Type 2 diabetes mellitus (T2DM) has been associated with insulin resistance and the failure of β-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 α-cells, in particular to the dysregulated secretion of glucagon. Our qualitative electron-microscopy-based observations gave an indication that mitochondria in α-cells are altered in Western-diet-induced T2DM. In particular, α-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 hypoglycemia and its oversecretion at high blood glucose concentrations. To this purpose, we constructed a novel computational model that links α-cell metabolism with their electrical activity and glucagon secretion. Our results show that defective mitochondrial metabolism in α-cells can account for dysregulated glucagon secretion in T2DM, thus improving our understanding of T2DM pathophysiology and indicating possibilities for new clinical treatments.

Computational α-cell

A computational α-cell model to simulate and explore several interconnected steps in the glucose-dependent signaling cascade form the initial metabolic processes to exocytosis. We combined a mathematical model for glycolysis and glucose driven mitochondrial activity [1] with a model for simulating α-cell electrical and Ca2+ activity and finally with glucagon secretion [2]. This unique coupling of the α-cell metabolism with the electrical activity enables us to study the interplay between processes related to glucagon secretion and ATP production in mitochondria. Most importantly, we adjusted the model and the parameters in order to fit several aspects of model predictions with experimental findings. In addition, we interconnected glucose and free fatty acid metabolism with a mechanism that enables the α-cell to regulate its energetics in a stimulation-dependent manner. We have also included an interaction between cytosolic ATP concentration and the activity ATP-ases. Fig. 1 features the scheme of the computational model with highlighted the crucial processes that are involved in ATP production and regulation of glucagon secretion. The whole mathematical model has been written in Berkeley Madonna software (University of California at Berkeley, California, USA) and C++.

Alfa_cell.rar