On 30 November at 11 Maarja Toots will defend her doctoral thesis „Pharmacological challenge in rodent models of Wolfram syndrome with emphasis on diabetic phenotype“.
professor Eero Vasar (MD, PhD), Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu
Mario Plaas (PhD), Laboratory animal center, Institute of Biomedicine and Translational Medicine, University of Tartu
Margit Mahlapuu (PhD, Associate Professor, University of Gothenburg, Gothenburg, Sweden)
Wolfram syndrome (WS) is an autosomal recessive disorder, caused by mutations in Wolframin1 (WFS1) gene. Main initial symptom is non-autoimmune diabetesmellitus, followed by optic nerve atrophy, deafness, psychiatric disorders, and neural degeneration. Patients usually die in their 30- and 40-s due to central apnea causedby brain stem atrophy. WS prevalence is estimated up to 0.001%, the carrier frequency is approximately 0.3-1%. Carriers of heterozygous WFS1 mutation have beenshown to have increased risk for development of type 2 diabetes.
Currently there is no cure to delay the progression of WS. Therefore, in current thesis, we aimed to identify new drug candidates for the treatment of WS. For thispurpose, transgenic Wfs1 deficient mice and rats were used.
Our first findings showed that stimulating muscarinic 3 and glucagon-like peptide-1 (GLP-1) receptors on Langerhans islets beta cells was able to stimulate insulinsecretion in Wfs1 deficiency and to normalize blood glucose levels in glucose tolerance test. Next we aimed to study whether repeated treatment with GLP-1 receptoragonist liraglutide was able to delay disease progression in the rat model of WS. Unlike Wfs1 deficient mice these transgenic rats developed insulin dependent diabetes.
Rats, missing 5th exon in Wfs1 gene, had normal glucose tolerance and insulin secretion at 2 months of age. After that they started to lose their pancreatic Langerhansislets beta cells and develop progressive glucose intolerance, resulting in insulin dependent diabetes at 13 months of age. Starting the chronic treatment of Wfs1 deficient rats at 2 months of age, before onset of disease symptoms, we established no changes in glucose tolerance of rats receiving medication for 4.5 months. Weshowed that liraglutide improved insulin and glucagon secretion and decreased endoplasmatic reticulum stress and inflammatory markers gene expression inLangerhans islets. Due to these improvements liraglutide receiving rats did not lose Langerhans islet mass, as did untreated animals.
In current study we established for the first time the potential therapeutic effect of preventive treatment with GLP-1 analogue against the progression of WS