A UB study identifies a potential therapeutic target against insulin resistance and type 2 diabetes

UB researchers have identified a key molecule in insulin resistance, a condition that favours the development of type 2 diabetes. The study, published in the science journal Metabolism. Clinical and Experimental, shows how the enzyme BACE1 and its product, soluble APPβ, are involved in the breaking out of the inflammatory process and insulin resistance. These results were obtained in mice and open the doors to the development of new drugs to treat this type of diabetes.

The study is led by the team led by the lecturer Manuel Vázquez Carrera, member of the Unit of Pharmacology, Therapeutics and Pharmacognosy of the Faculty of Pharmacy and Food Sciencesand the Institute of Biomedicine (IBUB) of the UB, as well as member of the Diabetes and Associated Metabolic Diseases Networking Biomedical Research Centre ( CIBERDEM). The following experts have also taken part in the study: Dolors Serra and Laura Herrero, from the Faculty of Pharmacy and Food Sciences and IBUB; Anna Gumà, from the Faculty of Biology and IBUB; Joan Vendrell and Sònia Fernández, from Pere i Virgili Institute and CIBERDEM, and other experts from the University of Dundee (United Kingdom).

A disease able to predict type 2 diabetes

A low-intensity chronic inflammatory process contributes to insulin resistance. In this condition, the regular amount of this hormone is not enough to fulfil its function. That is, to get the glucose from food enter cells to get its energy. This disease predicts the development of type 2 diabetes, a chronic disease which –if not controlled- can cause problems in the circulation, heart, eyes, kidneys and other organs.

The aim of the new study was to find whether BACE1 and its product, soluble APPβ, were involved in the breaking out of the inflammatory process and insulin resistance in the skeletal muscle, the most important tissue in glucose metabolism. “So far, we knew mice that lacked this enzyme were protected from glucose intolerance, induced by a diet rich in fats, but we did not know through which mechanisms the lack of BACE1 offered this protecting factor”, says Manuel Vázquez.

Researchers analysed the effects of blocking this enzyme and giving soluble APPβ to the mice. “BACE1 inhibition reduces the increase of the endoplasmic reticulum (a process favouring insulin resistance), lipid-induced inflammation and insulin resistance. Moreover, soluble APPβ administration in mice increases the inflammation in the muscle and reduces insulin response”.

Also, they also compared the levels of BACE1 and APPβ in samples from patients with diabetes and people without the disease. “The BACE1 expression increases in the adipose tissue in obese patients and patients with type 2 diabetes. However, APPβ levels are higher in the plasma of obese patients with type 2 diabetes compared to obese patients without diabetes”, notes Manuel Vázquez.

Potential pharmacological target

According to the researchers, these results point out that this enzyme and its product, soluble APPβ, are key determinants in the stress induction of endoplasmic reticulum, inflammation and insulin resistance in the skeletal muscle.

This link between BACE1 and soluble APPβ to insulin resistance opens the doors to its uses as a pharmacological target. “The challenge is to show the development of new drugs blocking BACE1 actions to be an effective therapeutic and safe strategy in the treatment on insulin resistance and type 2 diabetes”, concludes the researcher.

Referència de l’article:

G. Botteri, L. Salvadó, A. Gumà, D. L. Hamilton, P. J. Meakin, G. Montagut, M. L. Ashford, V. Ceperuelo-Mallafré, S. Fernández-Veledo, J. Vendrell, M. Calderón-Dominguez, D. Serra, L. Herrero, J. Pizarro, E. Barroso, X. Palomr, M. Vázquez-Carrera. “The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling”. Metabolism. Clinical and Experimental, August 2018. Doi: https://doi.org/10.1016/j.metabol.2018.03.005