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. 2023 Nov;25(11):3268-3278.
doi: 10.1111/dom.15225. Epub 2023 Jul 26.

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

Alba Sanz-González  1 , Irene Cózar-Castellano  1   2 , Christophe Broca  3 , Julia Sabatier  3 , Gerardo A Acosta  4   5   6 , Miriam Royo  4   5 , Carla Hernándo-Muñoz  7 , Tomás Torroba  7 , Germán Perdomo  1 , Beatriz Merino  1
Affiliations

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

Alba Sanz-González et al. Diabetes Obes Metab. 2023 Nov.

Abstract

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.

Keywords: antidiabetic drug; beta cell function; drug mechanism; insulin secretagogue; insulin secretion.

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References

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