The G Protein-Coupled Receptor Kinase Type 2 Inhibitor Paroxetine as Adjunctive Therapy to Improve Insulin Sensitivity in Patients With Type 2 Diabetes Mellitus

January 11, 2024 updated by: aya ramadan ashmawy sarhan
The aim of this study is to investigate the effect of GRK2 inhibitor paroxetine on insulin resistance in patients with type 2 diabetes mellitus.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

44

Phase

  • Phase 3

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients with established diagnosis of type 2 diabetes.
  • Patients with type 2 diabetes treated with metformin based combined oral hypoglycemic ( metformin plus DDP4 inhibitor or metformin plus sulfonylureas or metformin plus GLP-1 analogues)
  • Glycated hemoglobin (HbA1c) ≥ 7% and ≤9
  • Age between 20 and 65 years
  • BMI ≥25 kg/m2

Exclusion Criteria:

  • Pregnant and lactating women

    • Patients with diabetes complications except for hyperlipidemia if any.
    • Patients with acute or chronic illness (such as flu, cancer, rheumatoid arthritis, etc….)
    • Patients with renal impairment (S.Cr > 1.5 mg/dl) and hepatic impairment (Bilirubin level > 1.2 mg/dl).
    • Patients with cardiovascular diseases
    • Patients with condition that predispose to acidosis as COPD
    • Patients with glaucoma
    • Patients with thyroid disorders
    • Patients on the medications that affect carbohydrate metabolism such as beta blockers, contraceptives, thiazide diuretic, corticosteroids, sympathomimetic
    • Patients treated with any oral anti-diabetes agents other oral hypoglycemic agents or treated with insulin
    • Patients stabilized anticoagulants, antiplatelet, antipsychotics, MAOIs, amphetamines, NSAIDs, corticosteroids, ergotamine, levothyroxine, narcotic analgesic, tramadol, liver microsomal enzyme inhibitors and liver microsomal enzyme inducers

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: group 1 (control group)
which will receive metformin based combined oral hypoglycemic plus placebo tablets
Drug: Placebo
Patients with type 2 diabetes treated with metformin based combined oral hypoglycemic ( metformin plus DDP4 inhibitor or metformin plus sulfonylureas or metformin plus GLP-1 analogues) plus placebo daily
Active Comparator: group II (intervention group)
which will receive metformin based combined oral hypoglycemic plus 12.5 mg paroxetine daily at morning.
Drug: Paroxetine
intervention group n=22 Patients with type 2 diabetes treated with metformin based combined oral hypoglycemic ( metformin plus DDP4 inhibitor or metformin plus sulfonylureas or metformin plus GLP-1 analogues) plus paroxetine 12.5 mg daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
The primary outcome is the change in glycated Hemoglobin (HbA1c).
Time Frame: 3 months
3 months
Change in HOMA-IR .
Time Frame: 3 months
3 months

Secondary Outcome Measures

Outcome Measure
Time Frame
The secondary outcome is the change in expression of GRK2
Time Frame: 3 months
3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

aya ramadan ashmawy sarhan

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

January 1, 2024

Primary Completion (Estimated)

January 1, 2025

Study Completion (Estimated)

January 1, 2026

Study Registration Dates

First Submitted

November 17, 2023

First Submitted That Met QC Criteria

January 11, 2024

First Posted (Actual)

January 12, 2024

Study Record Updates

Last Update Posted (Actual)

January 12, 2024

Last Update Submitted That Met QC Criteria

January 11, 2024

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • paroxetine in type 2 diabetes

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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