Insulin resistance or hypersecretion? The βIG picture revisited

•Over-secretion of insulin may be the central defect underlying type 2 diabetes.•We construct a mathematical model of this ‘hypersecretion theory’.•We extend the well-known Topp model by assuming insulin influences beta-cell mass.•The revised model demonstrates how hypersecretion can lead to diabetes.

Mathematical models of glucose, insulin and pancreatic beta-cell mass dynamics are essential to our understanding of the physiological basis of the development of type 2 diabetes. The classical view of diabetes is that the disease develops due to insulin insufficiency. An alternate viewpoint that has recently staged a revival is that diabetogenesis is a hypersecretion disorder. A prominent model of diabetes progression is the βIG model due to Topp and coworkers. Here we study two new variants of the Topp model, which we name “Topp-IR” and “Topp-HS”. Topp-IR is a model in which increasing insulin resistance is sufficient to drive a system away from health towards hyperglycemia. Topp-HS describes the hypersecretion model in mathematical terms. We thus show that the hypersecretion hypothesis is theoretically sound, and is therefore a potential route to diabetes. On the basis of insights derived from modeling, we clarify several subtleties of that argument, including postulating a central role for transient insulin peaks in driving insulin resistance.