James L Trevaskis 1 , Chester Bittencourt Sacramento 2 , Hani Jouihan 2 , Safina Ali 2 , John Le Lay 2 , Stephanie Oldham 2 , Nicholas Bhagroo 2 , Brandon B Boland 2 , Jennifer Cann 3 , Yuan Chang 4 , Terrence O'Day 5 , Victor Howard 2 , Christina Reers 6 , Maria Sorhede Winzell 7 , David M Smith 8 , Michael Feigh 9 , Pernille Barkholt 9 , Kay Schreiter 6 , Matthias Austen 6 , Uwe Andag 6 , Simon Thompson 10 , Lutz Jermutus 11 , Matthew P Coghlan 11 , Joseph Grimsby 2 , Cord Dohrmann 6 , Christopher J Rhodes 2 , Cristina M Rondinone 2 , Arun Sharma 2
Neurturin (NRTN), a member of the glial-derived neurotrophic factor family, was identified from an embryonic chicken pancreatic cDNA library in a screen for secreted factors. In this study, we assessed the potential antidiabetic activities of NRTN relative to liraglutide, a glucagon-like peptide 1 receptor agonist, in Zucker diabetic fatty (ZDF) rats. Subcutaneous administration of NRTN to 8-week-old male ZDF rats prevented the development of hyperglycemia and improved metabolic parameters similar to liraglutide. NRTN treatment increased pancreatic insulin content and β-cell mass and prevented deterioration of islet organization. However, unlike liraglutide-treated rats, NRTN-mediated improvements were not associated with reduced body weight or food intake. Acute NRTN treatment did not activate c-Fos expression in key feeding behavior and metabolic centers in ZDF rat brain or directly enhance glucose-stimulated insulin secretion from pancreatic β-cells. Treating 10-week-old ZDF rats with sustained hyperglycemia with liraglutide resulted in some alleviation of hyperglycemia, whereas NRTN was not as effective despite improving plasma lipids and fasting glucose levels. Interestingly, coadministration of NRTN and liraglutide normalized hyperglycemia and other metabolic parameters, demonstrating that combining therapies with distinct mechanism(s) can alleviate advanced diabetes. This emphasizes that therapeutic combinations can be more effective to manage diabetes in individuals with uncontrolled hyperglycemia.