INGAP-Peptide Variants as a Novel Therapy for Type 1 Diabetes: Effect on Human Islet Insulin Secretion and Gene Expression
Islet transplantation offers a long-term cure for Type 1 Diabetes (T1D), freeing patients from daily insulin injections. Therapeutic peptides have shown potential to increase the insulin output of pancreatic islets, maximizing the impact of grafted cells. The islet neogenesis-associated protein (ING...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-08-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/9/1833 |
| _version_ | 1797483659375149056 |
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| author | James M. Porter Léa Guerassimoff Francisco Rafael Castiello André Charette Maryam Tabrizian |
| author_facet | James M. Porter Léa Guerassimoff Francisco Rafael Castiello André Charette Maryam Tabrizian |
| author_sort | James M. Porter |
| collection | DOAJ |
| description | Islet transplantation offers a long-term cure for Type 1 Diabetes (T1D), freeing patients from daily insulin injections. Therapeutic peptides have shown potential to increase the insulin output of pancreatic islets, maximizing the impact of grafted cells. The islet neogenesis-associated protein (INGAP), and its bioactive core (INGAP-P), stimulate beta-cell function and viability, offering the possibility for islet treatment prior to implant. However, dosing efficacy is limited by low circulation time and enzyme degradation. This proof-of-concept study presents the investigation of novel molecular variants of INGAP-P to find a more bioactive form. Custom-designed peptide variants of INGAP-P were synthesized and tested for their effect on the insulin secretion and gene expression of live human islets. We exposed the live islets of five donors to varying glucose concentrations with INGAP-P variants in solution. We identified four peptide variants (I9, I15Tyr, I19 and I15Cys) which displayed statistically significant enhancements over negative controls (representing a 1.6–2.8-fold increase in stimulation index). This is the first study that has assessed these INGAP-P variants in human islets. It highlights the potential for customized peptides for type 1 diabetes therapy and provides a foundation for future peptide-screening experiments. |
| first_indexed | 2024-03-09T22:50:10Z |
| format | Article |
| id | doaj.art-41e91f8a58a04d9999e888aa4e2e4205 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T22:50:10Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-41e91f8a58a04d9999e888aa4e2e42052023-11-23T18:21:23ZengMDPI AGPharmaceutics1999-49232022-08-01149183310.3390/pharmaceutics14091833INGAP-Peptide Variants as a Novel Therapy for Type 1 Diabetes: Effect on Human Islet Insulin Secretion and Gene ExpressionJames M. Porter0Léa Guerassimoff1Francisco Rafael Castiello2André Charette3Maryam Tabrizian4Department of Biological and Biomedical Engineering, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 0G4, CanadaDepartment of Biological and Biomedical Engineering, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 0G4, CanadaDepartment of Biological and Biomedical Engineering, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 0G4, CanadaCampus MIL, l’Université de Montréal, Montreal, QC H2V 0B3, CanadaDepartment of Biological and Biomedical Engineering, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 0G4, CanadaIslet transplantation offers a long-term cure for Type 1 Diabetes (T1D), freeing patients from daily insulin injections. Therapeutic peptides have shown potential to increase the insulin output of pancreatic islets, maximizing the impact of grafted cells. The islet neogenesis-associated protein (INGAP), and its bioactive core (INGAP-P), stimulate beta-cell function and viability, offering the possibility for islet treatment prior to implant. However, dosing efficacy is limited by low circulation time and enzyme degradation. This proof-of-concept study presents the investigation of novel molecular variants of INGAP-P to find a more bioactive form. Custom-designed peptide variants of INGAP-P were synthesized and tested for their effect on the insulin secretion and gene expression of live human islets. We exposed the live islets of five donors to varying glucose concentrations with INGAP-P variants in solution. We identified four peptide variants (I9, I15Tyr, I19 and I15Cys) which displayed statistically significant enhancements over negative controls (representing a 1.6–2.8-fold increase in stimulation index). This is the first study that has assessed these INGAP-P variants in human islets. It highlights the potential for customized peptides for type 1 diabetes therapy and provides a foundation for future peptide-screening experiments.https://www.mdpi.com/1999-4923/14/9/1833islet transplantationpeptide therapeuticsinsulin secretiongene expression |
| spellingShingle | James M. Porter Léa Guerassimoff Francisco Rafael Castiello André Charette Maryam Tabrizian INGAP-Peptide Variants as a Novel Therapy for Type 1 Diabetes: Effect on Human Islet Insulin Secretion and Gene Expression Pharmaceutics islet transplantation peptide therapeutics insulin secretion gene expression |
| title | INGAP-Peptide Variants as a Novel Therapy for Type 1 Diabetes: Effect on Human Islet Insulin Secretion and Gene Expression |
| title_full | INGAP-Peptide Variants as a Novel Therapy for Type 1 Diabetes: Effect on Human Islet Insulin Secretion and Gene Expression |
| title_fullStr | INGAP-Peptide Variants as a Novel Therapy for Type 1 Diabetes: Effect on Human Islet Insulin Secretion and Gene Expression |
| title_full_unstemmed | INGAP-Peptide Variants as a Novel Therapy for Type 1 Diabetes: Effect on Human Islet Insulin Secretion and Gene Expression |
| title_short | INGAP-Peptide Variants as a Novel Therapy for Type 1 Diabetes: Effect on Human Islet Insulin Secretion and Gene Expression |
| title_sort | ingap peptide variants as a novel therapy for type 1 diabetes effect on human islet insulin secretion and gene expression |
| topic | islet transplantation peptide therapeutics insulin secretion gene expression |
| url | https://www.mdpi.com/1999-4923/14/9/1833 |
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