Association Study of Genetic Polymorphisms of Candidate Genes With Thiazolidinedione-Related Peripheral Edema and Drug Responsiveness

According to the above evidence, though the exact mechanism contributing to the Thiazolidinediones (TZDs) associated peripheral edema is still unclear, the investigators hypothesize that the genetic variations of certain candidate genes involved in peroxisome proliferator-activated receptor (PPAR) gamma itself and PPAR gamma-regulated genes may contribute to TZDs-associated peripheral edema. Therefore, the investigators plan to conduct a case-control study to test the association between single nucleotide polymorphisms (SNPs) in certain candidate genes and TZDs related peripheral edema.

A large fraction of individuals, both with type 2 diabetes (38-41) or who are at risk for type 2 diabetes, do not respond to TZD therapy. In individuals with type 2 diabetes, non-response has not been carefully characterized, but data from studies in at-risk individuals suggests that a lack of improvement in insulin sensitivity (Si) may account for the lack of response to TZD therapy. In the Troglitazone In the Prevention Of Diabetes (TRIPOD) study, around 30% of treated women did not show an improvement in Si; they gained no protection from type 2 diabetes when compared with the placebo group. Assessment of baseline clinical and physiologic measurements revealed similar levels of adiposity, fasting glucose and insulin, Si and β-cell function, fasting lipids, contraceptive use, and compliance with study medication between responders and nonresponders, suggesting that these measures do not predict TZD response.

The adipose tissue-derived hormone adiponectin improves insulin sensitivity and its circulating levels are decreased in obesity induced insulin resistance. In ob/ob mice lacking adiponectin, the ability of PPARγ agonists, TZDs, to improve glucose tolerance is diminished. It implied that adiponectin is an important contributor to PPARγ-mediated improvements in glucose tolerance through mechanisms that involve the activation of the AMPK pathway. On the other hand, it has been shown that FOXO1 repressed PPARγ1 and γ2 promoters in primary adipocytes. It has also been reported that peroxisome proliferators activated receptor-γ coactivator-1α (PGC-1α) gene expression in brown and white adipocytes is a direct target of TZDs and activators of retinoid X receptor (RXR). Taken together, both FOXO1 and PGC-1α potentially played important roles on the antidiabetic action of TZDs.

In summary, though TZDs have been widely used in patients with type 2 diabetes mellitus, some of patients experienced TZD-related peripheral edema and some of patients had no good responsiveness to TZDs. The underlying contributing factors and molecular mechanisms have not been clearly elucidated. In this study, the investigators will identify the contributing factors of TZD-related peripheral edema and responsiveness to TZDs. The investigators will also identify the association of single nucleotide polymorphisms (SNPs) of certain candidate genes with TZD related peripheral edema and responsiveness to TZDs. It may identify some clinical and pharmacogenetic factors to predict the occurrence of TZD-related edema and the responsiveness to TZDs.

Study Overview

• Status: Unknown
• Conditions: Diabetes Mellitus

• Study Type: Observational
• Enrollment (Anticipated): 400

Contacts and Locations

• Study Contact: Name: Linda Huang; Phone Number: 886 9 37670020; Email: linda590203@gmail.com

Study Locations

• Taiwan
  • Taipei, Taiwan
    • Recruiting
    • Department of Internal Medicine, National Taiwan University Hospital
    • Contact: Linda Huang; Phone Number: 886 9 67670020; Email: linda590203@gmail.com
    • Principal Investigator: Tien-Jyun Chang, Ph D

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

TZDs User, no insulin; CHF, according to New York heart Association III-V, liver cirrhosis or renal insufficiency (Cr ≥ 1.7 mg/dL) before initiation of treatment with TZDs will be excluded.

Description

Inclusion Criteria:

• Clinical diagnosis of DM and with use TZDs

Exclusion Criteria:

• Patients with the diagnosis of congestive heart failure
• Liver cirrhosis (according to abdominal echo)
• Renal insufficiency (Cr ≥ 1.7 mg/dL)
• Patient with concomitant use of insulin, and/or diuretics before TZDs were excluded
• Pregnant

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
TZDs User

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
we plan to conduct a case-control study to test the association between single nucleotide polymorphisms (SNPs) in certain candidate genes and TZDs related peripheral edema	34 weeks

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital
• Investigators: Principal Investigator: Tien-Jyun Chang, Ph D, National Taiwan University Hospital

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (Anticipated): December 1, 2011

Study Registration Dates

• First Submitted: September 10, 2009
• First Submitted That Met QC Criteria: September 10, 2009
• First Posted (Estimate): September 11, 2009

Study Record Updates

• Last Update Posted (Estimate): March 18, 2010
• Last Update Submitted That Met QC Criteria: March 16, 2010
• Last Verified: March 1, 2010

More Information

Terms related to this study

• Other Study ID Numbers: 200902005R