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

Diabetes Mellitus Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00975169
• Other study ID #: 200902005R
• Status: Recruiting
• Phase: N/A
• First received: September 10, 2009
• Last updated: March 16, 2010
• Start date: February 2009

Study information

• Verified date: March 2010
• Source: National Taiwan University Hospital
• Contact: Linda Huang
• Phone: 886 9 37670020
• Email: linda590203[@]gmail.com
• Is FDA regulated: No
• Health authority: Taiwan: Department of Health
• Study type: Observational

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. primary completion date: December 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

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 Design

Observational Model: Case Control, Time Perspective: Retrospective

Related Conditions & MeSH terms

• Diabetes Mellitus

Locations

Country	Name	City	State
Taiwan	Department of Internal Medicine, National Taiwan University Hospital	Taipei

Sponsors (1)

Lead Sponsor	Collaborator
National Taiwan University Hospital

Country where clinical trial is conducted

Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No