*3.2. Impaired Glucagon and Insulin Secretion in the Pathogenesis of T2DM*

In the previous section we explored how the glucose concentration-dependent ATP production is affected by the mitochondrial dysfunction. Here we further investigate how T2DM-associated mitochondrial perturbations impair the secretion of glucagon and insulin secretion in the pancreatic alpha (Figure 4a) and beta cells (Figure 4b).

Under normal physiological circumstances, an increase in ATP concentration at high glucose concentration in alpha cells leads to a decrease in the conductivity of KATP channels and to cell depolarization [38]. As a result, the Ca2<sup>+</sup> inflow as well as the glucagon secretion rate is lower (Figure 4a, blue line). Impaired mitochondrial ATP synthesis lowers the intracellular ATP concentration and the ATP concentrations required for glucagon secretion are reached at higher glucose values. It turns out that the mitochondrial dysfunction causes an increased glucagon secretion in hyperglycemia, whereas glucagon secretion decreases in the hypoglycemic region, as the ATP production is not sufficient to fulfil the conditions for elevated glucagon secretion. Apparently, the T2DM-associated pathological state with mitochondrial dysfunction shifts glucagon secretion to higher glucose concentrations (Figure 4a). A detailed explanation of the cellular processes underlying the switch in secretion pattern can be found in our previous work [26]. It should be noted that here, in contrast to the previously published model [26], the glycolysis is modeled on the basis of the stationary state of ATP concentration (see Model). Despite this difference in the models, both lead to qualitatively the same results.

**Figure 4.** Relative glucagon and insulin secretion as a function of glucose concentration for normal cell function (blue line) and for the pathological state of T2DM under different levels of mitochondrial dysfunction: 10–40%. (**a**) Relative secretion of glucagon (RGS) in the alpha cell; (**b**) Relative insulin secretion (RIS) in the beta cell.

In beta cells under normal physiological conditions, higher glucose concentrations and the corresponding increase in ATP concentration enhances electrical activity. This in turn leads to a higher calcium influx, and finally to higher insulin secretion (Figure 4b). An impaired mitochondrial ATP production lowers the insulin secretion rates, which corresponds to the decrease in the intracellular ATP level. The differences in secretion profiles are mostly pronounced in hyperglycemic conditions. Abnormalities in mitochondrial function thus lead to lower glucose-stimulated insulin secretion in beta cells, which is a hallmark of T2DM.
