Harpers

158 / CHAPTER 19GLUCONEOGENESISP iADPH 2 OF-1,6-PaseH 2 OFructose 6-phosphateP iActiveF-2,6-PaseInactivePFK-2GlycogenGlucoseGlucagoncAMPcAMP-DEPENDENTPROTEIN KINASEPPROTEINPHOSPHATASE-2ATPP iFructose 2,6-bisphosphateFructose 1,6-bisphosphatePyruvateInactiveF-2,6-PaseActivePFK-2ADPCitrateATPPFK-1ADPFigure 19–3. Control of glycolysis and gluconeogenesisin the liver by fructose 2,6-bisphosphate and thebifunctional enzyme PFK-2/F-2,6-Pase (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase).(PFK-1,phosphofructokinase-1 [6-phosphofructo-1-kinase];F-1,6-Pase, fructose-1,6-bisphosphatase. Arrows withwavy shafts indicate allosteric effects.)fructose-1,6-bisphosphatase. When glucose is short,glucagon stimulates the production of cAMP, activatingcAMP-dependent protein kinase, which in turn inactivatesphosphofructokinase-2 and activates fructose2,6-bisphosphatase by phosphorylation. Therefore, gluconeogenesisis stimulated by a decrease in the concentrationof fructose 2,6-bisphosphate, which deactivatesphosphofructokinase-1 and deinhibits fructose-1,6-bisphosphatase.This mechanism also ensures that glucagonstimulation of glycogenolysis in liver results inglucose release rather than glycolysis.GLYCOLYSISSubstrate (Futile) Cycles Allow Fine TuningIt will be apparent that the control points in glycolysisand glycogen metabolism involve a cycle of phosphorylationand dephosphorylation catalyzed by: glucokinaseand glucose-6-phosphatase; phosphofructokinase-1 andfructose-1,6-bisphosphatase; pyruvate kinase, pyruvatecarboxylase, and phosphoenolypyruvate carboxykinase;and glycogen synthase and phosphorylase. If these wereallowed to cycle unchecked, they would amount to futilecycles whose net result was hydrolysis of ATP. Thisdoes not occur extensively due to the various controlmechanisms, which ensure that one reaction is inhibitedas the other is stimulated. However, there is a physiologicadvantage in allowing some cycling. The rate ofnet glycolysis may increase several thousand-fold in responseto stimulation, and this is more readily achievedby both increasing the activity of phosphofructokinaseand decreasing that of fructose bisphosphatase if bothare active, than by switching one enzyme “on” and theother “off” completely. This “fine tuning” of metaboliccontrol occurs at the expense of some loss of ATP.THE CONCENTRATION OF BLOODGLUCOSE IS REGULATED WITHINNARROW LIMITSIn the postabsorptive state, the concentration of bloodglucose in most mammals is maintained between 4.5and 5.5 mmol/L. After the ingestion of a carbohydratemeal, it may rise to 6.5–7.2 mmol/L, and in starvation,it may fall to 3.3–3.9 mmol/L. A sudden decrease inblood glucose will cause convulsions, as in insulin overdose,owing to the immediate dependence of the brainon a supply of glucose. However, much lower concentrationscan be tolerated, provided progressive adaptationis allowed. The blood glucose level in birds is considerablyhigher (14.0 mmol/L) and in ruminantsconsiderably lower (approximately 2.2 mmol/L insheep and 3.3 mmol/L in cattle). These lower normallevels appear to be associated with the fact that ruminantsferment virtually all dietary carbohydrate to lower(volatile) fatty acids, and these largely replace glucose asthe main metabolic fuel of the tissues in the fed condition.BLOOD GLUCOSE IS DERIVED FROMTHE DIET, GLUCONEOGENESIS,& GLYCOGENOLYSISThe digestible dietary carbohydrates yield glucose,galactose, and fructose that are transported via thehepatic portal vein to the liver where galactose andfructose are readily converted to glucose (Chapter 20).