Pharmacological activation of insulin-degrading enzyme improves insulin secretion and glucose tolerance in diet-induced obese mice.

Autor: Sanz-González A; Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Consejo Superior de Investigaciones Científicas (CSIC) y Universidad de Valladolid (UVa), Valladolid, Spain., Cózar-Castellano I; Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Consejo Superior de Investigaciones Científicas (CSIC) y Universidad de Valladolid (UVa), Valladolid, Spain.; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain., Broca C; Laboratory of Cell Therapy for Diabetes (LTCDPRIMS), IRMB Hop. St Eloi, CHU Montpellier, Montpellier, France., Sabatier J; Laboratory of Cell Therapy for Diabetes (LTCDPRIMS), IRMB Hop. St Eloi, CHU Montpellier, Montpellier, France., Acosta GA; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBERBBN), Barcelona, Spain.; Department of Surfactants and Nanobiotechnology, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain.; Department of Organic Chemistry, University of Barcelona, Barcelona, Spain., Royo M; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBERBBN), Barcelona, Spain.; Department of Surfactants and Nanobiotechnology, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain., Hernándo-Muñoz C; Department of Chemistry, Faculty of Science, University of Burgos, Burgos, Spain., Torroba T; Department of Chemistry, Faculty of Science, University of Burgos, Burgos, Spain., Perdomo G; Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Consejo Superior de Investigaciones Científicas (CSIC) y Universidad de Valladolid (UVa), Valladolid, Spain., Merino B; Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Consejo Superior de Investigaciones Científicas (CSIC) y Universidad de Valladolid (UVa), Valladolid, Spain.
Jazyk: angličtina
Zdroj: Diabetes, obesity & metabolism [Diabetes Obes Metab] 2023 Nov; Vol. 25 (11), pp. 3268-3278. Date of Electronic Publication: 2023 Jul 26.
DOI: 10.1111/dom.15225
Abstrakt: Aim: To investigate the use of synthetic preimplantation factor (sPIF) as a potential therapeutic tool for improving glucose-stimulated insulin secretion (GSIS), glucose tolerance and insulin sensitivity in the setting of diabetes.
Materials and Methods: We used a preclinical murine model of type 2 diabetes (T2D) induced by high-fat diet (HFD) feeding for 12 weeks. Saline or sPIF (1 mg/kg/day) was administered to mice by subcutaneously implanted osmotic mini-pumps for 25 days. Glucose tolerance, circulating insulin and C-peptide levels, and GSIS were assessed. In addition, β-cells (Min-6) were used to test the effects of sPIF on GSIS and insulin-degrading enzyme (IDE) activity in vitro. The effect of sPIF on GSIS was also tested in human islets.
Results: GSIS was enhanced 2-fold by sPIF in human islets ex vivo. Furthermore, continuous administration of sPIF to HFD mice increased circulating levels of insulin and improved glucose tolerance, independently of hepatic insulin clearance. Of note, islets isolated from mice treated with sPIF exhibited restored β-cell function. Finally, genetic (shRNA-IDE) or pharmacological (6bK) inactivation of IDE in Min-6 abolished sPIF-mediated effects on GSIS, showing that both the protein and its protease activity are required for its action.
Conclusions: We conclude that sPIF is a promising secretagogue for the treatment of T2D.
(© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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