Diabetes Mellitus, Type 2
Conditions
Keywords
Diabetes Mellitus, Type 2, Pharmacogenetics, Genetics, Obesity
Brief summary
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.
Detailed description
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.
Interventions
DRUGGlipizide
DRUGMetformin
OTHEROral Glucose Tolerance Test
Sponsors
Massachusetts General Hospital
Brigham and Women's Hospital
Joslin Diabetes Center
Broad Institute of MIT and Harvard
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
Yes
Inclusion criteria
* Male or non-pregnant female \> 18 years of age * Investigators will target preferentially people at risk of diabetes or requiring diabetes meds * The first tier of risk will be illustrated by one of the following variables (e.g. established type 2 diabetes on diet therapy alone, elevated random glucose in electronic medical record, PCOS, metabolic syndrome, obesity, history of gestational diabetes, etc.) * The second tier of risk will be illustrated by other features that correlate with diabetes risk, such as a history of hypertension or dyslipidemia * Otherwise healthy subjects may also be candidates for the study. * Able and willing to give consent relevant to genetic investigation
Exclusion criteria
* Pregnant, nursing or at risk of becoming pregnant * Currently taking any medications for the treatment of diabetes * Currently on metformin for any other indication (e.g. PCOS) * Onset of diabetes in a family member before age 25, with autosomal transmission of diabetes across three generations * History of liver or kidney disease * Known severe allergic reactions to sulfonamides * History of porphyria * Documented estimated glomerular filtration rate (GFR) \< 60 ml/min/1.73 m2, based on the most recent serum creatinine measurement available in the electronic medical record, and calculated by the Modification of Diet in Renal Disease equation (49) available at http://www.nephron.com/cgi-bin/MDRD\_GFR.cgi * Currently taking medications known to affect glycemic parameters, such as glucocorticoids, growth hormone or fluoroquinolones * Planned radiologic or angiographic study requiring contrast within one week of completion of this study * Established coronary artery disease (CAD), defined as: * History of myocardial infarction. * History of revascularization (coronary artery bypass grafting, percutaneous coronary intervention (e.g. stenting or balloon angioplasty). * Evidence of ischemia on cardiac stress test. * Enrolled in any other interventional study at time of screening through completion of study protocol * History of bariatric surgery * History of seizures * History of stroke/CVA
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Glipizide Response as Measured by Area Over the Glucose Curve Between Time 0 and 240 Minutes According to Genotype | 0, 30, 60, 90, 120, 180 and 240 minutes post 5mg oral glipizide dose, Day 1 (visit 1) | 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. |
| Glipizide Response as Measured by Area Under the Insulin Curve Between Time 0 and 240 Minutes According to Genotype | 0,30,60,90,120,180 and 240 minutes on Day 1 (Visit 1) | 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. |
| Metformin Response - Change in Fasting Glucose From Visit 1 to Visit 2 | Day 1 (Visit 1) and Day 8 (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. |
| Metformin Response - Change in HOMA-IR From Visit 1 to Visit 2 | Day 1 (Visit 1) and Day 8 (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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incretin Levels | 0, 5, 10, 15, 30, 60 and 120 minutes, Day 8 (Visit 2) | 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. |
| Proinsulin (Fasting) at Visit 1 and Visit 2 by Genotype for rs7903146 | Day 1 (Visit 1) and Day 8 (Visit 2) | Investigators will measure proinsulin levels at regular intervals during Visits 1 and 2, and compare them by genotype at selected loci. |
| Fasting Glucagon at Visit 1 and Visit 2 by Genotype for rs7903146 | Day 1 (Visit 1) and Day 8 (Visit 2) | Investigators will measure glucagon levels at regular intervals during Visits 1 and 2, and compare them by genotype at selected loci. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJose C Florez, MD, PhD
Massachusetts General Hospital
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 1,033 |
| Total | 1,033 |
Baseline characteristics
| Characteristic | Glipizide and Metformin |
|---|---|
| Age, Continuous | 47.2 years STANDARD_DEVIATION 16.2 |
| Body Mass Index (BMI) | 30.14 kg/m^2 STANDARD_DEVIATION 7.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants |
| Race (NIH/OMB) Asian | 59 Participants |
| Race (NIH/OMB) Black or African American | 229 Participants |
| Race (NIH/OMB) More than one race | 21 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 17 Participants |
| Race (NIH/OMB) White | 702 Participants |
| Region of Enrollment United States | 1033 participants |
| Sex: Female, Male Female | 557 Participants |
| Sex: Female, Male Male | 476 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 1,033 |
| other Total, other adverse events | 0 / 1,033 |
| serious Total, serious adverse events | 0 / 1,033 |
Outcome results
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.
Time frame: 0, 30, 60, 90, 120, 180 and 240 minutes post 5mg oral glipizide dose, Day 1 (visit 1)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glipizide and Metformin | Glipizide Response as Measured by Area Over the Glucose Curve Between Time 0 and 240 Minutes According to Genotype | Area over the Glucose curve for TCF7L2 CC genotype | 4893.5 mg/dl x time(minutes) | Standard Deviation 2079.4 |
| Glipizide and Metformin | Glipizide Response as Measured by Area Over the Glucose Curve Between Time 0 and 240 Minutes According to Genotype | Area over the Glucose curve for TCF7L2 CT genotype | 5032.6 mg/dl x time(minutes) | Standard Deviation 2161 |
| Glipizide and Metformin | Glipizide Response as Measured by Area Over the Glucose Curve Between Time 0 and 240 Minutes According to Genotype | Area over the Glucose curve for TCF7L2 TT Genotype | 6011 mg/dl x time(minutes) | Standard Deviation 3204.8 |
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.
Time frame: 0,30,60,90,120,180 and 240 minutes on Day 1 (Visit 1)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glipizide and Metformin | Glipizide Response as Measured by Area Under the Insulin Curve Between Time 0 and 240 Minutes According to Genotype | Area under the InsulinCurve for TCF7L2 CC genotype | 1141 mU/L x time (minutes) | Standard Deviation 1910 |
| Glipizide and Metformin | Glipizide Response as Measured by Area Under the Insulin Curve Between Time 0 and 240 Minutes According to Genotype | Area under the InsulinCurve for TCF7L2 CT genotype | 1278 mU/L x time (minutes) | Standard Deviation 1455 |
| Glipizide and Metformin | Glipizide Response as Measured by Area Under the Insulin Curve Between Time 0 and 240 Minutes According to Genotype | Area under the InsulinCurve for TCF7L2 TT genotype | 1400 mU/L x time (minutes) | Standard Deviation 1447 |
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.
Time frame: Day 1 (Visit 1) and Day 8 (Visit 2)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glipizide and Metformin | Metformin Response - Change in Fasting Glucose From Visit 1 to Visit 2 | FastingGlucose V2-FastingGlucose V1 in CC Genotype | -2.1 mg/dl | Standard Deviation 8.1 |
| Glipizide and Metformin | Metformin Response - Change in Fasting Glucose From Visit 1 to Visit 2 | FastingGlucose V2-FastingGlucose V1 in CT Genotype | -2.2 mg/dl | Standard Deviation 8.2 |
| Glipizide and Metformin | Metformin Response - Change in Fasting Glucose From Visit 1 to Visit 2 | FastingGlucose V2-FastingGlucose V1 in TT Genotype | -6.1 mg/dl | Standard Deviation 11 |
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.
Time frame: Day 1 (Visit 1) and Day 8 (Visit 2)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glipizide and Metformin | Metformin Response - Change in HOMA-IR From Visit 1 to Visit 2 | HOMA-IR Visit 1 - HOMA IR Visit 2 in CC Gentoype | 0.09 (mg/dl*uU/ml²) | Standard Deviation 1.9 |
| Glipizide and Metformin | Metformin Response - Change in HOMA-IR From Visit 1 to Visit 2 | HOMA-IR Visit 1 - HOMA IR Visit 2 in CT Gentoype | 0.04 (mg/dl*uU/ml²) | Standard Deviation 1.98 |
| Glipizide and Metformin | Metformin Response - Change in HOMA-IR From Visit 1 to Visit 2 | HOMA-IR Visit 1 - HOMA IR Visit 2 in TT Gentoype | -0.45 (mg/dl*uU/ml²) | Standard Deviation 0.29 |
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.
Time frame: Day 1 (Visit 1) and Day 8 (Visit 2)
Population: 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).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glipizide and Metformin | Fasting Glucagon at Visit 1 and Visit 2 by Genotype for rs7903146 | Glucagon at Visit 1 at CC Genotype | 29.9 pg/ml | Standard Deviation 18 |
| Glipizide and Metformin | Fasting Glucagon at Visit 1 and Visit 2 by Genotype for rs7903146 | Glucagon at Visit 1 at CT Genotype | 28.4 pg/ml | Standard Deviation 19.7 |
| Glipizide and Metformin | Fasting Glucagon at Visit 1 and Visit 2 by Genotype for rs7903146 | Glucagon at Visit 1 at TT Genotype | 25.7 pg/ml | Standard Deviation 16.3 |
| Glipizide and Metformin | Fasting Glucagon at Visit 1 and Visit 2 by Genotype for rs7903146 | Glucagon at Visit 2 at CC Genotype | 28.4 pg/ml | Standard Deviation 16.4 |
| Glipizide and Metformin | Fasting Glucagon at Visit 1 and Visit 2 by Genotype for rs7903146 | Glucagon at Visit 2 at CT Genotype | 28 pg/ml | Standard Deviation 15.9 |
| Glipizide and Metformin | Fasting Glucagon at Visit 1 and Visit 2 by Genotype for rs7903146 | Glucagon at Visit 2 at TT Genotype | 28.5 pg/ml | Standard Deviation 17.5 |
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.
Time frame: 0, 5, 10, 15, 30, 60 and 120 minutes, Day 8 (Visit 2)
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glipizide and Metformin | Incretin Levels | GLP-1 Total AUC at CC genotype | 1176.2 pmol/L x time (minutes) | Standard Deviation 523 |
| Glipizide and Metformin | Incretin Levels | GLP-1 Total AUC at CT genotype | 1286.4 pmol/L x time (minutes) | Standard Deviation 540.4 |
| Glipizide and Metformin | Incretin Levels | GLP-1 Total AUC at TT genotype | 1749.3 pmol/L x time (minutes) | Standard Deviation 1399 |
| Glipizide and Metformin | Incretin Levels | GLP-1 Active AUC at CC genotype | 879 pmol/L x time (minutes) | Standard Deviation 316.6 |
| Glipizide and Metformin | Incretin Levels | GLP-1 Active AUC at CT genotype | 1060.8 pmol/L x time (minutes) | Standard Deviation 687.3 |
| Glipizide and Metformin | Incretin Levels | GLP-1 Active AUC at TT genotype | 1415.7 pmol/L x time (minutes) | Standard Deviation 1681.2 |
| Glipizide and Metformin | Incretin Levels | GIP AUC at CC genotype | 23523 pmol/L x time (minutes) | Standard Deviation 8227 |
| Glipizide and Metformin | Incretin Levels | GIP AUC at CT genotype | 24041.2 pmol/L x time (minutes) | Standard Deviation 8126 |
| Glipizide and Metformin | Incretin Levels | GIP AUC at TT genotype | 20183.1 pmol/L x time (minutes) | Standard Deviation 5892.8 |
Secondary
Metabolomics
Investigators will perform metabolomic profiling of plasma samples at regular intervals during 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 study interventions.
Time frame: Day 1 (Visit 1) and 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.
Time frame: Day 1 (Visit 1) and Day 8 (Visit 2)
Population: 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).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Glipizide and Metformin | Proinsulin (Fasting) at Visit 1 and Visit 2 by Genotype for rs7903146 | ProInsulin at Visit 1 at CC Genotype | 20.5 pmol/L | Standard Deviation 21.2 |
| Glipizide and Metformin | Proinsulin (Fasting) at Visit 1 and Visit 2 by Genotype for rs7903146 | ProInsulin at Visit 1 at CT Genotype | 23.4 pmol/L | Standard Deviation 25.2 |
| Glipizide and Metformin | Proinsulin (Fasting) at Visit 1 and Visit 2 by Genotype for rs7903146 | ProInsulin at Visit 1 at TT Genotype | 25.1 pmol/L | Standard Deviation 21.2 |
| Glipizide and Metformin | Proinsulin (Fasting) at Visit 1 and Visit 2 by Genotype for rs7903146 | ProInsulin at Visit 2 at CC Genotype | 19.4 pmol/L | Standard Deviation 21.6 |
| Glipizide and Metformin | Proinsulin (Fasting) at Visit 1 and Visit 2 by Genotype for rs7903146 | ProInsulin at Visit 2 at CT Genotype | 19.1 pmol/L | Standard Deviation 19 |
| Glipizide and Metformin | Proinsulin (Fasting) at Visit 1 and Visit 2 by Genotype for rs7903146 | ProInsulin at Visit 2 at TT Genotype | 21.4 pmol/L | Standard Deviation 20.9 |
Secondary
Vitamin D
Investigators will measure 25-hydroxy vitamin D levels at baseline, and examine its effects on glycemic measures during Visits 1 and 2.
Time frame: Baseline