The landmark work on modeling T2D pathogenesis was done by Topp et al. (J. Theor. Biol. 2000; 206(4):605-19), who proposed that moderate but persistent increases in blood sugar mediate negative feedback to increase insulin secretion by increasing beta-cell mass, either by increased replication or reduced apoptosis. However, if that increase fails to occur or is inadequate to restore normal glucose homeostasis, further increases in glucose raise it to a level where it becomes toxic to beta cells. Instead of negative feedback, there is then positive feedback, which causes a catastrophic loss of beta-cell mass and T2D. We have extended and refined that model to more closely replicate the time course of T2D progression in rodents and humans (Ref. # 1). The most important qualitative change is the inclusion of regulation of beta-cell function, in two distinct forms, in addition to mass, as data show that such changes are more rapid and more extensive than changes in mass. This is especially true for humans, for whom beta-cell replication is very slow after adolescence. Our model retains the critical behavior universally observed in experiments, whereby glucose increases are relatively restrained until a threshold is crossed. This shows that the standard model of T2D, described in the Goals and Objectives section, is fully consistent with the fact that insulin rises earlier and more markedly than glucose. There is no need to posit an alternative theory that high insulin causes T2D. To decide which model is correct, however, requires more detailed consideration of the predictions of each in various circumstances, and we will address this in the future. The threshold behavior also has important clinical implications: it explains the empirical observation that prevention of T2D is much easier than reversal once the disease is established. Nonetheless, drastic interventions, such as gastric bypass surgery and extreme caloric restriction reverse even well-established T2D. The model indicates that this can happen because those interventions are rapid and potent enough to bring the patient back below threshold, where negative feedback again prevails and glucose-insulin homeostasis can be restored. In collaboration with our experimental partners in the Satin lab (University of Michigan), we were able to demonstrate one of the forms of functional compensation predicted by the model, reduced trafficking of K(ATP) channels to the plasma membrane, after overnight incubation in high glucose (Ref. # 2). The reduced K(ATP) expression shifts the glucose dose response curve to the left, allowing a greater increase in calcium influx and hence secretion at any given glucose level. A recently published paper (Chen et al,, Diabetes 2016;65:26762685) confirmed the model predictions about a second, slower form of functional compensation, which increases the maximum secretory capacity. We were invited to write a commentary about that paper (Ref. # 3). Further work in progress is addressing the different pathways to T2D and will be discussed in a future annual report.
