Hypoinsulinemia leads to hyperglycemia because insulin is necessary for the uptake of blood glucose by muscle and adipose tissue. Insulin dependency is seen in the glucose transporter (GLUT-4), where insulin is required for the movement of the transporter from intracellular storage sites to the cell surface. Additionally, insulin is necessary to inhibit hepatic gluconeogenesis and suppress the release of glucagon from pancreatic α cells. The increased insulin/glucagon ratio activates the kinase domain of bifunctional phosphofructokinase-2 (PFK-2), leading to the production of fructose 2,6-bisphosphate. This fructose 2,6-bisphosphate activates phosphofructokinase-1, which is involved in glycolysis. Simultaneously, it inhibits fructose 1,6-bisphosphatase, thus inhibiting gluconeogenesis. Consequently, hypoinsulinemia prevents the uptake of glucose from the blood while causing its release into the blood, resulting in hyperglycemia.

In the case of the blood glucose level surpassing the kidney's capacity to reabsorb glucose via the sodium-dependent glucose transporter (SGLT), excess glucose is excreted in the urine. The high concentration of glucose osmotically draws water from the body, causing dehydration and increased urination (polyuria).

During fatty acid (FA) β-oxidation, the generated NADH inhibits the tricarboxylic acid (TCA) cycle at the three NADH-producing dehydrogenase steps. As a result, acetyl CoA is shifted away from oxidation in the TCA cycle and directed towards hepatic ketogenesis.

MW was experiencing negative nitrogen balance, with more nitrogen being lost than gained. This is reflected in the elevated blood urea nitrogen (BUN) level observed in the patient. Muscle proteolysis and amino acid catabolism occur due to the decrease in insulin. Amino acid catabolism produces ammonia (NH3), which is converted to urea by the hepatic urea cycle and released into the blood.

The Kussmaul respiration observed in MW is a respiratory response to metabolic acidosis. Hyperventilation helps eliminate CO2 and water, reducing the concentration of protons (H+) and bicarbonate (HCO3−). The kidneys respond by excreting H+ as ammonium (NH4+). Degradation of branched-chain amino acids in skeletal muscle releases significant amounts of glutamine (Gln) into the blood. The kidneys uptake and catabolize Gln, generating NH3 in the process. The NH3 is then converted to NH4+ through the secretion of H+ and subsequently excreted.

Impaired β-oxidation reduces the ability to produce ketone bodies since FA β-oxidation supplies the acetyl CoA substrate required for ketogenesis. Ketone bodies serve as an alternative fuel to glucose, thus, a decrease in ketone body production increases dependence on glucose. Moreover, impaired β-oxidation affects the production of NADH and nucleoside triphosphates required for gluconeogenesis, resulting in decreased glucose production. This leads to a condition known as hypoketotic hypoglycemia, as seen in medium-chain acyl CoA dehydrogenase (MCAD) deficiency.
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