Chapter 10: Carbohydrates: Glycolysis and Glucose Homeostasis
You have a patient exhibiting severe episodes of hypoglycemia. Measurement of circulating insulin and glucagon levels indicate that they are normal and responsive to cycles of feeding and fasting. Which of the following enzyme defects would most likely explain the hypoglycemia?
A. a constitutively active glycogen synthase
B. glycogen synthase that lacks the phosphorylase kinase target site
C. hepatic glucokinase with a Km equal to that of muscle hexokinase
D. pancreatic glucokinase with a Km equal to that of hepatic glucokinase
E. PFK1 that is nonresponsive to the allosteric effects of fructose-2,6-bisphosphate
Answer C: The hepatic form of the glucose-phosphorylating enzyme is referred to as glucokinase, which is a hexokinase isoform. Humans express 4 distinct hexokinases that exhibit different patterns of expression and kinetic activities relative to substrates and catalytic rates. Hepatic glucokinase has a Km significantly higher than that of the hexokinase that is expressed in skeletal muscle. This prevents the liver from trapping glucose, thereby ensuring that peripheral tissues such as the brain and muscle have easy access to dietary carbohydrate. In the case of this patient, the expression of a variant glucokinase with a Km similar to that of muscle hexokinase would result in significant trapping of glucose inside hepatocytes. The outcome would be expected to be periods of hypoglycemia as described.
You are examining the effects of an experimental compound on the metabolic activities of primary hepatocytes in culture. You discover that addition of your compound to these cells activates changes in metabolic fluxes highly similar to those induced by addition of glucagon. Determination of phosphate incorporation shows that several proteins become hyperphosphorylated following addition of the compound. Which of the following statements would most accurately reflect these changes?
A. glycogen phosphorylase activity will be increased
B. PFK1 activity will be unaffected
C. PFK2 will exhibit an increased level of kinase activity
D. phosphorylase kinase activity will be decreased
E. phosphoprotein phosphatase-1 activity will be increased
Answer A: Within hepatocytes, glucagon activation of its receptor results in activation of the kinase PKA. Activation of PKA will then lead to the phosphorylation of numerous substrates. One of the substrates for PKA is glycogen synthase/phosphorylase kinase (phosphorylase kinase) which results in activation of this PKA substrate. Activation of phosphorylase kinase results in the phosphorylation of both glycogen synthase and glycogen phosphorylase. When glycogen phosphorylase is phosphorylated its level of ...