Modulating Glucose Tolerance With Dietary Tyrosine

NCT03872557 | Completed DMC

• 2 other identifiers: AAAS2124R01DK104740
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

Metabolic or Bariatric surgery is an effective treatment for type 2 diabetes mellitus (T2DM) diabetes associated with obesity. There remain some questions about the biochemical mechanism that drive how these surgeries work to reverse hyperglycemia. In the proposed human studies, the investigators will test the hypothesis that the amino acid tyrosine is a key metabolite in regulating blood sugar levels and that manipulation of the amount tyrosine supplied by nutrition is able to achieve some of the metabolic benefits seen in the early post-surgical period following bariatric surgery. The central hypothesis is that that the tyrosine content of the meal challenge affects post-prandial intestinal and plasma dopamine and levodopa and L-3,4-dihydroxyphenylalanine (L-DOPA) levels, which, in turn, impact β-cell insulin secretion and glucose excursions. The investigators now propose to characterize the possible effects of manipulating dopamine and L-DOPA levels in the gut and plasma on glucose tolerance, insulin secretion, and insulin sensitivity in healthy volunteers with a range of body mass indexes (BMIs).

Conditions

Glucose Tolerance

Keywords

Glucose tolerance; Tyrosine

Outcome Measures

Primary Outcomes (7)

• Whole blood glucose level

  Glucose concentration versus time profile following glucose challenge define glucose tolerance

  Up to 120 minutes from baseline

• Plasma insulin concentration

  Plasma insulin concentration versus time profile following glucose challenge define glucose tolerance

  Up to 120 minutes from baseline

• Plasma dopamine concentration

  Plasma dopamine concentration versus time profile following glucose challenge may affect glucose tolerance

  Up to 120 minutes from baseline

• Plasma L-DOPA concentration

  Plasma L-DOPA concentration versus time profile following glucose challenge may affect glucose tolerance

  Up to 120 minutes from baseline

• L-tyrosine concentration

  Plasma L-tyrosine concentration versus time profile following glucose challenge may affect glucose tolerance

  Up to 120 minutes from baseline

• Plasma glucagon concentration

  Plasma glucagon concentration versus time profile following glucose challenge impacts glucose tolerance

  Up to 120 minutes from baseline

• Plasma GLP-1 concentration

  Plasma GLP-1 concentration versus time profile following glucose challenge impacts glucose tolerance

  Up to 120 minutes from baseline

Study Arms (2)

Tyrosine (TYR) depletion, then oral TYR

ACTIVE COMPARATOR

TYR supplementation: Subjects will be directed to avoid consumption of L-DOPA and TYR enriched foods for 48 hours before oral glucose tolerance test (OGTT). On the evening prior to OGTT, subjects will substitute normal meal and snack for three prepackaged tyrosine-phenylalanine-free liquid meals. Visit 2. Placement of intravenous catheter for the collection of serial blood samples and an OGTT with supplementation with oral tyrosine supplement. To supplement the OGTT with Tyrosine, the contents of four (4) L-Tyrosine 500 mg capsule are given 45 minutes before the oral glucose solution is administered. The capsules are to be administered with less than eight ounces of water to minimize dilution of gastric acidity.

Dietary Supplement: Tyrosine (TYR) Supplementation

TYR depletion, then no oral TYR

NO INTERVENTION

Subjects will be directed to avoid consumption of L-DOPA and TYR enriched foods for 48 hours before OGTT. On the evening prior to OGTT, subjects will substitute normal meal and snack for three prepackaged tyrosine-phenylalanine-free liquid meals. Subsequent Visit 3. This visit will consist of placement of intravenous catheter for the collection of serial blood samples and an OGTT without supplementation with oral tyrosine supplement.

Interventions

Tyrosine (TYR) Supplementation DIETARY_SUPPLEMENT

L-Tyrosine dietary supplement will be provided as 500 mg capsules and 4 (four) 500 mg capsules are to be given before OGTT. The capsules are formed from animal gelatin, and the contents are formulated with magnesium stearate as a flow agent, but without binders, coatings or colorings and also have no added flavorings, sugars, salt, artificial sweeteners, preservatives or salicylates. The capsules are to be administered with less than eight ounces of water to minimize dilution of gastric acidity.

Tyrosine (TYR) depletion, then oral TYR

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Capable of giving written as well as oral informed consent.
• A fasting plasma glucose level (FPG) \< 126 mg/dL (\< 7.0 mmol/L) and an Hb1ac in the 5.7-6.4 % range.
• BMI in the range of 18-45 kg/m2.
• Normal Complete blood count (CBC), renal and liver function tests.

You may not qualify if:

• Any diabetes medication within previous three (3) months.
• Fasting plasma Glucose (FPG) \>126 mg/dl or HbA1c \> 6.4%
• Current use (or within 6 months) of antipsychotic, anti-anxiety, or antidepressant medications (e.g. monoamine oxidase (MAO) inhibitors, 5-Hydroxytryptophan (5HT) inhibitors, tricyclic antidepressants, L-DOPA), reserpine, β-2-receptor agonists (e.g., terbutaline), steroids, weight loss medication, anticoagulant medication, over-the-counter nutritional supplements other than standard vitamin and mineral supplements
• History of Phenylketonuria or other inherited disorders of amino acid metabolism.
• History of movement disorder such as Parkinson's disease or Huntington's disease
• Cardiovascular, renal, pulmonary, gastrointestinal, migraines or other medical conditions deemed significant by investigators
• History of/ or psychiatric illness such as major depression, bipolar disease, anxiety or schizophrenia.
• History of bariatric surgery with the exception of gastric band if the band has been removed
• Female of child-bearing age, currently pregnant, breastfeeding or not using a form of birth control.
• Previous or current use of cocaine, methamphetamine, ecstasy (3-4 methylenedioxymethamphetamine (MDMA))
• Current daily intake of caffeine \>500 mg/day (\>4-5 cups of coffee; \>10 12-oz cans of soda)
• Consumption of more than 1 alcoholic drink per day or smoking more than 5 cigarettes/day.
• Systolic Blood Pressure (SBP) \> 150 mmHg; Diastolic Blood Pressure (DBP) \> 100 mmHg.
• Recent history (in the past three months) of more than a 3% gain or loss in body wt.
• Difficulty in swallowing capsules.

Sponsors & Collaborators

• Columbia University: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Columbia University Irving Medical Center

New York, New York, 10032, United States

Location

Related Publications (1)

• Korner J, Cline GW, Slifstein M, Barba P, Rayat GR, Febres G, Leibel RL, Maffei A, Harris PE. A role for foregut tyrosine metabolism in glucose tolerance. Mol Metab. 2019 May;23:37-50. doi: 10.1016/j.molmet.2019.02.008. Epub 2019 Feb 27.

  PMID: 30876866 BACKGROUND

MeSH Terms

Interventions

Tyrosine; tyrosyltyrosine; Dietary Supplements

Intervention Hierarchy (Ancestors)

Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Food; Diet, Food, and Nutrition; Physiological Phenomena; Food and Beverages

Study Officials

• Judith Korner, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: March 11, 2019
• First Posted: March 13, 2019
• Study Start: August 7, 2019
• Primary Completion: January 24, 2020
• Study Completion: January 24, 2020
• Last Updated: May 5, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)