Obesity, PreDiabetes
Conditions
Brief summary
Th purpose of this study is to determine whether ADI-PEG20 (PEGylated arginine deiminase), an arginine catabolizing enzyme preparation, improves insulin sensitivity, mitochondrial respiration, and energy utilization in adolescents with prediabetes.
Detailed description
Obesity, insulin resistance, and their complications are major causes of morbidity and mortality in children, adolescents, and adults. Although caloric restriction is an effective treatment, intensive lifestyle changes are rarely durable. The investigators and others have shown that: (i.) fasting incites arginine catabolism, and forced arginine catabolism recapitulates several therapeutic effects of fasting, (ii.) exogenous, forced arginine catabolism improves metabolic health, and (iii.) ADI-PEG20 (PEGylated arginine deiminase) is an arginine catabolizing enzyme preparation that improves insulin sensitivity, mitochondrial respiration, and energy utilization in obese mice. The study will determine whether ADI-PEG20 also exerts beneficial effects on metabolic healthy in people. The investigators will perform a 12-week, randomized, double-blind, placebo-controlled trial in boys and girls with pre-diabetes to evaluate the efficacy of ADI-PEG20 treatment on: 1) body composition; 2) resting energy expenditure; 3) multi-organ insulin sensitivity; 3) β-cell function; and 4) muscle mitochondrial function.
Interventions
BIOLOGICALADI-PEG20
Intramuscular injection weekly for 8 weeks
OTHERPlacebo
Intramuscular injection weekly for 8 weeks
Sponsors
Children's Discovery Institute
Polaris Pharmaceuticals, Inc.
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Single-center, randomized, double-blind, placebo-controlled study
Eligibility
Sex/Gender
ALL
Age
18 Years to 22 Years
Healthy volunteers
No
Inclusion criteria
* age: ≥18 and ≤22 years; * BMI 25.0 - 44.9 kg/m2; * Prediabetes, defined as fasting plasma glucose of ≥100 mg/dL, or HbA1C ≥5.7%, or HOMA-IR ≥2.5.
Exclusion criteria
* HbA1C ≥6.5%; * Intolerance or allergies to ingredients in ADI-PEG20 or placebo; * Taking dietary supplements or medications known to affect our study outcomes; * Evidence of significant organ system dysfunction or diseases, * Metallic implants, which would preclude MRI
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in insulin sensitivity | Baseline and 8 weeks of ADI-PEG20 or placebo | Insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in oral glucose tolerance | Baseline and 4 weeks of ADI-PEG20 or placebo | Oral glucose tolerance will be assessed by measuring plasma glucose concentrations before and after ingesting 75 grams glucose |
| Change in β-cell function | Baseline and 4 weeks of ADI-PEG20 or placebo | β-cell function will be assessed from a modified oral glucose tolerance test |
| Change in resting energy expenditure | Baseline and 8 weeks of ADI-PEG20 or placebo | Resting energy expenditure (in kcal/min) will be assessed by using indirect calorimetry |
| Change in muscle mitochondrial respiration | Baseline and 8 weeks of ADI-PEG20 or placebo | Muscle mitochondrial respiration (in pmol O2/mg tissue) will be assessed by using high resolution respirometry, conducted on permeabilized muscle fibers obtained by muscle biopsy. |
| Change in intrahepatic triglyceride content | Baseline and 8 weeks of ADI-PEG20 or placebo | Intrahepatic triglyceride content will be assessed by magnetic resonance imagining (MRI) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in the transcriptome in muscle | Baseline and 8 weeks of ADI-PEG20 or placebo | The transcriptome will be evaluated by using RNA sequencing techniques |
| Change in the transcriptome in adipose tissue | Baseline and 8 weeks of ADI-PEG20 or placebo | The transcriptome will be evaluated by using RNA sequencing techniques |
Countries
United States
Outcome results
None listed