Type 2 diabetes mellitus (T2DM) has been associated with insulin resistance and the failure of ß-cells to produce and secrete enough insulin as the disease progresses. However, clinical treatments based solely on insulin secretion and action have had limited success. The focus is therefore shifting towards ?-cells, in particular to the dysregulated secretion of glucagon. Our qualitative electron-microscopy-based observations gave an indication that mitochondria in ?-cells are altered in Western-diet-induced T2DM. In particular, ?-cells extracted from mouse pancreatic tissue showed a lower density of mitochondria, a less expressed matrix and a lower number of cristae. These deformities in mitochondrial ultrastructure imply a decreased efficiency in mitochondrial ATP production, which prompted us to theoretically explore and clarify one of the most challenging problems associated with T2DM, namely the lack of glucagon secretion in hypoglycaemia and its oversecretion at high blood glucose concentrations. To this purpose, we constructed a novel computational model that links ?-cell metabolism with their electrical activity and glucagon secretion. Our results show that defective mitochondrial metabolism in ?-cells can account for dysregulated glucagon secretion in T2DM, thus improving our understanding of T2DM pathophysiology and indicating possibilities for new clinical treatments.
COBISS.SI-ID: 25073672
Self-organized critical dynamics is assumed to be an attractive mode of functioning for several real-life systems and entails an emergent activity in which the extent of observables follows a power-law distribution. The hallmarks of criticality have recently been observed in a plethora of biological systems, including beta cell populations within pancreatic islets of Langerhans. In the present study, we systematically explored the mechanisms that drive the critical and supercritical behavior in networks of coupled beta cells under different circumstances by means of experimental and computational approaches. Experimentally, we employed high-speed functional multicellular calcium imaging of fluorescently labeled acute mouse pancreas tissue slices to record calcium signals in a large number of beta cells simultaneously, and with a high spatiotemporal resolution. Our experimental results revealed that the cellular responses to stimulation with glucose are biphasic and glucose-dependent. Under physiological as well as under supraphysiological levels of stimulation, an initial activation phase was followed by a supercritical plateau phase with a high number of global intercellular calcium waves. However, the activation phase displayed fingerprints of critical behavior under lower stimulation levels, with a progressive recruitment of cells and a power-law distribution of calcium wave sizes. On the other hand, the activation phase provoked by pathophysiologically high glucose...
COBISS.SI-ID: 512903480
Residing in the islets of Langerhans in the pancreas, [beta]-cells contribute to glucose homeostasis by managing the body's insulin supply. Although it has been acknowledged that healthy [beta]-cells engage in heavy cell-to-cell communication to perform their homeostatic function, the exact role and effects of such communication remain partly understood. We offer a novel perspective on the subject in the form of (i) a dynamical network model that faithfully mimics fast calcium oscillations in response to above-threshold glucose stimulation and (ii) empirical data analysis that reveals a qualitative shift in the cross-correlation structure of measured signals below and above the threshold glucose concentration. Combined together, these results point to a glucose-induced transition in [beta]-cell activity thanks to increasing coordination through gap-junctional signaling and paracrine interactions. Our data and the model further suggest how the conservation of entire cell-cell conductance, observed in coupled but not uncoupled [beta]-cells, emerges as a collective phenomenon. An overall implication is that improving the ability to monitor [beta]-cell signaling should offer means to better understand the pathogenesis of diabetes mellitus.
COBISS.SI-ID: 512974648