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Sex-related Differences in Arterial Stiffness in Type 2 Diabetics: Role of Uric Acid

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03648996
Recruitment Status : Recruiting
First Posted : August 28, 2018
Last Update Posted : May 7, 2019
Information provided by (Responsible Party):
Camila Manrique, University of Missouri-Columbia

Brief Summary:
Two 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). At the beginning and end of both 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.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Hyperuricemia Other: Low-fructose diet Drug: Allopurinol Drug: Placebo Phase 2

Detailed Description:
Sedentary, overweight and obese subjects diagnosed with T2D, age > 55 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. Subjects in the fructose restriction arm will alcohol restrictions with the dietitian, and will be given a chance to acclimate to the hooded mode of the metabolic cart to prepare for future energy-expenditure measurements. Following screening, eligible subjects will be assigned to one of the three groups (allopurinol, placebo or fructose restriction). 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 fructose-restriction study in which dietary fructose is replaced by starch and body weight is held constant. The subjects in this group will not be blinded to the dietary treatment but the staff making measurements will be. Subjects in the three groups will be matched for age and BMI.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Sex-related Differences in Arterial Stiffness in Type 2 Diabetics: Role of Uric Acid
Actual Study Start Date : November 1, 2018
Estimated Primary Completion Date : September 30, 2021
Estimated Study Completion Date : September 30, 2021

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Low-fructose diet
Subjects assigned to this arm of the study will consume for 6 months a diet low in fructose
Other: Low-fructose diet
6 month of consumption a low fructose diet

Experimental: Allopurinol
Subjects assigned to this arm of the study will be treated for 6 months with allopurinol (max dose 300 mg)
Drug: Allopurinol
6 months of allopurinol treatment with the goal of decreasing uric acid compared to control group
Other Name: Zyloprim

Placebo Comparator: Placebo
Subjects assigned to this arm will receive placebo
Drug: Placebo
6 months of placebo treatment

Primary Outcome Measures :
  1. carotid femoral pulse wave velocity (cfPWV) [ Time Frame: This will be assessed at baseline, 3 months (interim) and 6 months (final). The goal is to assess changes from baseline when compared to interim and 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 Outcome Measures :
  1. Brachial artery flow mediated dilation (FMD) [ Time Frame: Baseline, 3 months (interim) and 6 months (final). The goal is to assess changes from baseline when compared to interim and final time point. ]
    Brachial artery FMD will be assessed at baseline and at 12-wk. 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.

  2. Insulin-stimulated leg blood flow [ Time Frame: Baseline and 6 months (final). The goal is to assess changes from baseline when compared to interim and final time point. ]
    Subjects will be instrumented with EKG for contrast-enhanced ultrasound (CEU) measurements. We will perform a hyperinsulinemic euglycemic clamp to evaluate microvascular perfusion of skeletal muscle via CEU. 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. At baseline and in the steady state phase of the insulin clamp, we will assess microvascular perfusion in the vastus lateralis muscle using CEU (IE-33, Philips Ultrasound), via infusion of perflutren lipid microspheres. Microvascular perfusion will be assessed as an A-value. A is the video intensity plateau after complete replenishment reflecting relative microvascular blood volume (MBV).

Information from the National Library of Medicine

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Ages Eligible for Study:   55 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Men and post-menopausal women older > 55 years at randomization and with type 2 diabetes diagnosed per ADA 2018 criteria > 3 months ago.
  • Women: no menstrual periods for > 6 mo.
  • BMI between 25.1 and 50 kg/m2.
  • A1C level obtained <3 mo before randomization of < 10%
  • Stable glucose lowering therapy for at least 3 months.

Exclusion Criteria:

  • serum uric acid < 5.5 mg/dL
  • 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 %

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03648996

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Contact: Camila Manrique Acevedo, MD 573-8820999

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United States, Missouri
University of Missouri Recruiting
Columbia, Missouri, United States, 65212
Contact: Camila Manrique Acevedo, MD    573-882-0999   
Sponsors and Collaborators
University of Missouri-Columbia
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Principal Investigator: Camila Manrique Acevedo, MD University of Missouri-Columbia

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Responsible Party: Camila Manrique, Associate Professor of Medicine, University of Missouri-Columbia Identifier: NCT03648996    
Other Study ID Numbers: 2012106
First Posted: August 28, 2018    Key Record Dates
Last Update Posted: May 7, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Camila Manrique, University of Missouri-Columbia:
arterial stiffness
endothelial dysfunction
type 2 diabetes
Additional relevant MeSH terms:
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Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Pathologic Processes
Uric Acid
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Gout Suppressants
Antirheumatic Agents
Free Radical Scavengers
Protective Agents
Physiological Effects of Drugs