Isoleucine Intake and Intermediary Metabolism in Type 2 Diabetes

NCT ID: NCT04461236

Last Updated: 2025-02-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 38 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-05-30
• Study Completion Date: 2020-03-02

Brief Summary

The primary objective of this study is to determine the mechanism of reduced branched-chain amino acid (BCAA) oxidation to propionyl CoA and isoleucine intake can affect TCA cycle function in obese insulin resistant T2D. We will test the hypotheses that isoleucine and valine oxidation to propionyl CoA is reduced and that week long oral administration of isoleucine in T2D subjects will increase propionyl CoA and succinyl CoA production in muscle.

The secondary objectives of this study are to determine the extent to which type 2 diabetics are capable of controlling and coordinating complex patterns of force using the upper and lower limb. This line of research has functional significance as upper body coordination and fine motor control is important for many activities associated with daily living and may contribute to therapy protocols for individuals with type 2 diabetes. Functional performance via six-minute walk and balance board measurement will also be tested with and without sensory augmentation via electrical stimulation of foot. Changes in peripheral blood mononuclear cells (PBMCs) mitochondrial respiration values will also be assessed between subject types and for diabetic after the 10-day supplementation period.

Detailed Description

Defects in mitochondrial β-oxidation and branched chain amino acid (BCAA) oxidation are associated with type 2 diabetes (T2D) and other conditions such as Huntington's disease and maple syrup urine disease. Because of these defective mitochondrial pathways, production of TCA cycle intermediates can be limited and obesity worsen the condition of the disease. Interestingly, supplying precursors for the TCA cycle such as propionyl CoA can promote anaplerosis through a pathway that is independent of the defective pathway. Therefore, we hypothesize that providing oral isoleucine, a branched-chain amino acid, which is commonly used for other conditions, will promote anaplerosis by supplying the precursor, propionyl CoA for the TCA cycle intermediate succinyl CoA to muscle of T2D patients. This innovative approach is intended to improve TCA function and insulin resistance in obese T2D and could serve as a model for other nutritional interventions.

Diabetes is a growing problem worldwide and has lead to 1.5 million deaths in 2012 and it's prevalence has increased to 9% in 2014, most like related to the steep increase in obesity rates. Research has shown that a combination of increased acetyl-carnitine and reduced propionyl- and isovaleryl-carnitine and elevated blood BCAA in T2D suggests reduced BCAA oxidation to propionyl-CoA, which can cause TCA cycle a malfunction. During homeostasis, transamination of valine and isoleucine leads to α-keto-isovalerate (KIV) and α-keto-methylvalerate (KMV) production, which can be further converted to propionyl CoA and the TCA cycle intermediate succinyl-CoA. Therefore, increased valine and isoleucine transamination can promote anaplerosis and stimulate mitochondrial energetic flux. Because of this, we believe that there is a critical need to identify therapies that can be used to restore TCA function in obese T2D.

Furthermore, Type 2 diabetes causes and contributes to a variety of central nervous system (CNS) complications. CNS complications with type 2 diabetes include cognitive and motor dysfunction. There have been a number of studies investigating the association between diabetes and cognitive decline indicating deficits in psychomotor speed, executive function, memory, and attention. Research has also indicated motor deficits with complex motor skills, motor coordination, balance, and muscle strength in type 2 diabetics. However, the majority of research investigating motor dysfunction in type 2 diabetes has focused on lower body dysfunction (balance/gait) and muscular strength (grip) using gross motor control. It is not clear from the literature how type 2 diabetes influences upper body coordination and fine motor control. Chronic inflammatory states, such as obesity, congestive heart failure, diabetes, Alzheimer's disease are also linked to changes in peripheral blood mononuclear cells (PBMCs) mitochondrial respiration values]. PBMC isolation is a non-invasive way to measure mitochondrial function through high-resolution respirometry.

Conditions

Type 2 Diabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: OTHER
• Blinding Strategy: DOUBLE

Study Groups

Isoleucine

Type 2 Diabetics randomized to isoleucine group

Group Type: EXPERIMENTAL

Oral Supplement

Intervention Type: DIETARY_SUPPLEMENT

Supplement provided in capsules. Half the capsules to be taken with lunch and the other half with dinner. All supplements are commercially available.

Placebo

Type 2 Diabetics randomized to placebo group

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DIETARY_SUPPLEMENT

Placebo

Healthy

gender-, age-, BMI-matched controls for baseline measurements only. No supplementation provided.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Oral Supplement

Supplement provided in capsules. Half the capsules to be taken with lunch and the other half with dinner. All supplements are commercially available.

Intervention Type: DIETARY_SUPPLEMENT

Placebo

Placebo

Intervention Type: DIETARY_SUPPLEMENT

Eligibility Criteria

Inclusion Criteria

• Age: 45-84 years old, inclusive
• Clinical diagnosis with type-II diabetes (Diabetics subjects only) and oral glucose lowering medication or insulin
• Stable body-weight (± 5%) for the past 3 months
• Body Mass Index (BMI): 28 kg/m2 or higher
• Subject is judged to be in satisfactory health based on medical history, physical examination, and laboratory screening evaluations.
• Ability to walk, sit down and stand up independently
• Ability to lie in supine or elevated position for up to 10 hours
• Willingness and ability to comply with the protocol

Exclusion Criteria

• Subject is expected to have surgery within one-month of screening
• Subject is currently participating or has participated in a study with an investigational compound or device within 30 days of signing the informed consent.
• Active dependence of alcohol or drugs
• Diagnosed and active treatment of Type 1 Diabetes Mellitus
• Medication: Use of substances known to influence protein metabolism: antibiotics within 3 weeks prior to the study visit, current use of corticosteroids, growth hormone, testosterone, estrogen, immunosuppressant, blood thinners, or insulin.
• Adherence to a weight loss diet.
• (Possible) pregnancy

• Minimum Eligible Age: 45 Years
• Maximum Eligible Age: 84 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Texas A&M University

OTHER

Sponsor Role: lead

Responsible Party

Marielle PKJ Engelen, PhD

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Texas A&M University CTRAL

College Station, Texas, United States

Countries

United States

References

Deutz LN, Wierzchowska-McNew RA, Deutz NE, Engelen MP. Reduced plasma glycine concentration in healthy and chronically diseased older adults: a marker of visceral adiposity? Am J Clin Nutr. 2024 Jun;119(6):1455-1464. doi: 10.1016/j.ajcnut.2024.04.008. Epub 2024 Apr 12.

Reference Type: DERIVED

PMID: 38616018 (View on PubMed)

Wierzchowska-McNew RA, Engelen MPKJ, Thaden JJ, Ten Have GAM, Deutz NEP. Obesity- and sex-related metabolism of arginine and nitric oxide in adults. Am J Clin Nutr. 2022 Dec 19;116(6):1610-1620. doi: 10.1093/ajcn/nqac277.

Reference Type: DERIVED

PMID: 36166849 (View on PubMed)

Other Identifiers

2018-1486

Identifier Type: -

Identifier Source: org_study_id