Diabetes Mellitus, Type 2 Clinical Trial
Official title:
The G Protein-Coupled Receptor Kinase Type 2 Inhibitor Paroxetine as Adjunctive Therapy to Improve Insulin Sensitivity in Patients With Type 2 Diabetes Mellitus
The aim of this study is to investigate the effect of GRK2 inhibitor paroxetine on insulin resistance in patients with type 2 diabetes mellitus.
Type 2 Diabetes Mellitus (T2DM) is one of the most common metabolic disorders worldwide and its development is primarily caused by a combination of two main factors including defective insulin secretion by pancreatic β-cells and the inability of insulin sensitive tissues to respond to insulin. Type 2 Diabetes Mellitus (T2DM) shares an intimate relationship with altered metabolism through the development of insulin resistance )IR(. The G protein-coupled receptor kinase type 2 (GRK2) is involved in the regulation of many pivotal cell functions and is a key player in human health and diseases.In fact, GRK2 regulates insulin signaling through serine phosphorylated events. G protein-coupled receptor kinase type 2 up-regulation inhibits insulin signaling and glucose extraction due to a time dependent insulin-stimulated association of GRK2 with Insulin Receptor Substrate 1 (IRS1), leading to IRS1 serine phosphorylation and inactivation. Inhibition of hepatic GRK2 expression is sufficient to improve glucose homeostasis and insulin sensitivity, which eventually improves endothelial dysfunction in T2DM. Preclinical studies reported that, genetic ablation of GRK2 in mice reduced insulin resistance. In this sense, inhibition of GRK2 activity could improve insulin sensitivity and might provide a new therapeutic target for the treatment of IR and T2DM. Paroxetine, an FDA-approved selective serotonin reuptake inhibitor (SSRI), was identified as a potent GRK2 inhibitor with higher selectivity for GRK2 over other GRKs both in vivo and in vitro. Paroxetine binds to the active site of GRK2 and stabilizes the kinase domain in a conformation that inhibits G protein-coupled receptor (GPCR) phosphorylation and desensitization.6 A case report study demonstrated that during 3 months of paroxetine treatment, 35-year-old woman with poorly controlled T2DM experienced an increased frequency of hypoglycemic episodes. After discontinuation of paroxetine, her awareness of hypoglycemia was dramatically improved. The authors hypothesized that her hypoglycemic unawareness might be caused by autonomic dysfunction, which is an atypical manifestation of serotonin syndrome. Paroxetine also increased insulin sensitivity in non-diabetic patients who experienced remitted depression in a randomized trial. ;
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