Insulin degrading enzyme is up-regulated in pancreatic β cells by insulin treatment
Cristina M. Fernández-Díaz1*, Luis Escobar-Curbelo2*, J.F. López-Acosta1, Carmen D. Lobatón1, Alfredo Moreno1, Julián Sanz-Ortega2, Germán Perdomo3 and Irene Cózar-Castellano1
1Institute of Molecular Biology and Genetics-IBGM (University of Valladolid-CSIC), Valladolid, 2Clinical Hospital San Carlos, Madrid and 3Department of Health Sciences, School of Health Sciences, University of Burgos, Burgos, Spain
*Both authors contributed equally
Offprint requests to: Irene Cózar-Castellano, PhD, Instituto de Biología y Genética Molecular (IBGM), Dpto. Fisiología y Bioquímica, Facultad de Medicina (5ª Planta), Universidad de Valladolid, C/ Ramón y Cajal, 7
47005 Valladolid, Spain. e-mail: irene.cozar@uva.es
Summary. Insulin Degrading Enzyme (IDE) is an endopeptidase that degrades insulin and glucagon. Ide gene has been associated with type-2 diabetes mellitus (DM2). However, the physiological role(s) of IDE in glucose homeostasis and its potential therapeutic benefit remain not completely known.
To contribute in the understanding of IDE's role in glucose metabolism, we analyzed IDE protein level in pancreatic islets from two hyperinsulinemic mouse models, db/db and high-fat diet (HFD) mice, as well as in human islets from DM2 patients treated with oral hypoglycemic agents (OHAs) or insulin. IDE protein level was detected by staining and by western-blot. INS1E cells, rat and human islets were treated with insulin and IDE protein level was studied.
We have shown for the first time IDE staining in rodent and human tissue, using the proper negative control, IDE null mouse tissue. Our staining indicates that IDE is expressed in both beta- and alpha-cells, with higher expression in alpha-cells. Db/db and HFD mice islets showed increased IDE protein level. Interestingly, human islets from DM2 patients treated with OHAs showed decreased IDE protein level in beta-cells. Meanwhile, islets from insulin-treated DM2 patients showed augmented IDE protein level compared to OHAs patients, pointing to an upregulation of IDE protein level stimulated by insulin. These data correlate nicely with insulin-stimulated upregulation of IDE in cultured INS1E cells, as well as in rat and human islets.
In conclusion, our study shows that IDE is expressed in pancreatic beta- and alpha-cells of both rodents and humans, having higher expression in alpha-cells. Furthermore, insulin stimulates IDE protein level in pancreatic beta-cells. These results may have implications in how DM2 patient's treatment affects their beta-cell function. Histol Histopathol 33, 1167-1180 (2018)
Key words: Insulin-degrading enzyme, Type 2 diabetes, Insulin treatment, OHAs, Beta-cells, Alpha-cells, Rodent islets, Human islets
DOI: 10.14670/HH-11-997