Genetic Variation in OCT1 and Response to Metformin

NCT00588172 | Withdrawn Phase 4

• 2 other identifiers: 07-004310OCT1 and metformin
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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

Keywords

Metformin; Type 2 diabetes; Oct1

Outcome Measures

Primary Outcomes (1)

• Change in glucose area under the curve after a mixed meal in response to metformin

  before and after 1 week of metformin

Secondary Outcomes (1)

• Change in glucose disappearance and suppression of endogenous glucose production in response to metformin

  before and after 1 week of metformin therapy

Study Arms (2)

1

SHAM COMPARATOR

Individuals with no nsSNPs or mutations known to alter oct1 function

Drug: Metformin

2

ACTIVE COMPARATOR

Individuals with nsSNPs or mutations known to alter oct1 function

Drug: Metformin

Interventions

Metformin DRUG

1000mg bid for 1 week

1; 2

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Age 18 - 40.
• Willingness to participate in this study.

You may not qualify if:

• Fasting glucose \> 100mg/dL on one occasion.
• Use of medication other than stable thyroid hormone replacement or oral contraception.
• Subjects must not be pregnant or \< 6 months postpartum at the time of study.
• Prior abdominal surgery other than hysterectomy, appendectomy or tubal ligation.

Sponsors & Collaborators

• Mayo Clinic: lead

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Neurofibromatosis, Type 3, mixed central and peripheral

Interventions

Metformin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Adrian Vella, MD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: December 22, 2007
• First Posted: January 8, 2008
• Study Start: June 1, 2010
• Primary Completion: June 1, 2010
• Study Completion: June 1, 2011
• Last Updated: August 17, 2010

Record last verified: 2010-08