Diabetes Mellitus, Type 2, Hyperuricemia
Conditions
Keywords
arterial stiffness, endothelial dysfunction, type 2 diabetes, hyperuricemia
Brief summary
Three separate interventions will be undertaken with the primary outcome of improving pulse wave velocity. Initially, age and BMI-matched men and post-menopausal women, all with type 2 diabetes, will be treated with allopurinol (20 men, 20 women) for 6 months, in order to reduce serum uric acid (SUA) concentrations relative to placebo (10 men, 10 women). In a second intervention, dietary fructose will be restricted for a period of 6 months in type 2 diabetes (T2D) subjects who will maintain a stable weight (20 men, 20 women). In a third intervention, dietary fructose will be restricted for a period of 6 months in type 2 diabetes (T2D) subjects who will achieve a caloric deficit and weight reduction (20 men, 20 women). At the beginning and end of each of the studies, measures of arterial stiffness will be combined with assessments of endothelial function (flow-mediated dilation and insulin stimulated leg blood flow), measurements of systemic inflammation and oxidative stress.
Detailed description
Sedentary, overweight and obese subjects diagnosed with T2D, ages 40-75 years old, will be recruited from the local community, via the University of Missouri's Endocrinology Clinic and the primary care clinics. During screening, and after consent, anthropometrics (waist circumference and body composition) will be obtained and fasting blood will be drawn for serum chemistries, A1c, complete blood count, liver and kidney function. Screening will also include completion of an oral glucose tolerance test with measurements of arterial stiffness and assessment of endothelial function. Following screening, eligible subjects will be assigned to one of the four groups (allopurinol, placebo, fructose restriction/isocaloric, or fructose restriction/hypocaloric). Allopurinol will be titrated to achieve a target dose of 300 mg/day. Along with placebo, this arm of the study is double-blinded. A separate group of men and women will be assigned to the isocaloric fructose-restriction study in which dietary fructose is replaced by starch and body weight is held constant. Lastly, a separate group of men and women will be assigned to the hypocaloric fructose-restriction in which baseline caloric intake will be reduced by 500 Calories/day while baseline intakes of protein and fat will remain constant. The subjects in these groups will not be blinded to the dietary treatment but the staff making measurements will be. Subjects in the four groups will be matched for age and BMI.
Interventions
OTHERLow-fructose diet, isocaloric
6 month of consumption a low fructose diet
DRUGAllopurinol
6 months of allopurinol treatment with the goal of decreasing uric acid compared to control group
DRUGPlacebo
6 months of placebo treatment
OTHERLow-fructose, hypocaloric
6 month of consumption a low fructose diet with a 500 Calorie/day energy restriction
Sponsors
University of Missouri-Columbia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Men and women ages 40-75 years at randomization * BMI between 25.1 and 50 kg/m2. * Type 2 diabetes diagnosed \> 3 months ago. Patients with T2D will be classified based on physician diagnosis.
Exclusion criteria
* serum uric acid \< 5.5 mg/dL (for medication/allopurinol and isocaloric low-fructose diet arm) * habitual diet containing low amount of sugars \< 5% of total energy intake * recent CVD event (stroke, heart failure hospitalization, revascularization or acute coronary event in the last 12 months). * abnormal thyroid tests or chronic liver disease * stage IV renal disease (GFR \<30) * hyperparathyroidism * use of azathioprine * active cancer * autoimmune diseases * excessive alcohol consumption (\>14 drinks/week for men, \>7 drinks/week for women) * current tobacco use * bodyweight change ≥10% within the last 6 months * history of gout or uncontrolled hypertension * A1C \>10 % (only for medication/placebo arm) * Pregnancy or lactation in women (or women not using contraceptives)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Carotid Femoral Pulse Wave Velocity (cfPWV) | This will be assessed at baseline and 6 months (final). The goal is to assess changes from baseline when compared to final time point. | It is the gold standard non-invasive index of arterial stiffness. Transit time between carotid and femoral pressure waves is calculated using the foot-to-foot method. cfPWV is calculated as distance traveled by the pulse wave (i.e., femoral location-sternal notch minus sternal notch-carotid location) divided by pulse transit time. All the measurements will be done by the same blinded technician |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Brachial Artery Flow Mediated Dilation (FMD) | Baseline and 6 months (final). The goal is to assess changes from baseline when compared to final time point. | Brachial artery FMD will be assessed at baseline and final. FMD is a measurement of conduit artery endothelial function. FMD is assessed immediately after each PWV measurement. Shear rate AUC until peak diameter is calculated as stimulus for FMD and used in covariate analysis as described. All measurements will be performed, under co-I supervision by the same blinded technician. |
| Insulin-stimulated Leg Blood Flow | The goal is to assess insulin stimulated responses in blood flow after 6 mo of intervention. | We will perform a hyperinsulinemic euglycemic clamp to evaluate insulin-stimulated leg blood flow (to be assessed via Doppler ultrasound). Insulin will be infused at a constant rate to mimic postprandial insulin concentrations and glucose maintained at fasting values via a variable 20% dextrose infusion. Femoral artery blood flow will be assessed at the beginning and at end of the 60-minute insulin infusion, and data are presented as percent of change from pre-insulin infusion values. |
Countries
United States
Participant flow
Pre-assignment details
The current Clinical trials.gov information reflects the number of subjects that were recruited for the clinical trial portion of this study. No subjects were recruited the isocaloric portion of this study.
Participants by arm
| Arm | Count |
|---|---|
| Allopurinol Subjects assigned to this arm of the study will be treated for 6 months with allopurinol (max dose 300 mg)
Allopurinol: 6 months of allopurinol treatment with the goal of decreasing uric acid compared to control group | 7 |
| Placebo Subjects assigned to this arm will receive placebo
Placebo: 6 months of placebo treatment | 5 |
| Low-fructose Diet, Hypocaloric Subjects assigned to this arm of the study will consume for 6 months a diet low in fructose with a 500 Calorie energy reduction.
Low-fructose, hypocaloric: 6 month of consumption a low fructose diet with a 500 Calorie/day energy restriction | 16 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 2 |
Baseline characteristics
| Characteristic | Allopurinol | Placebo | Low-fructose Diet, Hypocaloric | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 7 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 4 Participants | 9 Participants | 18 Participants |
| Age, Continuous | 60 years STANDARD_DEVIATION 8.6 | 58 years STANDARD_DEVIATION 7.5 | 59 years STANDARD_DEVIATION 12.1 | 59 years STANDARD_DEVIATION 10.3 |
| Baseline PWV | 9.87 m/s STANDARD_DEVIATION 3.36 | 8.62 m/s STANDARD_DEVIATION 1.45 | 8.17 m/s STANDARD_DEVIATION 1.19 | 8.7 m/s STANDARD_DEVIATION 2.06 |
| Brachial FMD | 4.75 Percentage (%) STANDARD_DEVIATION 3.37 | 4.29 Percentage (%) STANDARD_DEVIATION 0.77 | 5.15 Percentage (%) STANDARD_DEVIATION 3.14 | 4.86 Percentage (%) STANDARD_DEVIATION 2.83 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 5 Participants | 15 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 7 Participants | 5 Participants | 16 Participants | 28 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 9 Participants | 15 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 7 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 5 | 0 / 16 |
| other Total, other adverse events | 5 / 7 | 4 / 5 | 8 / 16 |
| serious Total, serious adverse events | 0 / 7 | 0 / 5 | 1 / 16 |
Outcome results
Primary
Carotid Femoral Pulse Wave Velocity (cfPWV)
It is the gold standard non-invasive index of arterial stiffness. Transit time between carotid and femoral pressure waves is calculated using the foot-to-foot method. cfPWV is calculated as distance traveled by the pulse wave (i.e., femoral location-sternal notch minus sternal notch-carotid location) divided by pulse transit time. All the measurements will be done by the same blinded technician
Time frame: This will be assessed at baseline and 6 months (final). The goal is to assess changes from baseline when compared to final time point.
Population: Measurement not available for all subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allopurinol | Carotid Femoral Pulse Wave Velocity (cfPWV) | 8.71 m/s | Standard Deviation 1.47 |
| Placebo | Carotid Femoral Pulse Wave Velocity (cfPWV) | 7.8 m/s | Standard Deviation 1.04 |
| Low-fructose Diet, Hypocaloric | Carotid Femoral Pulse Wave Velocity (cfPWV) | 8.28 m/s | Standard Deviation 1.4 |
Secondary
Brachial Artery Flow Mediated Dilation (FMD)
Brachial artery FMD will be assessed at baseline and final. FMD is a measurement of conduit artery endothelial function. FMD is assessed immediately after each PWV measurement. Shear rate AUC until peak diameter is calculated as stimulus for FMD and used in covariate analysis as described. All measurements will be performed, under co-I supervision by the same blinded technician.
Time frame: Baseline and 6 months (final). The goal is to assess changes from baseline when compared to final time point.
Population: Measurement not available for all subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allopurinol | Brachial Artery Flow Mediated Dilation (FMD) | 5.03 Percentage (%) | Standard Deviation 3.44 |
| Placebo | Brachial Artery Flow Mediated Dilation (FMD) | 4.4 Percentage (%) | Standard Deviation 2.8 |
| Low-fructose Diet, Hypocaloric | Brachial Artery Flow Mediated Dilation (FMD) | 7.10 Percentage (%) | Standard Deviation 2.19 |
Secondary
Insulin-stimulated Leg Blood Flow
We will perform a hyperinsulinemic euglycemic clamp to evaluate insulin-stimulated leg blood flow (to be assessed via Doppler ultrasound). Insulin will be infused at a constant rate to mimic postprandial insulin concentrations and glucose maintained at fasting values via a variable 20% dextrose infusion. Femoral artery blood flow will be assessed at the beginning and at end of the 60-minute insulin infusion, and data are presented as percent of change from pre-insulin infusion values.
Time frame: The goal is to assess insulin stimulated responses in blood flow after 6 mo of intervention.
Population: The percentage change in blood flow in response to insulin was calculated as femoral blood flow insulin - femoral blood flow insulin no insulin x 100
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allopurinol | Insulin-stimulated Leg Blood Flow | -7.68 Percetage (%) change | Standard Deviation 35.29 |
| Placebo | Insulin-stimulated Leg Blood Flow | 68.18 Percetage (%) change | Standard Deviation 153.59 |
| Low-fructose Diet, Hypocaloric | Insulin-stimulated Leg Blood Flow | 42.65 Percetage (%) change | Standard Deviation 75.12 |