METABOLIC COUPLING FACTORS IN PANCREATIC BETA-CELL SIGNAL-TRANSDUCTION

This chapter focuses on the biochemical mechanisms that mediate glucos e-stimulated insulin secretion (GSIS) from beta-cells of the islets of Langerhans and the potentiating role played by fatty acids. We summar ize evidence supporting the idea that glucose metabolism is required f or GSIS and that the GLUT-2 facilitated glucose transporter and the gl ucose phosphorylating enzyme glucokinase play important roles in measu ring changes in extracellular glucose concentration. The idea that glu cose metabolism is linked to insulin secretion through a sequence of e vents involving changes in ATP:ADP ratio, inhibition of ATP-sensitive K+ channels, and activation of voltage-gated Ca2+ channels is critical ly reviewed, and the relative importance of ATP generated from glycoly tic versus mitochondrial metabolism is evaluated. We also present the growing concept that an important signal for insulin secretion may res ide at the linkage between glucose and lipid metabolism, specifically the generation of the regulatory molecule malonyl CoA that promotes fa tty acid esterification and inhibits oxidation. Finally, we show that in contrast to its short term potentiating effect on GSIS, long-term e xposure of islets to high levels of fatty acids results in beta-cell d ysfunction, suggesting that hyperlipidemia associated with obesity may play a causal role in the diminished GSIS characteristic of non insul in-dependent diabetes mellitus (NIDDM).