incretins and Wolfram-Syndrome

Wolfram Syndrome (WS) is a rare condition caused by mutations in. Eight-month-old. 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.. 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.

Topics: Animals; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Infant; Insulin-Secreting Cells; Rats; Wolfram Syndrome

Wolfram syndrome (WS) is a rare autosomal recessive disorder caused by mutations in the WFS1 (Wolframin1) gene. The syndrome first manifests as diabetes mellitus, followed by optic nerve atrophy, deafness, and neurodegeneration. The underlying mechanism is believed to be a dysregulation of endoplasmic reticulum (ER) stress response, which ultimately leads to cellular death. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists has been shown to normalize ER stress response in several in vitro and in vivo models. Early chronic intervention with the GLP-1 receptor agonist liraglutide starting before the onset of metabolic symptoms prevented the development of glucose intolerance, improved insulin and glucagon secretion control, reduced ER stress and inflammation in Langerhans islets in Wfs1 mutant rats. Thus, treatment with GLP-1 receptor agonists might be a promising strategy as a preventive treatment for human WS patients.

Topics: Animals; Blood Glucose; Calmodulin-Binding Proteins; Disease Models, Animal; Endoplasmic Reticulum Stress; Gene Knockout Techniques; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Glucose Tolerance Test; Humans; Incretins; Injections, Subcutaneous; Insulin; Islets of Langerhans; Liraglutide; Male; Membrane Proteins; Rats; Rats, Transgenic; Treatment Outcome; Wolfram Syndrome