Modulating Glucose Tolerance With Dietary Tyrosine

Study Overview
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Brief Summary
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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).

Detailed Description
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Several biochemical mechanisms explaining how Roux-en-Y Gastric Bypass (RYGB) provides an effective treatment for obesity associated type 2 diabetes mellitus (T2DM) and improves hyperglycemia independently of weight loss have been proposed. Two are of particular interest; a) the hindgut hypothesis suggesting that nutrient delivery to the distal intestine drives the production of incretins which enhance insulin secretion (e.g. glucagon-like peptide-1 (GLP-1)), and b) the foregut hypothesis, positing that foregut bypass reduces the secretion of factors (i.e. anti-incretins) that normally defend against hypoglycemia. The investigators have been actively investigating this topic and have developed a hypothesis based on past studies that they wish to test in a limited human clinical study. In addition, preclinical data suggest that there exists a gut-to-beta cell pathway, responsive to nutritional tyrosine, regulating insulin secretion, and this pathway provides a mechanism for the early postoperative improvements in hyperglycemia observed in RYGB.

Official Title
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Modulating Glucose Tolerance With Dietary Tyrosine

Conditions
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Glucose Tolerance

Intervention / Treatment
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* Dietary Supplement: Tyrosine (TYR) Supplementation


Participation Criteria
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Eligibility Criteria
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i. Inclusion Criteria 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. ii. Exclusion Criteria: 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. Concurrent use of antacids or proton pump inhibitors (e.g.,Prilosec Prevacid, dexilant, Aciphex, Protonix, Nexium, Vimovo, Zegerid)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tyrosine (TYR) depletion, then oral TYR<br>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<br>* 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.<br>|
| No Intervention: TYR depletion, then no oral TYR<br>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. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glucose tolerance, Tyrosine