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Clinical Trials/NCT06203275
NCT06203275Not yet recruitingPhase 3

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

aya ramadan ashmawy sarhan0 sites44 target enrollmentStarted: January 2024Last updated:
Conditions
Interventions
Drugs

Trial Snapshot

Phase
Phase 3
Status
Not yet recruiting
Sponsor
Enrollment
44
Primary Endpoint
Change in HOMA-IR .

Study Overview

Brief Summary

The aim of this study is to investigate the effect of GRK2 inhibitor paroxetine on insulin resistance in patients with type 2 diabetes mellitus.

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 Design

Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel
Primary Purpose
Treatment
Masking
None

Eligibility Criteria

Ages
20 Years to 65 Years (Adult, Older Adult)
Sex
All
Accepts Healthy Volunteers
No

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

Arms & Interventions

group 1 (control group)

Placebo Comparator

which will receive metformin based combined oral hypoglycemic plus placebo tablets

Intervention: Placebo (Drug)

group II (intervention group)

Active Comparator

which will receive metformin based combined oral hypoglycemic plus 12.5 mg paroxetine daily at morning.

Intervention: Paroxetine (Drug)

Outcomes

Primary Outcomes

Change in HOMA-IR .

Time Frame: 3 months

The primary outcome is the change in glycated Hemoglobin (HbA1c).

Time Frame: 3 months

Secondary Outcomes

  • The secondary outcome is the change in expression of GRK2(3 months)

Investigators

Sponsor
aya ramadan ashmawy sarhan
Sponsor Class
Other
Responsible Party
Sponsor Investigator
Principal Investigator

aya ramadan ashmawy sarhan

tanta

Tanta University

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