Seminar, 25. October 2019 Marko Marhl

Friday, 25. October 2019, 11.00 a.m. 

Ernst-Abbe-Platz 2, Seminarraum 3423

Type II diabetes and metabolic alterations in pancreatic alpha and beta cells

Prof. Dr. Marko Marhl
(University of Maribor, Faculty of Education & Faculty of Natural Sciences and Mathematics, Maribor, Slovenia)

Diabetes Mellitus (DM) is a disease of epidemic characteristics in our modern society. Globally, the number of people with DM has risen from 108 million in 1980 to 422 million in 2014. In 2015, an estimated 1.6 million deaths were directly caused by diabetes. Higher-than-optimal blood glucose caused an additional 2.2 million deaths, by increasing the risks of cardiovascular and other diseases. The causes for DM, and in particular the dysregulations leading to Type II DM (T2DM), are still obscure. Homeostasis of blood glucose is complex and involves several mechanisms. It requires a fine-tuned control of glucagon and insulin secretin from – and -cells, respectively. For several decades, the focus was mainly on insulin and the first clinical therapies had evolved around this concept; however, with only limited success. It has been revealed that glucagon excess is at least as important as insulin deficiency. To elucidate the complex interplay between insulin and glucagon secretion, the biophysical and physiological mechanisms need to be found.

Our group combines experimental and theoretical approaches for studying the mechanisms of hormone secretion in pancreatic – and -cells. Using confocal microscopy, we measure Ca2+ dynamics in -cells in response to glucose stimulation. In a slice of pancreatic tissue, the Ca2+ signals are traced simultaneously for all the cells. This enables analysing the collective behaviour of -cells in islets of Langerhans. A theoretical network-based approach is applied to analyse the topological characteristics of the functional networks. We found a transition from typical small-world topologies under physiological conditions to more regular network structures related to pathologies and unphysiological conditions. Changes in cluster distributions can also be observed for different stimulatory glucose concentrations. Moreover, the phenomenon of self-organising criticality (SOC) has been established under conditions of physiologically relevant oscillatory glucose concentrations.

At the cellular level, we developed a mathematical model linking the metabolic processes with the hormone secretion in – and -cells. We can explain how the close-related – and -cells with similar mechanisms, provide a counter-regulated hormone secretion, glucagon at low glucose concentrations and insulin at high glucose concentrations. The model predictions show that the differences in the metabolism of glucose and fatty acids (FA) play a crucial role in this counter-regulation of hormone secretion in – and -cells. However, the model predictions also show that the fine-tuned regulation of hormone secretion via different substrate utilization in – and -cells is vulnerable. In particular, a dysregulated FA oxidation in -cells might lead to dysfunctions characterising the early stages of T2DM. The metabolic pathways of the dysregulated FA oxidation in -cells resemble those typically observed in -cells. Therefore, these studies might also contribute to a better understanding of the transdifferentiation between – and -cells, which is a hot topic concerning the future pharmacological treatments of T2DM. In particular, the transdifferentiation of – into -cells appears clinically attractive because of primarily more affected -cells in T2DM.