Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH)
The SUGAR-MGH investigators are studying the influence of inherited gene variants on the response to two commonly prescribed type 2 diabetes medications, metformin and glipizide. They hypothesize that variants in genes that are associated with type 2 diabetes or related traits may impact the effect of anti-diabetic medications. In addition, physiological responses to an insulin secretagogue or an insulin sensitizer may shed light on the mechanism of action of reported genetic associations.
Diabetes Mellitus, Type 2
Other: Oral Glucose Tolerance Test
|Study Design:||Endpoint Classification: Pharmacodynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
|Official Title:||Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans|
- Glipizide response [ Time Frame: Between 0-240 minutes, Visit 1 ] [ Designated as safety issue: No ]Investigators will measure insulin and glucose levels for 240 minutes after Glipizide administration on Visit 1, and compare them by genotype at selected loci.
- Metformin response [ Time Frame: 7 days ] [ Designated as safety issue: No ]Investigators will measure the change in glycemic measures between Visit 1 and Visit 2 as an index of Metformin response, and compare them by genotype at selected loci.
- Incretin levels [ Time Frame: 120 minutes, Visit 2 ] [ Designated as safety issue: No ]Investigators will measure GLP-1 and GIP during the 120 minutes of Visit 2, and compare them by genotype at selected loci.
- Proinsulin, glucagon [ Time Frame: 7 days ] [ Designated as safety issue: No ]Investigators will measure proinsulin and glucagon levels at regular intervals during Visits 1 and 2, and compare them by genotype at selected loci.
- Metabolomics [ Time Frame: 7 days ] [ Designated as safety issue: No ]Investigators will perform metabolomic profiling of plasma samples at regular intervals in Visits 1 and 2, by using initially a targeted approach on an existing platform that measures ~400 metabolites (both polar and non-polar); they will compare their relative concentrations by genotype at selected loci before and after the interventions.
- Vitamin D [ Time Frame: Baseline ] [ Designated as safety issue: No ]Investigators will measure 25-hydroxy vitamin D levels at baseline, and examine its effects on glycemic measures during Visits 1 and 2.
|Study Start Date:||January 2008|
|Estimated Study Completion Date:||October 2015|
|Estimated Primary Completion Date:||October 2015 (Final data collection date for primary outcome measure)|
Glipizide and Metformin
On day 1, subjects will receive a single oral dose of glipizide 5 mg, and will have blood drawn at various time points for up to 240 minutes. During study days 2-7, the participants will fill out a dietary intake food record, including 3 weekdays and one weekend day. During days 6-8, the subject will receive a short-course metformin treatment of four 500-mg doses. On the morning of study day 8, 60 minutes after taking the fourth metformin dose, the subject will do a 75g Oral Glucose Tolerance Test. Blood draws will again be taken at time points for 120 minutes.
|Drug: Glipizide Drug: Metformin Other: Oral Glucose Tolerance Test|
Several common genetic variants have been reliably associated with type 2 diabetes and related glycemic traits. Study investigators hypothesize that variants in genes that are reproducibly associated with type 2 diabetes or related glycemic traits may impact the effect of anti-diabetic medications. In particular, sulfonylureas may have differential effects on individuals depending on the allelic variant they carry at KCNJ11 E23K; conversely, because TCF7L2 is postulated to influence insulin secretion by regulating the action of glucagon-like peptide 1 (GLP-1), and sulfonylureas act at a different step in the insulin secretion pathway, the effect of sulfonylureas on insulin secretion could be independent of genetic variation at TCF7L2. In addition, physiological responses to an insulin secretagogue or an insulin sensitizer may shed light on the mechanism of action of reported genetic associations.
Despite the convincing associations of several genetic variants with type 2 diabetes and their involvement in physiological pathways involved in drug response, their impact on pharmacological interventions has not been systematically examined. The completion of the Human Genome Project and the high-density characterization of common human variation in four different ethnic groups highlight the promise of genomic medicine. The elucidation of the genetic architecture of complex phenotypes may help clinicians understand disease heterogeneity, uncover new pathophysiological mechanisms, open the opportunity for novel therapeutic interventions, provide predictive diagnostic and prognostic information, and allow for individually tailored therapy that takes into account both the probability of response and the incidence of drug-induced complications.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01762046
|Contact: Ayesha Muhammad, BSfirstname.lastname@example.org|
|Contact: Marlene Fernandez, BSemail@example.com|
|United States, Massachusetts|
|Brigham and Women's Hospital||Recruiting|
|Boston, Massachusetts, United States, 02116|
|Contact: Marlene Fernandez, BS 617-643-5417 firstname.lastname@example.org|
|Principal Investigator: Margo Hudson, MD|
|Sub-Investigator: Bindu Chamarthi, MD, MMSc|
|Joslin Diabetes Center||Recruiting|
|Boston, Massachusetts, United States, 02116|
|Contact: Lauren DeVita, BA 617-309-4478 Lauren.DeVita@joslin.harvard.edu|
|Principal Investigator: Allison Goldfine, MD|
|Massachusetts General Hospital||Recruiting|
|Boston, Massachusetts, United States, 02114|
|Contact: Ayesha Muhammad email@example.com|
|Contact: Marlene Fernandez firstname.lastname@example.org|
|Principal Investigator: Jose C Florez, MD, PhD|
|Sub-Investigator: Geoffrey Walford, MD|
|Sub-Investigator: Liana K Billings, MD, MMSc|
|Principal Investigator:||Jose C Florez, MD, PhD||Massachusetts General Hospital|