Glucose Tolerance
Conditions
Keywords
Glucose tolerance, Tyrosine
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).
Detailed description
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.
Interventions
DIETARY_SUPPLEMENTTyrosine (TYR) Supplementation
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.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Columbia University
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
i. Inclusion Criteria 1. Capable of giving written as well as oral informed consent. 2. A fasting plasma glucose level (FPG) \< 126 mg/dL (\< 7.0 mmol/L) and an Hb1ac in the 5.7-6.4 % range. 3. BMI in the range of 18-45 kg/m2. 4. Normal Complete blood count (CBC), renal and liver function tests. ii.
Exclusion criteria
1. Any diabetes medication within previous three (3) months. 2. Fasting plasma Glucose (FPG) \>126 mg/dl or HbA1c \> 6.4% 3. 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 4. History of Phenylketonuria or other inherited disorders of amino acid metabolism. 5. History of movement disorder such as Parkinson's disease or Huntington's disease 6. Cardiovascular, renal, pulmonary, gastrointestinal, migraines or other medical conditions deemed significant by investigators 7. History of/ or psychiatric illness such as major depression, bipolar disease, anxiety or schizophrenia. 8. History of bariatric surgery with the exception of gastric band if the band has been removed 9. Female of child-bearing age, currently pregnant, breastfeeding or not using a form of birth control. 10. Previous or current use of cocaine, methamphetamine, ecstasy (3-4 methylenedioxymethamphetamine (MDMA)) 11. Current daily intake of caffeine \>500 mg/day (\>4-5 cups of coffee; \>10 12-oz cans of soda) 12. Consumption of more than 1 alcoholic drink per day or smoking more than 5 cigarettes/day. 13. Systolic Blood Pressure (SBP) \> 150 mmHg; Diastolic Blood Pressure (DBP) \> 100 mmHg. 14. Recent history (in the past three months) of more than a 3% gain or loss in body wt. 15. Difficulty in swallowing capsules. 16. Concurrent use of antacids or proton pump inhibitors (e.g.,Prilosec Prevacid, dexilant, Aciphex, Protonix, Nexium, Vimovo, Zegerid)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Whole blood glucose level | Up to 120 minutes from baseline | Glucose concentration versus time profile following glucose challenge define glucose tolerance |
| Plasma insulin concentration | Up to 120 minutes from baseline | Plasma insulin concentration versus time profile following glucose challenge define glucose tolerance |
| Plasma dopamine concentration | Up to 120 minutes from baseline | Plasma dopamine concentration versus time profile following glucose challenge may affect glucose tolerance |
| Plasma L-DOPA concentration | Up to 120 minutes from baseline | Plasma L-DOPA concentration versus time profile following glucose challenge may affect glucose tolerance |
| L-tyrosine concentration | Up to 120 minutes from baseline | Plasma L-tyrosine concentration versus time profile following glucose challenge may affect glucose tolerance |
| Plasma glucagon concentration | Up to 120 minutes from baseline | Plasma glucagon concentration versus time profile following glucose challenge impacts glucose tolerance |
| Plasma GLP-1 concentration | Up to 120 minutes from baseline | Plasma GLP-1 concentration versus time profile following glucose challenge impacts glucose tolerance |
Countries
United States
Outcome results
None listed