Regulation of pancreatic B-cell glucokinase and GLUT2 glucose transporter gene expression.

Introduction Randle’s original idea of a signal function of fuel metabolism for the initiation of insulin secretion by glucose is now generally accepted (for review see [ 13); in the pancreatic B-cell glucose is both a fuel and, at millimolar concentrations, a physiological stimulus for insulin secretion and insulin biosynthesis. The device in the pancreatic B-cell, which translates changes in millimolar blood glucose concentration into corresponding signal-generating metabolic flux rates for the initiation of insulin secretion, is composed of the plasma membrane low-afinity GLUT2 glucose transporter and glucokinase, a low-affinity glucose phosphorylating enzyme. These structures are present in the pancreatic B-cell in addition to the high-affinity GLUT1 glucose transporter and high-affinity hexokinase isoenzymes. Glucokinase, the flux-regulating enzyme, is strategically positioned at the entrance to the glycolytic chain and is therefore able to control the metabolic flux through this pathway (for details of this concept see [Z]). Thus this enzyme functions, in the pancreatic B-cell, as the so-called signal recognition enzyme for glucose-induced insulin secretion [2, 31. Recently, defective glucokinase function has also been associated with certain forms of human diabetes (for review see [4]). Glucose uptake into pancreatic B-cells, by facilitated diffusion via the GLUT2 isotype glucose transporter, is not usually rate limiting [2, 31; however, under certain well-defined conditions, it may be critical for glucose recognition by the pancreatic B-cell.