Figure 2.

(A) Schematic showing the benefits of restoring pulsatility in the beta-cell and hepatocyte. Numerous beneficial effects may take place in the beta cell (left) and hepatocyte (right) after glucokinase activity is normalized and pulsatility is restored. (B) Shifting glucose dose-response curves based on changing levels of glycolytic activity. (i). Long before diabetes is diagnosed, glucose sensing becomes left-shifted due to excess glucose phosphorylation by glucokinase. This leads to hyperinsulinemia and lowers the threshold for oscillations (dashed portion of line). (ii). Slightly reducing beta-cell activity (right-shift) by reducing glucokinase activity can restore normal glucose sensing and pulsatility in an appropriate range of glucose (dashed portion of line). (iii). Full inhibition during beta-cell rest does not permit oscillations and almost completely stops insulin secretion in physiological blood glucose levels.