422 Preclinical drug screen leads to clinical trial for treatment of hypoglycemia unawareness in type 1 diabetes mellitus
Objectives/Goals: People with insulin-treated diabetes face hypoglycemia risk due to imperfect insulin replacement and impaired counterregulation. We identified the dopamine antagonist, metoclopramide, as a potential treatment. Hypothesis: Treatment with metoclopramide will prevent the development o...
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| Language: | English |
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Cambridge University Press
2025-04-01
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| Series: | Journal of Clinical and Translational Science |
| Online Access: | https://www.cambridge.org/core/product/identifier/S205986612401029X/type/journal_article |
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| author | Micah Devore Ashley N. Iles Lily A. Schoeder Megan B. Music Bansi V. Patel Ashlee R. Marksbury Mason M. Wooten Andrea M. Woodcox Zachary Beckner Erica L. Macon Simon J. Fisher |
| author_facet | Micah Devore Ashley N. Iles Lily A. Schoeder Megan B. Music Bansi V. Patel Ashlee R. Marksbury Mason M. Wooten Andrea M. Woodcox Zachary Beckner Erica L. Macon Simon J. Fisher |
| author_sort | Micah Devore |
| collection | DOAJ |
| description | Objectives/Goals: People with insulin-treated diabetes face hypoglycemia risk due to imperfect insulin replacement and impaired counterregulation. We identified the dopamine antagonist, metoclopramide, as a potential treatment. Hypothesis: Treatment with metoclopramide will prevent the development of impaired counterregulatory response to hypoglycemia. Methods/Study Population: In a pre-clinical model, diabetes was induced in 10-week-old Sprague-Dawley rats with streptozotocin (STZ, 65 mg/kg IP). Rats were divided into three groups: 1) diabetic controls (STZ+RS, n = 6), 2) recurrent hypoglycemia (STZ+RH, n = 7), and 3) recurrent hypoglycemia + metoclopramide (STZ+RH+MET, 3 mg/kg IP, n = 7). After 3 days, all rats underwent a hyperinsulinemic (50 mU/kg/min) and hypoglycemic (~45 mg/dl) clamp. In the clinical trial, adults with Type 1 diabetes (age 20–60, ≥5 years duration) were enrolled in a phase II, double-blinded, placebo-controlled trial. Awareness status was assessed via Gold score, and subjects maintained drug regimens and underwent two hyperinsulinemic-hypoglycemic clamps (where blood glucose was lowered to 100, 65, 55, and 45 mg/dl) to assess counterregulation. Results/Anticipated Results:
In the pre-clinical model, glucose infusion rates (GIR) to maintain hypoglycemia were higher in STZ+RH (27±0.9 mg/kg/min) than STZ+RS (19±0.8 mg/kg/min, p Discussion/Significance of Impact: Metoclopramide improves glucoregulatory, sympathoadrenal, and counterregulatory responses to hypoglycemia in pre-clinical models, suggesting dopaminergic regulation. While clinical data are still blinded, increased epinephrine and growth hormone responses suggest treatment may preserve or restore counterregulation. |
| format | Article |
| id | doaj-art-fb81778290844dc09fdca788b458c695 |
| institution | Kabale University |
| issn | 2059-8661 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Cambridge University Press |
| record_format | Article |
| series | Journal of Clinical and Translational Science |
| spelling | doaj-art-fb81778290844dc09fdca788b458c6952025-08-20T03:40:18ZengCambridge University PressJournal of Clinical and Translational Science2059-86612025-04-01912612710.1017/cts.2024.1029422 Preclinical drug screen leads to clinical trial for treatment of hypoglycemia unawareness in type 1 diabetes mellitusMicah Devore0Ashley N. Iles1Lily A. Schoeder2Megan B. Music3Bansi V. Patel4Ashlee R. Marksbury5Mason M. Wooten6Andrea M. Woodcox7Zachary Beckner8Erica L. Macon9Simon J. Fisher10University of KentuckyUniversity of KentuckyUniversity of KentuckyUniversity of KentuckyUniversity of KentuckyUniversity of KentuckyUniversity of KentuckyUniversity of KentuckyUniversity of KentuckyUniversity of KentuckyUniversity of KentuckyObjectives/Goals: People with insulin-treated diabetes face hypoglycemia risk due to imperfect insulin replacement and impaired counterregulation. We identified the dopamine antagonist, metoclopramide, as a potential treatment. Hypothesis: Treatment with metoclopramide will prevent the development of impaired counterregulatory response to hypoglycemia. Methods/Study Population: In a pre-clinical model, diabetes was induced in 10-week-old Sprague-Dawley rats with streptozotocin (STZ, 65 mg/kg IP). Rats were divided into three groups: 1) diabetic controls (STZ+RS, n = 6), 2) recurrent hypoglycemia (STZ+RH, n = 7), and 3) recurrent hypoglycemia + metoclopramide (STZ+RH+MET, 3 mg/kg IP, n = 7). After 3 days, all rats underwent a hyperinsulinemic (50 mU/kg/min) and hypoglycemic (~45 mg/dl) clamp. In the clinical trial, adults with Type 1 diabetes (age 20–60, ≥5 years duration) were enrolled in a phase II, double-blinded, placebo-controlled trial. Awareness status was assessed via Gold score, and subjects maintained drug regimens and underwent two hyperinsulinemic-hypoglycemic clamps (where blood glucose was lowered to 100, 65, 55, and 45 mg/dl) to assess counterregulation. Results/Anticipated Results: In the pre-clinical model, glucose infusion rates (GIR) to maintain hypoglycemia were higher in STZ+RH (27±0.9 mg/kg/min) than STZ+RS (19±0.8 mg/kg/min, p Discussion/Significance of Impact: Metoclopramide improves glucoregulatory, sympathoadrenal, and counterregulatory responses to hypoglycemia in pre-clinical models, suggesting dopaminergic regulation. While clinical data are still blinded, increased epinephrine and growth hormone responses suggest treatment may preserve or restore counterregulation.https://www.cambridge.org/core/product/identifier/S205986612401029X/type/journal_article |
| spellingShingle | Micah Devore Ashley N. Iles Lily A. Schoeder Megan B. Music Bansi V. Patel Ashlee R. Marksbury Mason M. Wooten Andrea M. Woodcox Zachary Beckner Erica L. Macon Simon J. Fisher 422 Preclinical drug screen leads to clinical trial for treatment of hypoglycemia unawareness in type 1 diabetes mellitus Journal of Clinical and Translational Science |
| title | 422 Preclinical drug screen leads to clinical trial for treatment of hypoglycemia unawareness in type 1 diabetes mellitus |
| title_full | 422 Preclinical drug screen leads to clinical trial for treatment of hypoglycemia unawareness in type 1 diabetes mellitus |
| title_fullStr | 422 Preclinical drug screen leads to clinical trial for treatment of hypoglycemia unawareness in type 1 diabetes mellitus |
| title_full_unstemmed | 422 Preclinical drug screen leads to clinical trial for treatment of hypoglycemia unawareness in type 1 diabetes mellitus |
| title_short | 422 Preclinical drug screen leads to clinical trial for treatment of hypoglycemia unawareness in type 1 diabetes mellitus |
| title_sort | 422 preclinical drug screen leads to clinical trial for treatment of hypoglycemia unawareness in type 1 diabetes mellitus |
| url | https://www.cambridge.org/core/product/identifier/S205986612401029X/type/journal_article |
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