The Effects of Leucine and Isoleucine on Glucose Metabolism (AA+GLU)

Diabetes is classified as an impairment of the body's ability to control blood glucose levels. Uncontrolled hyperglycemia can give rise to macrovascular (i.e., heart disease and stroke) and microvasculature damage such as retinopathy, nephropathy and neuropathy. These comorbidities may definitively reduce quality of life.

Hypotheses to be tested:

1. The ingestion of amino acids L-Isoleucine and L-Leucine at a therapeutic dose prior to a glucose load will concurrently and independently improve glucose tolerance.
2. The ingestion of L-Isoleucine and L-Leucine separately or together will have a minimal effect on incretin responses of Glucagon-like peptide-1 and Glucose-dependent insulinotropic peptide (GLP-1, GIP).

Study Overview

• Status: Completed
• Conditions: Hyperglycemia
• Intervention / Treatment: Dietary supplement: Leucine Supplement; Dietary supplement: Isoleucine Supplement; Dietary supplement: Leucine Supplement combined with Isoleucine Supplement

Detailed Description

Specific Aims and Hypothesis Diabetes is classified as an impairment of the body's ability to control blood glucose levels. Uncontrolled hyperglycemia can give rise to macrovascular (i.e., heart disease and stroke) and microvasculature damage such as retinopathy, nephropathy and neuropathy. These comorbidities may definitively reduce quality of life.

Hypotheses to be tested:

1. The ingestion of amino acids L-Isoleucine and L-Leucine at a therapeutic dose prior to a glucose load will concurrently and independently improve glucose tolerance.
2. The ingestion of L-Isoleucine and L-Leucine separately or together will have a minimal effect on incretin responses (GLP-1, GIP).

Specific Aims:

1. Specific Aim I will test the hypothesis that the ingestion of amino acids L-Isoleucine and L-Leucine at a therapeutic dose prior to a glucose load will concurrently and independently improve glucose tolerance.
2. Specific Aim II will test the hypothesis that the ingestion of L-Isoleucine and L-Leucine will have a minimal effect on incretin responses in conjunction with prior research.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. age range of 20 to 40 years of age
2. (sedentary lifestyle) Participants whom exercise less than the American College of Sports Medicine recommendation of weekly physical activity levels or are completely sedentary may be admitted into the study
3. Apparently healthy
4. Currently not using supplemental branch chain amino acids (BCAA) or whey protein
5. Non-smoking

Exclusion Criteria:

1. Chronic or acute health problems
2. Smoker
3. Currently using supplemental BCAA or whey protein -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: control; Control Treatment with Oral Glucose Tolerance Test: Blood glucose and insulin will be obtained following the protocol of Eicher et al (4). Participants will ingest a Placebo (inert, calorie free, stevia sweetener) with blood collections at 0,2,4,6,8,10,30 prior to a standard 75 g glucose solution, followed by blood collections at 0,2,4,6,8,10,30,60,90,120 minutes post glucose ingestion. A total of 16 blood collections will be taken.
Experimental: Leucine Supplement; Control Treatment with Oral Glucose Tolerance Test:	Dietary supplement: Leucine Supplement; For this visit participants will ingest a powdered form of Leucine in the amount of 0.3g/kg of lean body mass weight with water (150 mL) with additional water if needed to ensure dose is fully consumed. The amino acid solution will be ingested 30 min prior to 75 g glucose solution
Experimental: Isoleucine Supplement; Isoleucine Combined with Oral Glucose Tolerance Test:	Dietary supplement: Isoleucine Supplement; For this visit participants will ingest a powdered form of Isoleucine in the amount of 0.3g/kg of lean body mass weight with water (150 mL) with additional water if needed to ensure dose is fully consumed. The amino acid solution will be ingested 30 min prior to 75 g glucose solution.
Experimental: Leucine and Isoleucine Supplement; Leucine and Isoleucine Combined with Oral Glucose Tolerance Test:	Dietary supplement: Leucine Supplement combined with Isoleucine Supplement; For this visit participants will ingest a powdered form of Leucine and Isoleucine in the amount of 0.3g/kg of lean body mass weight (equal in total dosage to other treatments) with water (150 mL) with additional water if needed to ensure dose is fully consumed. The amino acid solution will be ingested 30 min prior to 75 g glucose solution.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in plasma glucose (0-150 minutes)	Blood collections	baseline (0), 2, 4, 6, 8, 10, 30, 32, 34, 36, 38, 40, 60, 90, 120, 150 minutes
Change in plasma insulin (0-150 minutes)	Blood collections	baseline (0), 2, 4, 6, 8, 10, 30, 32, 34, 36, 38, 40, 60, 90, 120, 150 minutes
Change in plasma GIP (0-150 minutes)	Blood Collections	baseline (0), 2, 4, 6, 8, 10, 30, 32, 34, 36, 38, 40, 60, 90, 120, 150 minutes
Change in plasma GLP-1 (0-150 minutes)	Blood collections	baseline (0), 2, 4, 6, 8, 10, 30, 32, 34, 36, 38, 40, 60, 90, 120, 150 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in plasma glucagon (0-150 minutes)	Blood collections	baseline (0), 2, 4, 6, 8, 10, 30, 32, 34, 36, 38, 40, 60, 90, 120, 150 minutes
Change in plasma c-peptide (0-150 minutes)	Blood Collections	baseline (0), 2, 4, 6, 8, 10, 30, 32, 34, 36, 38, 40, 60, 90, 120, 150 minutes
Change in plasma L-Leucine (0-150 minutes)	Blood Collections	baseline (0), 2, 4, 6, 8, 10, 30, 32, 34, 36, 38, 40, 60, 90, 120, 150 minutes
Change in plasma L-Isoleucine (0-150 minutes)	Blood Collections	baseline (0), 2, 4, 6, 8, 10, 30, 32, 34, 36, 38, 40, 60, 90, 120, 150 minutes

Collaborators and Investigators

• Sponsor: Texas Woman's University
• Investigators: Study Chair: Vic Ben-Ezra, PhD, Texas Woman's University Kinesiology Department

Publications and helpful links

General Publications

• Nuttall FQ, Schweim KJ, Gannon MC. Effect of orally administered phenylalanine with and without glucose on insulin, glucagon and glucose concentrations. Horm Metab Res. 2006 Aug;38(8):518-23. doi: 10.1055/s-2006-949523.
• Kalogeropoulou D, Lafave L, Schweim K, Gannon MC, Nuttall FQ. Leucine, when ingested with glucose, synergistically stimulates insulin secretion and lowers blood glucose. Metabolism. 2008 Dec;57(12):1747-52. doi: 10.1016/j.metabol.2008.09.001.
• Gannon MC, Nuttall FQ. Amino acid ingestion and glucose metabolism--a review. IUBMB Life. 2010 Sep;62(9):660-8. doi: 10.1002/iub.375.
• Yoshizawa F. New therapeutic strategy for amino acid medicine: notable functions of branched chain amino acids as biological regulators. J Pharmacol Sci. 2012;118(2):149-55. doi: 10.1254/jphs.11r05fm. Epub 2012 Jan 27.
• Nilsson M, Holst JJ, Bjorck IM. Metabolic effects of amino acid mixtures and whey protein in healthy subjects: studies using glucose-equivalent drinks. Am J Clin Nutr. 2007 Apr;85(4):996-1004. doi: 10.1093/ajcn/85.4.996.
• Petersen BL, Ward LS, Bastian ED, Jenkins AL, Campbell J, Vuksan V. A whey protein supplement decreases post-prandial glycemia. Nutr J. 2009 Oct 16;8:47. doi: 10.1186/1475-2891-8-47.
• Doi M, Yamaoka I, Fukunaga T, Nakayama M. Isoleucine, a potent plasma glucose-lowering amino acid, stimulates glucose uptake in C2C12 myotubes. Biochem Biophys Res Commun. 2003 Dec 26;312(4):1111-7. doi: 10.1016/j.bbrc.2003.11.039.
• Nishitani S, Takehana K, Fujitani S, Sonaka I. Branched-chain amino acids improve glucose metabolism in rats with liver cirrhosis. Am J Physiol Gastrointest Liver Physiol. 2005 Jun;288(6):G1292-300. doi: 10.1152/ajpgi.00510.2003. Epub 2004 Dec 9.

Study record dates

Study Major Dates

• Study Start: December 1, 2015
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): September 1, 2016

Study Registration Dates

• First Submitted: December 9, 2015
• First Submitted That Met QC Criteria: December 15, 2015
• First Posted (Estimate): December 17, 2015

Study Record Updates

• Last Update Posted (Actual): April 27, 2017
• Last Update Submitted That Met QC Criteria: April 25, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: leucine; isoleucine
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperglycemia
• Other Study ID Numbers: 17757 (REB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No