The primary purpose of this study is to determine whether isoleucine repletion attenuates increases in insulin sensitivity typically observed when people with obesity follow a healthy, low-isoleucine diet.
Isoleucine restriction promotes insulin sensitivity in preclinical models and is a promising strategy for preventing type 2 diabetes. This project aims to identify clinical and molecular changes in skeletal muscle and adipose tissues when adults with obesity switch from a typical American style diet to a plant-based diet low in isoleucine with or without isoleucine repletion.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
TRIPLE
Enrollment
40
Participants will follow a habitual American style diet. All participants transition to a healthy, low-isoleucine diet the study team provides, but only the isoleucine group receives isoleucine supplements to replete the overall diet to typical intake levels.
Healthy, weight-maintaining, low-isoleucine meals and snacks will be provided directly to participants for 4 weeks. Diets are formulated by registered dietitians to meet energy, protein, and amino-acid requirements while minimizing weight change; target macronutrient distribution ≈ 10% protein / 60% carbohydrate / 30% fat38. Isoleucine content will meet minimum needs of 23 mg/kg.
University of Kentucky
Lexington, Kentucky, United States
Change in insulin sensitivity (M value)
The primary clinical outcome is insulin sensitivity, quantified as the M value derived from the hyperinsulinemic-euglycemic clamp. Hyperinsulinemic-euglycemic clamps will be performed to measure insulin sensitivity (IS). Briefly, after a ≥8 hour fast, participants will be admitted to the PC clinical unit and two IVs will be inserted; one for infusion, the other for blood draws. The primary metric will be an absolute change in M value from baseline to post intervention.
Time frame: The first measure is taken immediately after the run-in and the final measure will be taken immediately after the completion of the low-isoleucine diet and isoleucine vs placebo supplement intervention four weeks later.
Change in ratio of phosphorylation IRS-1 in skeletal muscle
Phosphorylation of IRS-1 at Ser636/639 will be quantified in skeletal muscle tissue obtained at baseline and after the intervention. Levels of phosphorylated IRS-1 and total IRS-1 will be measured, and the outcome will be expressed as the change in the phospho-to-total IRS-1 protein ratio from baseline to post-intervention.
Time frame: The first measure is taken immediately after the run-in and the final measure will be taken immediately after the completion of the low-isoleucine diet and isoleucine vs placebo supplement intervention four weeks later.
Absolute change in visceral fat
Abdominal adiposity will be assessed by computed tomography (CT). A single slice at the L4/L5level will be obtained at baseline and post-intervention. Visceral and subcutaneous fat volumes will be quantified using ImageJ.
Time frame: The first measure is taken immediately after the run-in and the final measure will be taken immediately after the completion of the low-isoleucine diet and isoleucine vs placebo supplement intervention four weeks later.
Change in ratio of phosphorylation Akt in skeletal muscle
Phosphorylation of Akt (Thr308 and Ser473) will be quantified in skeletal muscle tissue obtained at baseline and after the intervention. Levels of phosphorylated Akt and total Akt will be measured, and the outcome will be expressed as the change in the phospho-to-total Akt protein ratio from baseline to post-intervention.
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Time frame: The first measure is taken immediately after the run-in and the final measure will be taken immediately after the completion of the low-isoleucine diet and isoleucine vs placebo supplement intervention four weeks later.