Case 3: Answers to Thought Questions
TQ1.Hypoinsulinemia results in hyperglycemia because insulin is required for the uptake of blood glucose by muscle and adipose tissue. Their glucose transporter (GLUT-4) is insulin dependent in that insulin is required for movement of the transporter to the cell surface from intracellular storage sites. Insulin is also required to suppress hepatic gluconeogenesis. Insulin suppresses the release of glucagon from pancreatic α cells. The resulting rise in the insulin/glucagon ratio results in the dephosphorylation and activation of the kinase domain of bifunctional phosphofructokinase-2 (PFK-2). The fructose 2,6bisphosphate produced by PFK-2 activates phosphofructokinase-1 of glycolysis (see figure below). It also inhibits fructose 1,6-bisphosphatase (FBP-2), thereby inhibiting gluconeogenesis. With hypoinsulinemia, the failure to take up glucose from the blood while simultaneously sending it out into the blood results in hyperglycemia.
TQ2.The blood glucose level has exceeded the capacity of the kidney to reabsorb glucose (via a sodium-dependent glucose transporter [SGLT]). The high concentration of glucose in the urine osmotically draws water from the body. This causes increased urination (polyuria) with loss of water that results in dehydration. TQ3.The NADH generated in FA β-oxidation inhibits the tricarboxylic acid (TCA) cycle at the three NADH-producing dehydrogenase steps. This shifts acetyl CoA away from oxidation in the TCA cycle and toward use as a substrate in hepatic ketogenesis.
TQ4.MW was in negative nitrogen balance: More nitrogen was going out than coming in. This is reflected in the elevated blood urea nitrogen (BUN) level seen in the patient (see figure at top right). [Note: The BUN value also reflects dehydration.] Muscle proteolysis and amino acid catabolism are occurring as a result of the fall in insulin. (Recall that skeletal muscle does not express the glucagon receptor.) Amino acid catabolism produces ammonia (NH3), which is converted to urea by the hepatic urea cycle and sent into the blood. [Note: Urea in the urine is reported as urinary urea nitrogen.] TQ5.The Kussmaul respiration seen in MW is a respiratory response to the metabolic acidosis. Hyperventilation blows off CO2 and water, reducing the concentration of protons (H+) and bicarbonate (HCO3−) as reflected in the following equation: The renal response includes, in part, the excretion of H+ as ammonium (NH4+). Degradation of branched-chain amino acids in skeletal muscle results in the release of large amounts of glutamine (Gln) into the blood. The kidneys take up and catabolize the Gln, generating NH3 in the process. The NH3 is converted to NH4+ by secreted H+ and is excreted (see figure at middle right). [Note: When ketone bodies are plentiful, enterocytes shift to using them as a fuel instead of
Gln. This increases the amount of Gln going to the kidney.] TQ6.Because FA β-oxidation supplies the acetyl CoA substrate for ketogenesis, impaired β-oxidation decreases the ability to make ketone bodies. Ketone bodies are an alternate to the use of glucose, and, thus, dependence on glucose increases. Because FA β-oxidation supplies the NADH and the nucleoside triphosphates needed for gluconeogenesis, glucose production decreases. The result is a hypoketotic hypoglycemia. Recall that this was seen with medium-chain acyl CoA dehydrogenase (MCAD) deficiency.
Case 4: Answers to Review Questions