The liver plays a central role in maintaining blood glucose homeostasis.  It contains the highest concentration of glycogen of any organ in the body and is one of the few organs that can regenerate glucose from metabolic byproducts.  The liver can replenish glucose in muscle and brain tissue during times of fasting, and it can help prevent lactate accumulation during intense physical activity.Von Gierke disease is a rare autosomal recessive disorder that arises from inactivating mutations in the liver enzyme glucose 6-phosphatase (G6Pase).  It affects roughly 1 in 100,000 individuals, and the resulting loss of enzymatic activity leads to hypoglycemia (low blood sugar) that cannot be counteracted by catabolic hormones like glucagon.  Von Gierke can also cause an increase in blood acidity concurrent with lactate build-up.  Patients typically become symptomatic shortly after birth with convulsions, hyperventilation, and tremors.  Left untreated, patients may develop gout, osteoporosis, and life-threatening complications such as kidney failure and liver tumors.In an effort to examine the biochemical consequences of this disorder, scientists generated a genetically engineered mouse model with liver G6Pase expression under the control of the Tet-Off system at both alleles.  Under this system, addition of the small molecule tetracycline in the water source of the mouse rapidly shuts off G6Pase gene expression and therefore can recapitulate von Gierke disease.  Blood glucose and pH levels were measured daily in two groups of genetically engineered mice over 20 days: group A mice received no tetracycline and group B mice were given tetracycline starting at day 10.  All mice were fed identical low-sugar diets throughout the experiment.Adapted from Froissart R, Piraud M, Boudjemline AM, et al. Glucose-6-phosphatase deficiency. Orphanet J Rare Dis. 2011;6:27. Question 7Treatment with which of the following could help counteract hypoglycemia in patients with von Gierke disease?A.InsulinB.Vitamin AC.EpinephrineD.Starch

Glycogen storage disease type I (GSD I) or von Gierke's disease, is the most common of the glycogen storage diseases. This genetic disease results from deficiency of the enzyme glucose-6-phosphatase.The metabolic outcomes of GSD I are likely to include :Group of answer choicesHigh blood glucose, decreased blood pH, decreased glycogen storage in liver and kidneysLow blood glucose, increased blood pH, decreased glycogen storage in liver and kidneysHigh blood glucose, increased blood pH, increased glycogen storage in liver and kidneysHigh blood glucose, decreased blood pH, increased glycogen storage in liver and kidneysLow blood glucose, increased blood pH, increased glycogen storage in liver and kidneysLow blood glucose, decreased blood pH, decreased glycogen storage in liver and kidneysHigh blood glucose, increased blood pH, decreased glycogen storage in liver and kidneysLow blood glucose, decreased blood pH, increased glycogen storage in liver and kidneys

Von Gierke’s and McArdle’s disease are two of the most common glycogen storage diseases.Which of the following statements are TRUE for these diseases? i) Von Gierke’s disease typically results from a mutation in glucose 6-phosphatase.ii) McArdle’s disease typically results from a mutation in glycogen phosphorylase.iii) McArdle’s disease typically results from a mutation in glucose 6-phosphatase.iv) Von Gierke’s disease typically results from a mutation in glycogen phosphorylase.v) Von Gierke’s disease patients cannot release glucose to the blood, have enlarged livers and kidneys and elevated lipids in the blood (hyperlipidaemia).vi) McArdle’s disease patients cannot release glucose to the blood, have enlarged livers and kidneys and elevated lipids in the blood (hyperlipidaemia).vii) McArdle’s disease patients suffer from severe muscle cramps with initial attempts of exercise, but these cramps subside with repeated attempts.viii) Von Gierke’s disease patients suffer from severe muscle cramps with initial attempts of exercise, but these cramps subside with repeated attempts.

Although the ketone body β-hydroxybutyrate (BHB) is commonly associated with the pathologic condition diabetic ketoacidosis, its most recognized physiologic function is as an alternative fuel source produced by the liver when glucose is sparse.  More recently, evidence has emerged that BHB also serves as a signaling and regulatory molecule that is associated with protection against the effects of aging, inflammation, and neuronal excitotoxicity.BHB released from the liver is taken up by muscle, brain, and other peripheral tissues, where it is trafficked to the mitochondria.  BHB is reversibly converted to acetoacetyl-CoA (Figure 1), which can then be processed through β-oxidation.  Because BHB is processed in the mitochondria, the cytosolic NAD+ pool is preserved.  In addition to its use as a redox cofactor, cytosolic NAD+ also acts as a substrate for the sirtuin and poly(ADP-ribose) polymerase (PARP) enzymes; by preserving the cytosolic NAD+ pool, increased BHB levels enhance the anti-aging and anti-apoptotic effects of the sirtuin and PARP enzymes.Figure 1  Conversion of BHB to acetoacetyl-CoABHB acts directly as an agonist for several receptors, including the hydroxycarboxylic acid receptor 2 (HCAR2), a Gi-coupled G protein–coupled receptor (GPCR) that upon activation inhibits adenylyl cyclase and its downstream effectors.  In adipocytes, BHB-mediated activation of HCAR2 reduces lipolysis, decreasing serum levels of proinflammatory free fatty acids.  In the colonic epithelium, HCAR2 activation is critical in the maintenance of gut membrane integrity.  In this way, BHB acts similarly to the short-chain fatty acids (eg, butyric acid), produced from fermentation of dietary fiber, in protecting gut health.Several mechanisms have been proposed to explain BHB's action as a neuroprotectant against excitotoxicity.  In glutamatergic neurons, BHB inhibits vesicular glutamate transporter 2 (VGLUT2), inhibiting the packaging of the excitatory neurotransmitter glutamate.  In GABAergic neurons, BHB infusion stimulates production of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and decreases α-ketoglutarate levels. Question 40Based on the passage, hepatocytes (ie, liver cells) that are producing BHB are also most likely to have:A.downregulated phosphofructokinase-2 (PFK2) activity.B.downregulated phosphorylase kinase activity.C.upregulated acetyl-CoA carboxylase (ACC) activity.D.upregulated glycogen synthase activity.

Which of the following regulatory mechanisms helps increase net glucose catabolism in the liver after a meal?A.Inhibition of hexokinase by glucose-6-phosphateB.Allosteric suppression of phosphofructokinase-1 by ATP bindingC.Hormonal suppression of fructose-2,6-bisphosphate synthesisD.Allosteric inhibition of fructose-1,6-bisphosphatase activity

Glycolysis and gluconeogenesis are tightly regulated, opposing metabolic pathways that help control blood glucose levels.  Glycolysis converts glucose to two pyruvate molecules, whereas gluconeogenesis consumes a net total of 6 NTPs (4 ATPs and 2 GTPs) to convert two pyruvate molecules back to glucose.  When glycolysis is upregulated, gluconeogenesis is downregulated, and vice versa.As shown in Figure 1, glycolysis and gluconeogenesis in the liver are largely regulated by the allosteric action of the small molecule fructose-2,6-bisphosphate (F2,6BP) on the enzymes phosphofructokinase-1 (PFK-1) and fructose-1,6-bisphosphatase (F1,6BPase).  PFK-1 is a kinase that uses ATP to phosphorylate fructose-6-phosphate (F6P) in an irreversible step of glycolysis, forming fructose-1,6-bisphosphate (F1,6BP) and ADP.  During gluconeogenesis, F1,6BPase removes the phosphate group by hydrolysis.Figure 1  Activities of (A) PFK-1 and (B) F1,6BPase on their respective substrates in the presence (solid lines) and absence (dashed lines) of F2,6BPA bifunctional enzyme that contains a phosphofructokinase-2 (PFK-2) domain and a fructose-2,6-bisphosphatase (F2,6BPase) domain controls F2,6BP levels in the liver.  The PFK-2 domain converts F6P to F2,6BP, and the F2,6BPase domain converts F2,6BP back to F6P.  When blood glucose levels are low, the enzyme becomes phosphorylated.  This phosphorylation event simultaneously activates the F2,6BPase domain and inactivates the PFK-2 domain.  Under high blood glucose conditions, the enzyme becomes dephosphorylated, activating the PFK-2 domain and inactivating the F2,6BPase domain.Question 13Which metabolic process most likely provides the energy necessary for sustained gluconeogenesis?A.Fatty acid oxidationB.GlycogenolysisC.FermentationD.Pentose phosphate pathway