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| ID | Type | Description | Link |
|---|---|---|---|
| R01DK104740 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
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| 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| 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 |
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i. Inclusion Criteria
ii. Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Judith Korner, MD | Columbia University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Columbia University Irving Medical Center | New York | New York | 10032 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30876866 | Background | 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. |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| ICF | No | No | Yes | Informed Consent Form | Apr 24, 2019 | Apr 30, 2021 | ICF_000.pdf |
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| ID | Term |
|---|---|
| D014443 | Tyrosine |
| C042696 | tyrosyltyrosine |
| D019587 | Dietary Supplements |
| ID | Term |
|---|---|
| D024322 | Amino Acids, Aromatic |
| D000598 | Amino Acids, Cyclic |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
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| D005502 | Food |
| D000066888 | Diet, Food, and Nutrition |
| D010829 | Physiological Phenomena |
| D019602 | Food and Beverages |