Genetic Variation in OCT1 and Response to Metformin

NCT ID: NCT00588172

Last Updated: 2010-08-17

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE4
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-06-30
• Study Completion Date: 2011-06-30

Brief Summary

Type 2 diabetes its microvascular and macrovascular complications have become a major global health problem. Metformin is often used as first-line therapy for this disorder given that it is cheap, may cause weight loss and does not have significant side-effects in healthy patients. On the other hand, as many as one third of all patients with type 2 diabetes initially treated with metformin never achieve a meaningful response to this intervention. Recently, genetic variation in the organic cation transporter 1 (Oct1) gene which encodes a protein, OCT1, mediating metformin uptake by the liver, its primary site of action, has been shown alter metformin action. In Oct1-deficient mice the glucose-lowering effects of metformin are completely abolished. Moreover a polymorphism with a 20% minor allele frequency in Caucasians also alters the effect of metformin on glucose tolerance (the net result of glucose uptake and glucose release) after ingestion of 75g of glucose. However, it is unknown if this polymorphism affects suppression of endogenous glucose production or stimulation of peripheral glucose uptake by metformin, or both, and to what degree. We propose to utilize established methodology to measure glucose turnover in response to a mixed meal to determine how common genetic variation in OCT1 alters response to metformin in healthy volunteers. This will clarify the effect of these variants on response to metformin in humans. The knowledge gained from this study will help to design future studies examining the role of OCT1 genotype in determining initial therapy for type 2 diabetes.

Conditions

Type 2 Diabetes

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

1

Individuals with no nsSNPs or mutations known to alter oct1 function

Group Type: SHAM_COMPARATOR

Metformin

Intervention Type: DRUG

1000mg bid for 1 week

2

Individuals with nsSNPs or mutations known to alter oct1 function

Group Type: ACTIVE_COMPARATOR

Metformin

Intervention Type: DRUG

1000mg bid for 1 week

Interventions

Metformin

1000mg bid for 1 week

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Heterozygous or homozygous for the nsSNPs R61C, G401S, 420Del, G465R, G174S (see supplementary info (3)) or without any nsSNPs that could potentially alter gene function.

2. Age 18 - 40.

3. Willingness to participate in this study.

Exclusion Criteria

1. Fasting glucose > 100mg/dL on one occasion.

2. Use of medication other than stable thyroid hormone replacement or oral contraception.

3. Subjects must not be pregnant or < 6 months postpartum at the time of study.

4. Prior abdominal surgery other than hysterectomy, appendectomy or tubal ligation.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Mayo Clinic

OTHER

Sponsor Role: lead

Responsible Party

Mayo Clinic

Principal Investigators

Adrian Vella, MD

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

Other Identifiers

OCT1 and metformin

Identifier Type: -

Identifier Source: secondary_id

07-004310

Identifier Type: -

Identifier Source: org_study_id