Development of metabolic targeted approach to improve glucose-stimulated insulin synthesis and secretion in pancreatic beta-cells
PhD Student: Karthikeyan Mohanraj
Supervisor at TUD: Tiago C. Alves, Barbara Ludwig
Supervisor at KCL: Shanta Persaud
Start Date: 17.02.2020
Diabetes is a serious health issue that has reached alarming levels. At present, nearly half a billion people have diabetes across the world. Whether due to autoimmune response (Type 1 Diabetes) or calorie imbalance (Type 2 Diabetes), dysfunctional pancreatic beta cells are key to the development of diabetes. The pathogenesis of Type 2 Diabetes, in particular, is characterized by the development of insulin resistance associated with compensatory initial hyperinsulinemia. Over time, overstimulation of beta cells results in the loss of their function, which aggravates hyperglycemia-related complications. Although pharmacological therapies are available, cohort studies have shown that preserving beta-cell mass/function has a protective effect against the progression of diabetes. Therefore, the goal of this project is to identify targets capable of increasing the responsiveness and functionality of pancreatic beta cells as potential therapy for diabetic patients.
We will quantify the metabolism of the pancreatic beta cells in response to different stimulatory concentrations of glucose, which is key to determine the responsiveness of the metabolic system and VPC. Additionally, the metabolic flux response to glucose-stimulation will be tested in the presence of specific enzyme modulators for the major metabolic pathways. The reactions with highest potential to modulate metabolic flux and insulin secretion will be modulated in models of primary beta cells. Finally, the selected reactions will be tested in healthy and diabetic human islets. The expectation is that by modulating those pathways, we can increase VPC and consequently glucose-stimulated insulin secretion in diabetic islets.
In conclusion, this project aims to bring to light the pathways that are key in the interaction between glucose levels and insulin secretion. Through this study, finding a way to manipulate these pathways that improve beta-cell function is expected to provide valuable information for the development of new therapies for Type 2 Diabetes.
Publications:
IMPPAT: A curated database of Indian Medicinal Plants, Phytochemistry And Therapeutics. K. Mohanraj*, B.S. Karthikeyan*, R.P. Vivek-Ananth, R.P.B. Chand, S.R. Aparna, P. Mangalapandi, A. Samal. Sci Rep. 2018;8:4329.
Comparative systems analysis of the secretome of the opportunistic pathogen Aspergillus fumigatus and other Aspergillus species. R.P. Vivek-Ananth, K. Mohanraj, M. Vandanashree, A. Jhingran, J.P. Craig, A. Samal. Sci Rep. 2018;8:6617.
Broad Substrate-Specific Phosphorylation Events Are Associated With the Initial Stage of Plant Cell Wall Recognition in Neurospora crassa. M.A.C. Horta, N. Thieme, Y. Gao, K.E. Burnum-Johnson, C.D. Nicora, M.A. Gritsenko, M.S. Lipton, K. Mohanraj, L.J. de Assis, L. Lin, C. Tian, G.H. Braus, K.A. Borkovich, M. Schmoll, L.F. Larrondo, A. Samal, G.H. Goldman, J.P. Benz. Front Microbiol. 2019;10:2317.
A curated knowledgebase on endocrine disrupting chemicals and their biological systems-level perturbations. B.S. Karthikeyan, J. Ravichandran, K. Mohanraj, R. Vivek-Ananth, A. Samal. Science of The Total Environment. 2019;692:281-296.
Metabolic Syndrome and COVID-19: Endocrine-Immune Vascular Interactions Shape the Clinical Course. A. Barthel, K. Mohanraj, A.M. Biener, S.R. Bornstein. Endocrinology. 2020;161(12). pii: 5986352.
MeFSAT: a curated natural product database specific to secondary metabolites of medicinal fungi. R.P. Vivek-Ananth, A.K. Sahoo, K. Kumaravel, K. Mohanraj, A. Samal. RSC Adv. 2021;11:2596-2607.