Evaluating the effectiveness of a novel somatostatin receptor 2 antagonist, ZT-01, for hypoglycemia prevention in a rodent model of type 2 diabetes
Background: Elevated levels of somatostatin blunt glucagon counterregulation during hypoglycemia in type 1 diabetes (T1D) and this can be improved using somatostatin receptor 2 (SSTR2) antagonists. Hypoglycemia also occurs in late-stage type 2 diabetes (T2D), particularly when insulin therapy is ini...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-02-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1302015/full |
| _version_ | 1797272248191549440 |
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| author | Ninoschka C. D’Souza Julian A. Aiken Emily G. Hoffman Sara C. Atherley Sabrina Champsi Nadia Aleali Dorsa Shakeri Maya El-Zahed Nicky Akbarian Mehran Nejad-Mansouri Parinaz Z. Bavani Richard L. Liggins Owen Chan Michael C. Riddell |
| author_facet | Ninoschka C. D’Souza Julian A. Aiken Emily G. Hoffman Sara C. Atherley Sabrina Champsi Nadia Aleali Dorsa Shakeri Maya El-Zahed Nicky Akbarian Mehran Nejad-Mansouri Parinaz Z. Bavani Richard L. Liggins Owen Chan Michael C. Riddell |
| author_sort | Ninoschka C. D’Souza |
| collection | DOAJ |
| description | Background: Elevated levels of somatostatin blunt glucagon counterregulation during hypoglycemia in type 1 diabetes (T1D) and this can be improved using somatostatin receptor 2 (SSTR2) antagonists. Hypoglycemia also occurs in late-stage type 2 diabetes (T2D), particularly when insulin therapy is initiated, but the utility of SSTR2 antagonists in ameliorating hypoglycemia in this disease state is unknown. We examined the efficacy of a single-dose of SSTR2 antagonists in a rodent model of T2D.Methods: High-fat fed (HFF), low dose streptozotocin (STZ, 35 mg/kg)-induced T2D and HFF only, nondiabetic (controls-no STZ) rats were treated with the SSTR2 antagonists ZT-01/PRL-2903 or vehicle (n = 9–11/group) 60 min before an insulin tolerance test (ITT; 2–12 U/kg insulin aspart) or an oral glucose tolerance test (OGTT; 2 g/kg glucose via oral gavage) on separate days.Results: This rodent model of T2D is characterized by higher baseline glucose and HbA1c levels relative to HFF controls. T2D rats also had lower c-peptide levels at baseline and a blunted glucagon counterregulatory response to hypoglycemia when subjected to the ITT. SSTR2 antagonists increased the glucagon response and reduced incidence of hypoglycemia, which was more pronounced with ZT-01 than PRL-2903. ZT-01 treatment in the T2D rats increased glucagon levels above the control response within 60 min of dosing, and values remained elevated during the ITT (glucagon Cmax: 156 ± 50 vs. 77 ± 46 pg/mL, p < 0.01). Hypoglycemia incidence was attenuated with ZT-01 vs. controls (63% vs. 100%) and average time to hypoglycemia onset was also delayed (103.1 ± 24.6 vs. 66.1 ± 23.6 min, p < 0.05). ZT-01 administration at the OGTT onset increased the glucagon response without exacerbating hyperglycemia (2877 ± 806 vs. 2982 ± 781), potentially due to the corresponding increase in c-peptide levels (6251 ± 5463 vs. 14008 ± 5495, p = 0.013).Conclusion: Treatment with SSTR2 antagonists increases glucagon responses in a rat model of T2D and results in less hypoglycemia exposure. Future studies are required to determine the best dosing periods for chronic SSTR2 antagonism treatment in T2D. |
| first_indexed | 2024-03-07T14:25:38Z |
| format | Article |
| id | doaj.art-d6004c849ef2466b9d45505754e327f6 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-07T14:25:38Z |
| publishDate | 2024-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-d6004c849ef2466b9d45505754e327f62024-03-06T08:38:15ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-02-011510.3389/fphar.2024.13020151302015Evaluating the effectiveness of a novel somatostatin receptor 2 antagonist, ZT-01, for hypoglycemia prevention in a rodent model of type 2 diabetesNinoschka C. D’Souza0Julian A. Aiken1Emily G. Hoffman2Sara C. Atherley3Sabrina Champsi4Nadia Aleali5Dorsa Shakeri6Maya El-Zahed7Nicky Akbarian8Mehran Nejad-Mansouri9Parinaz Z. Bavani10Richard L. Liggins11Owen Chan12Michael C. Riddell13School of Kinesiology and Health Science, York University, Toronto, ON, CanadaSchool of Kinesiology and Health Science, York University, Toronto, ON, CanadaSchool of Kinesiology and Health Science, York University, Toronto, ON, CanadaSchool of Kinesiology and Health Science, York University, Toronto, ON, CanadaSchool of Kinesiology and Health Science, York University, Toronto, ON, CanadaSchool of Kinesiology and Health Science, York University, Toronto, ON, CanadaSchool of Kinesiology and Health Science, York University, Toronto, ON, CanadaSchool of Kinesiology and Health Science, York University, Toronto, ON, CanadaSchool of Kinesiology and Health Science, York University, Toronto, ON, CanadaSchool of Kinesiology and Health Science, York University, Toronto, ON, CanadaSchool of Kinesiology and Health Science, York University, Toronto, ON, CanadaZucara Therapeutics, Vancouver, BC, CanadaDepartment of Internal Medicine, Division of Endocrinology, University of Utah, Salt LakeCity, UT, United StatesSchool of Kinesiology and Health Science, York University, Toronto, ON, CanadaBackground: Elevated levels of somatostatin blunt glucagon counterregulation during hypoglycemia in type 1 diabetes (T1D) and this can be improved using somatostatin receptor 2 (SSTR2) antagonists. Hypoglycemia also occurs in late-stage type 2 diabetes (T2D), particularly when insulin therapy is initiated, but the utility of SSTR2 antagonists in ameliorating hypoglycemia in this disease state is unknown. We examined the efficacy of a single-dose of SSTR2 antagonists in a rodent model of T2D.Methods: High-fat fed (HFF), low dose streptozotocin (STZ, 35 mg/kg)-induced T2D and HFF only, nondiabetic (controls-no STZ) rats were treated with the SSTR2 antagonists ZT-01/PRL-2903 or vehicle (n = 9–11/group) 60 min before an insulin tolerance test (ITT; 2–12 U/kg insulin aspart) or an oral glucose tolerance test (OGTT; 2 g/kg glucose via oral gavage) on separate days.Results: This rodent model of T2D is characterized by higher baseline glucose and HbA1c levels relative to HFF controls. T2D rats also had lower c-peptide levels at baseline and a blunted glucagon counterregulatory response to hypoglycemia when subjected to the ITT. SSTR2 antagonists increased the glucagon response and reduced incidence of hypoglycemia, which was more pronounced with ZT-01 than PRL-2903. ZT-01 treatment in the T2D rats increased glucagon levels above the control response within 60 min of dosing, and values remained elevated during the ITT (glucagon Cmax: 156 ± 50 vs. 77 ± 46 pg/mL, p < 0.01). Hypoglycemia incidence was attenuated with ZT-01 vs. controls (63% vs. 100%) and average time to hypoglycemia onset was also delayed (103.1 ± 24.6 vs. 66.1 ± 23.6 min, p < 0.05). ZT-01 administration at the OGTT onset increased the glucagon response without exacerbating hyperglycemia (2877 ± 806 vs. 2982 ± 781), potentially due to the corresponding increase in c-peptide levels (6251 ± 5463 vs. 14008 ± 5495, p = 0.013).Conclusion: Treatment with SSTR2 antagonists increases glucagon responses in a rat model of T2D and results in less hypoglycemia exposure. Future studies are required to determine the best dosing periods for chronic SSTR2 antagonism treatment in T2D.https://www.frontiersin.org/articles/10.3389/fphar.2024.1302015/fulltype 2 diabetesglucagonhypoglycemiacounterregulationsomatostatin receptor antagonist |
| spellingShingle | Ninoschka C. D’Souza Julian A. Aiken Emily G. Hoffman Sara C. Atherley Sabrina Champsi Nadia Aleali Dorsa Shakeri Maya El-Zahed Nicky Akbarian Mehran Nejad-Mansouri Parinaz Z. Bavani Richard L. Liggins Owen Chan Michael C. Riddell Evaluating the effectiveness of a novel somatostatin receptor 2 antagonist, ZT-01, for hypoglycemia prevention in a rodent model of type 2 diabetes Frontiers in Pharmacology type 2 diabetes glucagon hypoglycemia counterregulation somatostatin receptor antagonist |
| title | Evaluating the effectiveness of a novel somatostatin receptor 2 antagonist, ZT-01, for hypoglycemia prevention in a rodent model of type 2 diabetes |
| title_full | Evaluating the effectiveness of a novel somatostatin receptor 2 antagonist, ZT-01, for hypoglycemia prevention in a rodent model of type 2 diabetes |
| title_fullStr | Evaluating the effectiveness of a novel somatostatin receptor 2 antagonist, ZT-01, for hypoglycemia prevention in a rodent model of type 2 diabetes |
| title_full_unstemmed | Evaluating the effectiveness of a novel somatostatin receptor 2 antagonist, ZT-01, for hypoglycemia prevention in a rodent model of type 2 diabetes |
| title_short | Evaluating the effectiveness of a novel somatostatin receptor 2 antagonist, ZT-01, for hypoglycemia prevention in a rodent model of type 2 diabetes |
| title_sort | evaluating the effectiveness of a novel somatostatin receptor 2 antagonist zt 01 for hypoglycemia prevention in a rodent model of type 2 diabetes |
| topic | type 2 diabetes glucagon hypoglycemia counterregulation somatostatin receptor antagonist |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1302015/full |
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