Dataset Information

Treatment with the dual-incretin agonist DA-CH5 demonstrates potent therapeutic effect in a rat model of Wolfram Syndrome.

ABSTRACT:

Aim

Wolfram Syndrome (WS) is a rare condition caused by mutations in Wfs1, with a poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1 (GLP-1) have demonstrated disease-modifying potential in pre-clinical and clinical settings. Dual agonists that target GLP-1 and glucose-dependent insulinotropic polypeptide (GIP-1) are reportedly more efficacious; hence, we evaluated the therapeutic potential of dual incretin agonism in a loss-of-function rat model of WS.

Methods

Eight-month-old Wfs1 knock-out (KO) and wild-type control rats were continuously treated with either the dual agonist DA-CH5 or saline for four months. Glycemic profile, visual acuity and hearing sensitivity were longitudinally monitored pre-treatment, and then at 10.5 and 12 months. Pancreata and retina were harvested for immunohistological analysis.

Results

DA-CH5 therapy reversed glucose intolerance in KO rats and provided lasting anti-diabetogenic protection. Treatment also reversed intra-islet alterations, including reduced endocrine islet area and β-cell density, indicating its regenerative potential. Although no rescue effect was noted for hearing loss, visual acuity and retinal ganglion cell density were better preserved in DA-CH5-treated rats.

Conclusion

We present preclinical evidence for the pleiotropic therapeutic effects of long-term dual incretin agonist treatment; effects were seen despite treatment beginning after symptom-onset, indicating reversal of disease progression. Dual incretins represent a promising therapeutic avenue for WS patients.

SUBMITTER: Jagomae T

PROVIDER: S-EPMC10611518 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Treatment with the dual-incretin agonist DA-CH5 demonstrates potent therapeutic effect in a rat model of Wolfram Syndrome.

Jagomäe Toomas T Gaur Nayana N Seppa Kadri K Reimets Riin R Pastak Marko M Plaas Mihkel M Kaasik Allen A Vasar Eero E Plaas Mario M

Frontiers in endocrinology 20231013

<h4>Aim</h4>Wolfram Syndrome (WS) is a rare condition caused by mutations in <i>Wfs1</i>, with a poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1 (GLP-1) have demonstrated disease-modifying potential in pre-clinical and clinical settings. Dual agonists that target GLP-1 and glucose-dependent insulinotropic polypeptide (GIP-1) are reportedly more efficacious; hence, we evaluated the therapeutic potential of dual incretin agonism in a loss-of-function rat mo ...[more]

PMID: 37900147

Similar Datasets

Project description:Background and aimWolfram syndrome (WS) is a rare autosomal disorder caused by WFS1 gene mutations, currently lacking approved treatments. Preclinical and clinical reports suggest that diabetes medications, such as glucagon-like peptide-1 receptor agonist (GLP1-RA), slow WS-related diabetes and neurodegeneration, improving patient outcomes. Gamma-aminobutyric acid (GABA) has crucial role in pancreatic islet function and blood glucose regulation. However, its specific role in WS diabetic pathophysiology has never been explored. The aim of this study was to enhance the therapeutic efficacy of liraglutide in mitigating the progression of diabetes associated with WS through supplementation with GABA.MethodsIn this study, 5-month-old glucose intolerant WS rats and their wild-type littermates where daily treated with GABA (1 g/kg/day), liraglutide (0.4 mg/kg/day), or a combination of both. During the four-month experimental period, the diabetic phenotype was closely monitored using intraperitoneal glucose tolerance tests (IPGTT) and corresponding hormone measurements via enzyme-linked immunoassay. Following the treatments, immunohistochemical staining was performed to examine the morphology, cellular distribution, and health of Langerhans islets.ResultsUnlike in conventional diabetes models, GABA monotherapy alone had no significant effect on the diabetic phenotype in WS rats. In contrast, liraglutide monotherapy effectively delayed diabetes progression. Remarkably, the combined therapy of GABA and liraglutide reversed the diabetic phenotype, significantly enhancing glucose homeostasis, as well as insulin and C-peptide secretion. The combined treatment also increased β-cell mass and corrected the pancreatic Langerhans intra-islet ratio of α-, β-, and δ-cells. As a result, the overall morphology and cytoarchitecture of the pancreatic islets were fully restored, suggesting a potential role for these agents in preserving islet integrity. Additionally, both liraglutide and combination therapy increased the number of GAD (glutamic acid decarboxylase) 65/67-positive β-cells in WS rats, indicating an improvement in general β-cell health.ConclusionGABA monotherapy had no significant effect on the diabetic phenotype in WS rats, while liraglutide monotherapy effectively delayed diabetes progression. However, the combination therapy of GABA and liraglutide demonstrated a markedly superior effect, not only reversing the diabetic phenotype but also significantly enhancing glucose homeostasis, insulin and C-peptide secretion, and β-cell mass. This combined treatment led to a restoration of Langerhans islet architecture, correction of the endocrine cell proportions, and a notable increase in GAD65/67-positive β-cells, indicating improved β-cell health and function. These findings provide strong evidence supporting the evaluation of GABA and GLP-1 RAs as a combination therapy in clinical trials. Their synergistic effects may offer enhanced β-cell protection, promote functional recovery, and uncover novel therapeutic pathways for treating patients with WS.

Dataset Information

Treatment with the dual-incretin agonist DA-CH5 demonstrates potent therapeutic effect in a rat model of Wolfram Syndrome.

Aim

Methods

Results

Conclusion

Publications

Treatment with the dual-incretin agonist DA-CH5 demonstrates potent therapeutic effect in a rat model of Wolfram Syndrome.

Similar Datasets

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