Impact of potentiating the glucose-sensing pathway on glucose-stimulated insulin synthesis and secretion in pancreatic beta-cells

• Applicant: Tiago Cardoso Alves, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism ; Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 448013946

This project describes an innovative approach to improve beta-cell function through the modulation of intracellular metabolism. Despite the abundant evidence suggesting an important role of glucose metabolism in the stimulation of both insulin synthesis and secretion, the underlying mechanisms are still largely unexplored. This is partly explained by the complexity of cellular metabolism and by the lack of tools to accurately study it. In this field, the applicant’s development of the means to perform high-resolution flux analysis was a major breakthrough. The combined use of mass spectrometry and stable isotopes allowed the characterization of the metabolism of beta-cells both in terms of flux magnitude and regulation. The underlying premise of the work proposed here is that the analysis of metabolism using stable isotopes is able to identify the metabolic path(s) regulating glucose-stimulated insulin synthesis and secretion. Upon identification, the working hypothesis is that increasing the flux through those reactions can improve beta-cell function. Through the use of high-resolution flux analysis, the applicant has previously identified a pathway of glucose-sensing in beta-cells. Based on these preliminary data, the role of metabolism in the regulation of beta-cell function will be divided in the following areas: 1) Impact of metabolic modulation on glucose-stimulated insulin secretion. Here, the flux through the glucose-sensing pathway and the corresponding changes in insulin secretion will be studied in terms of responsiveness to small perturbations in the surrounding metabolism. 2) Impact of metabolic modulation on glucose-stimulated insulin synthesis. Changes in the rate of insulin synthesis will be measured following the modulation of the glucose-sensing path. 3) Identify the metabolic factor(s) capable of amplifying the glucose sensing. Special focus will be placed on NADH turnover as the amplifying mechanism of glucose-sensing. In conclusion, the goal of this proposal is to harness the power of the latest technology of metabolic flux analysis, developed by the applicant, to identify the key steps involved in the interaction between glucose metabolism and insulin secretion and synthesis. The study of how these pathways can be manipulated to improve beta-cell function is expected to provide valuable information for the development of new therapies for Type 2 Diabetes.

• DFG Programme: Research Grants