*3.1. Mitochondrial Function A*ff*ects ATP Production*

In models for the alpha as well as for the beta cell, the ATP production depends on glycolysis and mitochondrial metabolism and is driven by glucose and FFA oxidation. Altered mitochondrial metabolism has therefore a decisive effect on the drop in intracellular ATP concentration and consequently on the secretion of the two pancreatic hormones. In Figure 3, we show how mitochondrial ATP synthesis in both cell types depends on glucose concentration. In both panels the blue lines correspond to the cell's normal physiological function without mitochondrial dysfunction. A comparison of ATP production with regard to the cell type reveals that in both alpha and beta cells the ATP production monotonically increases with increasing glucose concentrations. However, the differences provoked by different stimulation levels are much more pronounced in the beta cell. Namely, in alpha cells at low glucose concentration, the ATP production is high compared to beta cells due to the oxidation of FFAs in mitochondria. As the concentration of glucose increases, part of FFAO in mitochondria is replaced by glucose oxidation (Figure 3a). At the same time, glucose is also

metabolized by glycolysis in the cytoplasm, which is the key element that rises the ATP concentration at higher glucose levels in the alpha cell [27]. In contrast, in the beta cell the ATP production is low during hypoglycemia (Figure 3b), whereas in hyperglycemia it reaches approximately the same value as it is observed in the alpha cell. Because the production of ATP in beta cells is predominantly mediated by the mitochondrial glucose oxidation [2,36,37], this allows for very significant increase in ATP concentration when glucose levels are increased.

**Figure 3.** Glucose-dependent ATP concentration levels under normal mitochondrial conditions (blue line) and under different levels of mitochondrial dysfunction: 10% (dashed line), 20% (dotted line), 30% dash-dotted line, and 40% (red line), for the pancreatic alpha (**a**) and beta (**b**) cell.

Results in Figure 3 also demonstrate the change in cytosolic ATP concentration due to a defective mitochondrial metabolism associated with the pathogenesis of T2DM. It is known that the mitochondrial function is decreased by 30–40% in T2DM [16,22,23]. The ATP concentration due to mitochondrial dysfunction, which is determined in Equation (1), specifically by the *k*md parameter, is shown by black lines, with each line illustrating an additional decrease in mitochondrial activity by 10%. The red line illustrates a maximum of 40% mitochondrial dysfunction. It can be observed that mitochondrial dysfunction results in a drop in ATP concentration in both alpha and beta cells. In alpha cells, the decline is approximately the same for all glucose concentrations and reflects a direct decrease in mitochondrial ATP production, which is weakly modulated by glucose. This drop is due to a direct decrease in mitochondrial ATP production, which is approximately the same at low and high glucose. Namely, mitochondrial ATP production in alpha cells is close to saturated even at low glucose levels due to FFAO. The increase in cytosolic ATP concentration with increasing glucose is due to anaerobic glycolytic ATP production, which is not affected by the mitochondrial dysfunction. In contrast to alpha cells, in beta cells, a decrease in ATP production is pronounced mainly in the hyperglycemic state, which occurs primarily at the expense of increased glucose oxidation in mitochondria, which is perturbed by mitochondrial dysfunction.
