Fig. 4.

Physiological mechanism of a proposed concept for GLUT2-induced diabetic symptoms. Under normal conditions (left), glucose uptake by far exceeds subsequent glucose phosphorylation, making glucokinase the rate-limiting step in GSIS. Accordingly, both, triggering and amplifying pathway are activated resulting in a biphasic GSIS. A slight reduction in GLUT2 surface expression (middle) has no impact on GSIS, as long as glucose uptake is ≥ glucose usage. When GLUT2 is markedly reduced (right) glucose uptake falls below the rate of glucose usage, making glucose uptake the rate-limiting step in GSIS. Consequently, the triggering pathway cannot be activated, resulting in a monopahsic GSIS. The contribution of additional GLUTs (gray) to the sustained second phase of GSIS is unclear. The mechanisms underlying retained insulin secretion are unknown