ABSTRACT
This chapter aims to understand how the system breaks down in type-2 diabetes and identify principles that apply broadly to other hormone circuits. It shows how dynamic compensation occurs in the BIG model. The insulin-glucose feedback loop of the minimal model explained the rise and fall of glucose after a meal but failed to explain how glucose levels are maintained when physiological parameters, like insulin sensitivity, change. The slow feedback loop of cell mass dynamics keeps beta cells at a proper functional mass and keeps glucose, averaged over weeks, at 5 mM. All three constraints – organ size control, robustness, and mutant resistance – are addressed by a single integrated circuit design – the secrete-and-grow circuit. Prediabetes is often associated with insulin resistance. When insulin resistance is strong, beta cells must grow in functional mass by a large factor to compensate.
