance
• Male
• Mice
• Myoblasts (drug effects, metabolism)
• Myocardium (pathology)
• Oxidative Stress (drug effects)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Signal Transduction (drug effects)