Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| Brigham and Women's Hospital | OTHER |
| Joslin Diabetes Center | OTHER |
| Broad Institute of MIT and Harvard | OTHER |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
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.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Glipizide and Metformin | Other | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Glipizide | Drug |
| ||
| Metformin |
| Measure | Description | Time Frame |
|---|---|---|
| Glipizide Response as Measured by Area Over the Glucose Curve Between Time 0 and 240 Minutes According to Genotype | Investigators will measure glucose levels at 0,30,60,90,120,180 and 240 minutes post 5mg Glipizide administration on Visit 1(Day1), and compare them by genotype at selected loci. | 0, 30, 60, 90, 120, 180 and 240 minutes post 5mg oral glipizide dose, Day 1 (visit 1) |
| Glipizide Response as Measured by Area Under the Insulin Curve Between Time 0 and 240 Minutes According to Genotype | Investigators will measure insulin levels at 0,30,60,90,120,180 and 240 minutes post 5mg Glipizide administration on Visit 1(Day1), and compare them by genotype at selected loci. | 0,30,60,90,120,180 and 240 minutes on Day 1 (Visit 1) |
| Metformin Response - Change in Fasting Glucose From Visit 1 to Visit 2 | Investigators will measure the change in glycemic measures between Visit 1 (Day 1) and Visit 2 (Day 8) as an index of Metformin response, and compare them by genotype at selected loci. HOMA-IR is calculated from fasting glucose and fasting insulin values at both visit 1 (day 1) and visit 2 (day 8). HOMA-IR was calculated using (fasting glucose*fasting insulin)/405) formula. | Day 1 (Visit 1) and Day 8 (Visit 2) |
| Metformin Response - Change in HOMA-IR From Visit 1 to Visit 2 | Investigators will measure the change in glycemic measures between Visit 1 (Day 1) and Visit 2 (Day 8) as an index of Metformin response, and compare them by genotype at selected loci. HOMA-IR is calculated from fasting glucose and fasting insulin values at both visit 1 (day 1) and visit 2 (day 8). HOMA-IR was calculated using (fasting glucose*fasting insulin)/405) formula. A bigger difference/drop between visit 1 and visit 2 will show that metformin had an effect on insulin resistance index for these participants. The higher the HOMA-IR, the more insulin resistant you are. | Day 1 (Visit 1) and Day 8 (Visit 2) |
| Measure | Description | Time Frame |
|---|---|---|
| Incretin Levels | Investigators will measure GLP-1 and GIP during the OGTT from 0 to 120 minutes of Visit 2, and compare them by genotype at selected loci. | 0, 5, 10, 15, 30, 60 and 120 minutes, Day 8 (Visit 2) |
| Proinsulin (Fasting) at Visit 1 and Visit 2 by Genotype for rs7903146 |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Jose C Florez, MD, PhD | Massachusetts General Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Massachusetts General Hospital | Boston | Massachusetts | 02114 | United States | ||
| Brigham and Women's Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31709648 | Derived | Chen L, Li JH, Kaur V, Muhammad A, Fernandez M, Hudson MS, Goldfine AB, Florez JC. The presence of two reduced function variants in CYP2C9 influences the acute response to glipizide. Diabet Med. 2020 Dec;37(12):2124-2130. doi: 10.1111/dme.14176. Epub 2019 Nov 25. | |
| 29326107 | Derived | Srinivasan S, Kaur V, Chamarthi B, Littleton KR, Chen L, Manning AK, Merino J, Thomas MK, Hudson M, Goldfine A, Florez JC. TCF7L2 Genetic Variation Augments Incretin Resistance and Influences Response to a Sulfonylurea and Metformin: The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH). Diabetes Care. 2018 Mar;41(3):554-561. doi: 10.2337/dc17-1386. Epub 2018 Jan 11. |
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | 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. Glipizide Metformin Oral Glucose Tolerance Test |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | 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. Glipizide Metformin Oral Glucose Tolerance Test |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 1033 subjects were enrolled and completed the study but some disqualified for various reasons like not fasting for the fasting visit due to having chewed gum, or having had black coffee, and in the end we have 1000 subjects with viable phenotype and genotype data. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Glipizide Response as Measured by Area Over the Glucose Curve Between Time 0 and 240 Minutes According to Genotype | Investigators will measure glucose levels at 0,30,60,90,120,180 and 240 minutes post 5mg Glipizide administration on Visit 1(Day1), and compare them by genotype at selected loci. | 1000 subjects were genotyped for SNP rs7903146 (in the TCF7L2 gene). We are showing Area over the curve for glucose that was measured between time 0 to 240 minutes. 10 subjects didn't pass the QC for genotype analysis. | Posted | Mean | Standard Deviation | mg/dl x time(minutes) | 0, 30, 60, 90, 120, 180 and 240 minutes post 5mg oral glipizide dose, Day 1 (visit 1) |
|
8 days (on day 1 the subjects had their first study visit and their second study visit was on day 8).
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. Glipizide Metformin Oral Glucose Tolerance Test |
Not provided
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jose C. Florez, MD, PhD | Massachusetts General Hospital | 6176433308 | jcflorez@partners.org |
Not provided
| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D009765 | Obesity |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D005913 | Glipizide |
| D008687 | Metformin |
| D005951 | Glucose Tolerance Test |
| ID | Term |
|---|---|
| D013453 | Sulfonylurea Compounds |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
| Oral Glucose Tolerance Test | Other |
|
Investigators will measure proinsulin levels at regular intervals during Visits 1 and 2, and compare them by genotype at selected loci. |
| Day 1 (Visit 1) and Day 8 (Visit 2) |
| Fasting Glucagon at Visit 1 and Visit 2 by Genotype for rs7903146 | Investigators will measure glucagon levels at regular intervals during Visits 1 and 2, and compare them by genotype at selected loci. | Day 1 (Visit 1) and Day 8 (Visit 2) |
| Boston |
| Massachusetts |
| 02116 |
| United States |
| Joslin Diabetes Center | Boston | Massachusetts | 02116 | United States |
| 25812009 | Derived | Walford GA, Colomo N, Todd JN, Billings LK, Fernandez M, Chamarthi B, Warner AS, Davis J, Littleton KR, Hernandez AM, Fanelli RR, Lanier A, Barbato C, Ackerman RJ, Khan SQ, Bui R, Garber L, Stolerman ES, Moore AF, Huang C, Kaur V, Harden M, Taylor A, Chen L, Manning AK, Huang P, Wexler D, McCarthy RM, Lo J, Thomas MK, Grant RW, Goldfine A, Hudson MS, Florez JC. The study to understand the genetics of the acute response to metformin and glipizide in humans (SUGAR-MGH): design of a pharmacogenetic resource for type 2 diabetes. PLoS One. 2015 Mar 26;10(3):e0121553. doi: 10.1371/journal.pone.0121553. eCollection 2015. |
| Mean |
| Standard Deviation |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Body Mass Index (BMI) | 1033 subjects completed the study but 33 subjects were disqualified for various reasons (such as: having chewed gum before the fasting visits, had coffee before the fasting visit etc.), and in the end we have 1000 subjects with viable phenotype and genotype data. | Mean | Standard Deviation | kg/m^2 |
|
|
|
| Primary | Glipizide Response as Measured by Area Under the Insulin Curve Between Time 0 and 240 Minutes According to Genotype | Investigators will measure insulin levels at 0,30,60,90,120,180 and 240 minutes post 5mg Glipizide administration on Visit 1(Day1), and compare them by genotype at selected loci. | 1000 subjects were genotyped for SNP rs7903146 (in the TCF7L2 gene). We are showing Area under the curve for Insulin that was measured between time 0 to 240 minutes. 10 subjects didn't pass the QC for genotype analysis. | Posted | Mean | Standard Deviation | mU/L x time (minutes) | 0,30,60,90,120,180 and 240 minutes on Day 1 (Visit 1) |
|
|
|
| Primary | Metformin Response - Change in Fasting Glucose From Visit 1 to Visit 2 | Investigators will measure the change in glycemic measures between Visit 1 (Day 1) and Visit 2 (Day 8) as an index of Metformin response, and compare them by genotype at selected loci. HOMA-IR is calculated from fasting glucose and fasting insulin values at both visit 1 (day 1) and visit 2 (day 8). HOMA-IR was calculated using (fasting glucose*fasting insulin)/405) formula. | We looked at fasting glucose at Visit 2 minus fasting glucose at visit 1 to see if there are differences by genotype at rs7903146 after Metformin treatment in the 1000 subjects in this study. 10 subjects didn't pass the QC for genotype analysis. | Posted | Mean | Standard Deviation | mg/dl | Day 1 (Visit 1) and Day 8 (Visit 2) |
|
|
|
| Primary | Metformin Response - Change in HOMA-IR From Visit 1 to Visit 2 | Investigators will measure the change in glycemic measures between Visit 1 (Day 1) and Visit 2 (Day 8) as an index of Metformin response, and compare them by genotype at selected loci. HOMA-IR is calculated from fasting glucose and fasting insulin values at both visit 1 (day 1) and visit 2 (day 8). HOMA-IR was calculated using (fasting glucose*fasting insulin)/405) formula. A bigger difference/drop between visit 1 and visit 2 will show that metformin had an effect on insulin resistance index for these participants. The higher the HOMA-IR, the more insulin resistant you are. | We looked at HOMA-IR at Visit 2 minus HOMA-IR at visit 1 to see if there are differences by genotype at rs7903146 after Metformin treatment in the 1000 subjects in this study. 10 subjects didn't pass the QC for genotype analysis. | Posted | Mean | Standard Deviation | (mg/dl*uU/ml²) | Day 1 (Visit 1) and Day 8 (Visit 2) |
|
|
|
| Secondary | Incretin Levels | Investigators will measure GLP-1 and GIP during the OGTT from 0 to 120 minutes of Visit 2, and compare them by genotype at selected loci. | We only measured GLP-1 and GIP in a subset of the study population. We are showing Area under the curve results for GLP-1 total, GLP-1 active, and GIP by genotype at rs7903146 in TCF7L2. | Posted | Mean | Standard Deviation | pmol/L x time (minutes) | 0, 5, 10, 15, 30, 60 and 120 minutes, Day 8 (Visit 2) |
|
|
|
| Secondary | Proinsulin (Fasting) at Visit 1 and Visit 2 by Genotype for rs7903146 | Investigators will measure proinsulin levels at regular intervals during Visits 1 and 2, and compare them by genotype at selected loci. | Fasting Proinsulin were measured only in a subset of study samples. We are showing fasting data at Day 1, Visit 1 and Day 8, Visit 2 by genotype at rs7903146 (in TCF7L2). | Posted | Mean | Standard Deviation | pmol/L | Day 1 (Visit 1) and Day 8 (Visit 2) |
|
|
|
| Secondary | Fasting Glucagon at Visit 1 and Visit 2 by Genotype for rs7903146 | Investigators will measure glucagon levels at regular intervals during Visits 1 and 2, and compare them by genotype at selected loci. | Fasting glucagon were measured only in a subset of study samples. We are showing fasting data at Day 1, Visit 1 and Day 8, Visit 2 by genotype at rs7903146 (in TCF7L2). | Posted | Mean | Standard Deviation | pg/ml | Day 1 (Visit 1) and Day 8 (Visit 2) |
|
|
|
| 0 |
| 1,033 |
| 0 |
| 1,033 |
| 0 |
| 1,033 |
Not provided
Not provided
Not provided
| D004700 | Endocrine System Diseases |
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D001645 |
| Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D001774 | Blood Chemical Analysis |
| D019963 | Clinical Chemistry Tests |
| D019411 | Clinical Laboratory Techniques |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D003940 | Diagnostic Techniques, Endocrine |
| D008919 | Investigative Techniques |
|
| Area under the InsulinCurve for TCF7L2 TT genotype |
|
|
|
| FastingGlucose V2-FastingGlucose V1 in TT Genotype |
|
|
|
| HOMA-IR Visit 1 - HOMA IR Visit 2 in TT Gentoype |
|
|
|
| GLP-1 Total AUC at TT genotype |
|
|
| GLP-1 Active AUC at CC genotype |
|
|
| GLP-1 Active AUC at CT genotype |
|
|
| GLP-1 Active AUC at TT genotype |
|
|
| GIP AUC at CC genotype |
|
|
| GIP AUC at CT genotype |
|
|
| GIP AUC at TT genotype |
|
|
|
| ProInsulin at Visit 1 at TT Genotype |
|
|
| ProInsulin at Visit 2 at CC Genotype |
|
|
| ProInsulin at Visit 2 at CT Genotype |
|
|
| ProInsulin at Visit 2 at TT Genotype |
|
|
|
| Glucagon at Visit 1 at TT Genotype |
|
|
| Glucagon at Visit 2 at CC Genotype |
|
|
| Glucagon at Visit 2 at CT Genotype |
|
|
| Glucagon at Visit 2 at TT Genotype |
|
|