Time-dependent mechanisms in beta-cell glucose sensing.

The relation between plasma glucose and insulin release from pancreatic beta-cells is not stationary in the sense that a given glucose concentration leads to a specific rate of insulin secretion. A number of time-dependent mechanisms appear to exist that modify insulin release both on a short and a longer time scale. Typically, two phases are described. The first phase, lasting up to 10 min, is a pulse of insulin release in response to fast changes in glucose concentration. The second phase is a more steady increase of insulin release over minutes to hours, if the elevated glucose concentration is sustained. The paper describes the glucose sensing mechanism via the complex dynamics of the key enzyme glucokinase, which controls the first step in glucose metabolism: phosphorylation of glucose to glucose-6-phosphate. Three time-dependent phenomena (mechanisms) are described. The fastest, corresponding to the first phase, is a delayed negative feedback regulating the glucokinase activity. Due to the delay, a rapid glucose increase will cause a burst of activity in the glucose sensing system, before the glucokinase is down-regulated. The second mechanism corresponds to the translocation of glucokinase from an inactive to an active form. As the translocation is controlled by the product(s) of the glucokinase reaction rather than by the substrate glucose, this mechanism gives a positive, but saturable, feedback. Finally, the release of the insulin granules is assumed to be enhanced by previous glucose exposure, giving a so-called glucose memory to the beta-cells. The effect depends on the insulin release of the cells, and this mechanism constitutes a second positive, saturable feedback system. Taken together, the three phenomena describe most of the glucose sensing behaviour of the beta-cells. The results indicate that the insulin release is not a precise function of the plasma glucose concentration. It rather looks as if the beta-cells just increase the insulin production, until the plasma glucose has returned to normal. This type of integral control has the advantage that the precise glucose sensitivity of the beta-cells is not important for normal glucose homeostasis.