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OOC #3 Due: Monday, March 19, 2018, 5pm CASE: The Runners’ Experiment, Integration of Metabolism Case Study Overview This case is designed to help students understand the importance of glucogenic substrates in human metabolism and the interconnections between carbohydrate, fat, and protein metabolism in humans. Because the focus of this case is the integration of metabolic pathways, we recommend that students be exposed to the topics through Chapter 23 (Chapters 19 and 20 are not necessarily required); referring to Sections 27.4 and 27.5 of the textbook (Stryer 8E) before beginning this case may also be useful for this out-of-class assignment. You may work individually or in groups to complete this case study, but you must submit your own work in Canvas (“Enter your ooc #3 answers here”). You are encouraged to refer to your textbook throughout the case, and internet access is permitted, although it is not necessary for the completion of the case. You will need to iteratively acquire, analyze, and integrate data as you progress through the case and answer assessment questions found throughout the case. You are encouraged to carefully consider investigation options; guessing is discouraged. Your score on this assignment will reflect correct answers. Learning Objectives This case is intended for remediating or extending student capabilities in these difficult topics: 1) The real-world applications of the study of human metabolism. Students will: • Use real biochemical tests to evaluate and ‘solve’ a metabolic disorder case. • Consider the importance of factors like personal and family history, diet, medications taken, and symptoms in solving a biochemical case. 2) Critical and interrelated pathways in human central metabolism. Students will: • Review carbohydrate, lipid, and amino acid metabolic pathways. • Review fatty acid metabolism and recognize the distinctions between the oxidation of even- and odd-chain fatty acids. 3) Connections between carbohydrate, fat, and protein metabolism in humans. Students should be able to: • Outline and explain the importance of glucogenic substrates in human metabolism. o Understand why the inability to convert acetyl-CoA to glucogenic substrates in humans leads to protein wasting. o Explain the importance of ketone body formation and ammonia transport/disposal in human metabolism. • Explain the important differences between the metabolic intermediates produced by the oxidation of even- vs. odd-chain fatty acids. 4) Practice critical thinking skills involving data. Students will: • Evaluate data provided by metabolite and enzyme tests. • Integrate multiple pieces of biochemical data. “The Runners’ Experiment”, Integration of Metabolism Case Study Introduction Race day had come. ‘Finally’ thought Michael. He was a marathon veteran, but this race was different. He felt terrible: “Probably a cold” he had told his girlfriend, but nothing was going to stop him today. Today was the day he would finally prove his brother Dave wrong and he had 26.2 miles to do it. The two young men shook hands shortly before the race started. Dave was thin, like Michael, but not ‘gaunt’. Michael’s girlfriend Jan, had actually used that word to describe Michael a few days prior. His cheeks had receded recently. “Seriously, you should stop this... you look terrible!” Jan said. ‘It’s just pre-race training... and of course, the experiment’ he thought. “I’ll be fine!” he assured her with a wink before leaving their apartment. “Today is the day we settle this!” he now called to Dave as they took off down the race route. But Dave only smiled and accelerated to leave Michael behind. As Dave disappeared into the crowd, Michael called out: “It’s not about speed! It’s about endurance dummy!”, but Dave was too far ahead to hear. 1 For weeks they had been talking about their plan, the experiment, and how much money they were going to make. Michael smiled to himself and then put his head down to focus on the run. Dave was long gone but Michael was certain that he would see him again soon enough... that is, until he started to feel dizzy... Juan had worked at several marathon-medical tents before. It was always the same: people try to run the race without training properly, and they end up at the tents. Most are dehydrated and exhausted, others just ‘hit the wall’, when their bodies run out of glycogen and some even have heart attacks, mainly due to poor training. This particular day wasn’t very hot, but it didn’t take much to overwhelm people during a marathon. Working the races was a nice excuse for an ER doctor to get out in the sun for a few hours on the weekend and a chance to help some people... for Juan that was as addicting as running. Two hours in and Juan was bored. The chatter on the radio was the same as always: dehydrated runners at both tents, and one elderly person from the crowd had to be treated for heat exhaustion, just from standing too long... so far it was a slow day. Suddenly the radio chatter picked up. The ambulance from the medical tent at the 10-mile mark was headed in to his direction with a young man who was unresponsive. The incoming call was interrupted by a second voice: the ambulance from the medical tent at the 20-mile mark ALSO had an unresponsive man. ‘What are the odds?’ Juan thought. The two ambulances arrived simultaneously. Runner ID tags identified both subjects immediately: Michael and Dave Gard, two brothers! Dave was unconscious, but otherwise looked OK. When Juan saw Michael however, he was startled into action; he would not have guessed that the two men were brothers! You are a biochemistry student who is shadowing an ER doctor who has just admitted two young males. One man, Dave, regained consciousness prior to arrival, while the other, Michael, regained consciousness only after arriving at the hospital and is still delirious. Neither man was particularly dehydrated, having drunk water during the race. Both have been stabilized, but blood and urine samples from before they were treated are available for you to test. It is up to you to discover what might be the problem with the two brothers. Consider that there are two primary questions to answer in this case study: • What caused both brothers to lose consciousness during the race? Here are some potential biochemical hypotheses for you to consider: Ketoacidosis Lactic acidosis Ammonia toxicity Mercury poisoning Acute hyperglycemia due to type II diabetes Hypoglycemia Phenylketonuria Maple-syrup urine disease • What is the biochemical explanation for the differences in the conditions of the two brothers? You may now conduct additional investigations to explore the details of this case and to test hypotheses so that you can eventually answer both of these questions. Note: for this case, you are encouraged to explore ALL possible investigations to gather as much information as possible to explain the brothers’ conditions before finishing the case by continuing to the final assessments. You will be scored on this exercise based on your answers to assessment questions found throughout the case so you are STRONGLY encouraged to use your textbook to complete this exercise; you may also use the internet as necessary. RECOMMENDED INITIAL INVESTIGATIONS: Evaluate the overall physical appearance of the two brothers including insect bites or other injuries Results: The men are identical in height. Dave has a lean, athletic build, but is not unusually thin for a long- distance runner. Michael, on the other hand, appears to be severely emaciated. You note sunken eyes and 2 cheek bones and protruding ribs, indicating a lack of not only body fat but also muscle tone. No injuries or other abnormalities are apparent. Investigate past medical history including current medications Results: Neither man smokes, drinks, or uses illegal drugs. They are not on any medications. Dave reports that Michael had not been feeling well prior to the race, but had thought that he was “just coming down with a cold or something”. Given that the men were both avid marathoners, no one apart from Michael’s girlfriend Jan had been concerned about Michael’s recent and rapid weight-loss. Investigate the relationship between the two brothers in greater detail Dave explains that the two of them are not just brothers, they are best friends and despite their grossly different appearances at the moment, they are identical twins! He says: “Before we started our experiment just a few weeks ago, most people couldn’t tell us apart!” Dave mentioned something about an experiment; you could ask him more about this. The following is now a new investigation option: Ask Dave about “The Experiment” Results: Dave tells you that the two brothers had been planning to develop a new dietary supplement company, Gard Nutraceuticals, selling purified fish oil, which they believe is a health panacea. They disagreed on the best fish oil to bring to market however, so the men had been conducting an experiment to settle this disagreement. Both had been taking fish-oil pills along with a multi-vitamin for the past three weeks while they tapered back their training runs dramatically. When you press Dave about what else he and Michael were eating, shockingly he says “nothing”. They had been eating enough fish oil to consume 3000 Calories per day, which is normal for marathon training (approximately 330 grams of fish oil per day). Each brother had been touting a different product: Michael was taking wild-caught salmon oil, while Dave was eating oil from a flathead (striped) mullet. The bet was to determine whether fish oil was an adequate caloric- replacement supplement for athletes, and whose product was better. To make the decision unambiguous, the pair was going to use the marathon to decide the winner since the boys had nearly identical marathon times in previous races. The details of this fish-oil experiment may merit further investigation. In particular, some fish contain high levels of mercury, which could be toxic if consumed in large quantities. You now have the following two new investigation options available to you: Test hair for common toxins (heavy metals and narcotics) and ask Dave about mercury contamination in the supplements Investigate the composition of the dietary supplements the subjects were eating SECONDARY INVESTIGATIONS: DETERMINE BLOOD SERUM CONCENTRATIONS OF: Common immunoglobins (IgG, IgA, IgM) and ammonium (NH4+) levels Results for Dave: All values for immunoglobin concentrations are at the low end of the normal ranges, which is normal for someone finishing a marathon. (normal ranges: [IgG] = 560–1800 mg/dL; [IgM] = 45–250 mg/dL; [IgA] = 100–400 mg/dL); [NH4+] = 20 mmol/L (normal range: 12- 48 mmol/L) Results for Michael: Severely low levels of IgG, IgM, and IgA. [NH4+] = 67 mmol/L (normal range: 12–48mmol/L)

1. Which of the following might cause the concentration of ammonium ions found in the blood to increase? (Select ALL that apply!) A. An increase in the rate of fatty acid catabolism by β-oxidation B. An increase in the rate of protein and amino acid catabolism C. An increase in the rate of glucose oxidation through the pentose phosphate pathway D. An increase in the rate of glucose oxidation through glycolysis and the citric acid cycle E. A defect in the urea cycle F. Galactosemia G. Lactose intolerance

Free fatty acids (FFAs) and triacylglycerides (TAGs) Results for Dave: 500 mg/dL FFAs (normal range: 190–420 mg/dL); 190 mg/dL TAGs (normal range: 40–150 mg/dL) Results for Michael: 660 mg/dL FFAs (normal range: 190–420 mg/dL); 230 mg/dL TAGs (normal range: 40–150 mg/dL) Glucose and Glycosylated Hemoglobin (HbA1c as a marker) Results for Dave: [Glc] = 39 mg/dL (normal range: 70–110 mg/dL) Note: This value indicates severe hypoglycemia; HbA1c = 4.4% (normal range: 4–6.5%) Results for Michael: [Glc] = 31 mg/dL (normal range: 70–110 mg/dL) Note: This value indicates severe hypoglycemia; HbA1c = 3.2% (normal range: 4–6.5%)

2. When a typical person runs a marathon, they do not become severely hypoglycemic to the extent that either Michael or Dave did. Some people consume carbohydrates during the race in the form of foods, gels, or sports drinks that have added sugar. However, even when dietary carbohydrates are not consumed during the race, how does the body of a healthy individual maintain adequate levels of blood glucose during sustained aerobic exercise such as running a marathon? (Select ALL that apply!) Hint: You may wish to review pages 657-661, 698-699, & 814-819 of Stryer 8E before attempting this question! In addition, remember to consider the sources of glucose, not ATP. A. Even numbered fatty acids are catabolized and the carbon is used for gluconeogenesis in the liver. B. Muscles run gluconeogenesis and export glucose into blood. C. Ketone bodies are produced by adipose cells and converted into glucose by the liver. D. Muscles convert lactate back into glucose and export this glucose back out into the blood. E. The exclusively ketogenic amino acids (leucine and lysine) are deaminated and the carbon skeletons used to synthesize glucose. F. Glucogenic amino acids are deaminated and the carbon skeletons used to synthesize glucose. G. Most blood glucose will come from the breakdown of muscle glycogen (glycogenolysis) and the export of this glucose from muscles to the blood. H. Most blood glucose will come from the breakdown of brain glycogen (glycogenolysis) and the export of this glucose from brain to the blood. I. Most blood glucose will come from the breakdown of liver glycogen (glycogenolysis) and the export of this glucose from the liver to the blood.

H3O+ ions: blood pH Results for Dave: pH = 7.31 (normal range: 7.35–7.45) Results for Michael: pH = 7.2 (normal range: 7.35–7.45) The physician you are shadowing tells you that a value of 7.31 indicates acidosis but this value will not normally cause a loss of consciousness. A pH value of 7.2 indicates severe acidosis and could result in neurological problems. 4 Ketone bodies (acetoacetate and acetone) Results for Dave: low but detectable levels (normal range: undetectable) Results for Michael: dangerously high levels of both found.

3. What macromolecules can be catabolized such that the resulting carbon can be used to create ketone bodies? A. Fatty acids B. Amino acids C. Glucose D. Glycogen E. All of the above can be used to produce acetyl-CoA, so they can all be used to make ketone bodies.

4. When are ketone bodies produced in an otherwise healthy human being? A. When fatty acid levels in the blood are low B. When glutamine levels in the blood are low C. When glucose levels in the blood are low D. When lactate levels in the blood are low E.

When blood pH is low Lactate and pyruvate Results for Dave: [lactate] = 2.0 meq/L (normal range: 0.5–2.2 meq/L); [pyruvate] = 0.05 meq/L (normal range: 0–0.11 meq/L) Results for Michael: [lactate] = 0.7 meq/L (normal range: 0.5–2.2 meq/L); [pyruvate] = 0.02 meq/L (normal range: 0–0.11 meq/L) DETERMINE URINE CONCENTRATIONS OF: branched-chain a-keto acids Results for both Dave and Michael: undetectable levels (normal range: undetectable)

5. What would an increased amount of branched-chain a-keto acids in the urine indicate? (Select ALL that apply!) A. A defect in fatty acid catabolism B. A defect in fatty acid transport C. A defect in a citric acid cycle enzyme D. A defect in carbohydrate metabolism E. A defect in amino acid catabolism F. Phenylketonuria G. Lactose intolerance H. Maple-syrup urine disease phenyl-pyruvate (a phenylketone)

Results: Both Dave and Michael: undetectable levels (normal range: undetectable)

6. What would an increased amount of phenyl-pyruvate in the urine indicate? (Select ALL that apply!) A. A defect in fatty acid catabolism B. A defect in fatty acid transport C. A defect in a citric acid cycle enzyme D. A defect in carbohydrate metabolism E. A defect in amino acid catabolism F. Phenylketonuria G. Lactose intolerance H. Maple-syrup urine disease

SPECIFIC ENZYME TESTS: Lactate dehydrogenase (LDH) Results for both Dave and Michael: [LDH] = 150 U/L (normal range: 110–210 U/L) Liver Asp amino-transaminases (AST) and Ala amino-transferase (ALT) Results for Dave: Both enzymes are within normal range (normal range: 7–55 U/L) Results for Michael: Both enzyme expression levels are elevated. Pyruvate dehydrogenase (PDH) Results for both Dave and Michael: PDH complex activity= 2.5 nmol/(min•mg) (normal range: 2– 2.5 nmol/(min•mg) Test cells for Electron Transport Chain enzyme activities Results for both Dave and Michael: ETC enzyme activities were normal. SPECIAL INVESTIGATIONS Test hair for common toxins (heavy metals and narcotics) and ask Dave about mercury contamination in the supplements Results: Dave immediately points out that they worked with a chemist to extensively purify the fish oils to remove any mercury contamination. An independent laboratory verified that there are only trace levels of mercury left in their formulations, and Dave brings up the documentation on his smart-phone, showing that the analysis is good. Mercury toxicity will be negligible regardless of how much oil is consumed. Also, no heavy metals or narcotics were detected in hair samples from either brother. Investigate the composition of the dietary supplements the subjects were eating. Results: Complete hydrolysis followed by esterification of the TAGs in the two fish oil samples allowed fatty acid composition to be analyzed by gas chromatography. The table shows the compositions of oil consumed by Dave (from the striped mullet Mugil cephalus) and Michael (from Atlantic salmon Salmo salar) Dave Michael 16:0 fatty acid 11% 16% 16:1∆7 fatty acid 5% 6% 18:1∆9 fatty acid 15% 20% 20, 22, or 24 carbon omega-3 or omega-6 fatty acids 36% 45% 15, 17, 19, and 21 carbon fatty acids 25% 4% 12 or 14 carbon fatty acids 6% 7% Unidentified 2% 2% 6

7. What is the most significant difference between these two fish oil samples in terms of their fatty acid compositions? Note: it may be helpful to briefly review fatty acid structure and nomenclature from Section 12.1, pages 342-344, Table 12.1 of Stryer 8E before answering this question. A. The oil that Dave is consuming is much higher in saturated fatty acids than Michael’s oil. B. The oil that Dave is consuming is much higher in oleic acid than Michael’s oil. C. The oil that Dave is consuming is much higher in palmitic acid than Michael’s oil. D. The oil that Michael is consuming is much higher in omega-3 fatty acids than in omega-6 fatty acids. E. The oil that Dave is consuming is much higher in odd-numbered fatty acids than Michael’s oil. F. The oil that Michael is consuming is much higher in unsaturated fatty acids than Dave’s oil.

8. What is different about the metabolism of odd- vs. even-numbered fatty acids? (Select ALL that apply!) A. Odd-numbered fatty acids are not broken down by β-oxidation. B. Odd-numbered fatty acids are primarily broken down by ω-oxidation. C. Odd-numbered fatty acids cannot be broken down by humans. D. Odd-numbered fatty acids require additional enzymatic steps to fully degrade. E. Odd-numbered fatty acids do not require carnitine in order to be transported into the mitochondria. F. Odd-numbered fatty acid metabolism produces a four-carbon succinyl group attached to CoA.

9. What is an important consequence of producing succinyl-CoA at the end of odd-numbered fatty acid metabolism rather than the normal product by β-oxidation of even-numbered fatty acids? A. Acetyl-CoA is a citric acid cycle intermediate but succinyl-CoA is not. B. Acetyl-CoA is glucogenic but succinyl-CoA is strictly ketogenic. C. Succinyl-CoA is glucogenic, but acetyl-CoA is strictly ketogenic. D. None of the above are true.

10. Review again which brother is taking which oil and which oil contains a large percentage of odd- numbered fatty acids. What is a critical physiological consequence of this difference? A. Michael can make ketones from the oil in his diet but Dave cannot. B. Dave can make ketones from the oil in his diet but Michael cannot. C. Michael can make ATP using the oil in his diet but Dave cannot. D. Dave can make ATP using the oil in his diet but Michael cannot. E. Dave can make far more glucose from the oil in his diet than Michael can. F. Michael can make glucose from the oil in his diet but Dave cannot. You have uncovered a critically important aspect of this case. As you continue your investigation, consider what biochemical consequences might occur when someone is not consuming glucose and cannot convert the food that they are eating into glucose. ENDING THE CASE AND THE ASSESSMENT QUESTIONS: The student should be able to fully explain the reason(s) for Dave and Michael’s incidents in biochemical and physiological terms, including reasons for the significant differences between the two brothers’ conditions and to fully justify and completely explain their reasoning based on the evidence gathered. Criteria to complete the case are the selection of ALL possible investigation options and completion of the associated assessment questions. If all of the criteria are not met: you may be missing vital information to sufficiently explain this incident. Assessment Questions for “The Runners’ Experiment”

11. The citric acid cycle begins with the condensation of acetyl-CoA with oxaloacetate. Possible sources for carbon that may be converted into acetyl-CoA in active muscle include: (Select ALL that apply!) A. Pyruvate B. β-oxidation of fatty acids C. Amino acid catabolism D. Conversion of ketone bodies from the blood back to acetyl-CoA E. Stored glycogen in the muscle

12. Though not included in the case, both men had elevated levels of the enzymes carnitine acyltransferase I and II. Why might the men have elevated levels of these enzymes? A. These enzyme levels rise after eating a carbohydrate-rich meal to aid in carbohydrate metabolism (glycolysis). B. Carnitine levels rise after eating and these enzymes are expressed to catabolize the extra carnitine. C. Both men are producing abnormally high levels of these enzymes as a side effect of utilizing amino acids for energy. D. These enzymes are elevated because both men are getting their energy primarily from β- oxidation and these enzymes are needed for fatty acids to be transported into the mitochondria. E. Likely both men have high levels of these enzymes because they are identical twins and share a genetic polymorphism.

13. Why is glucose a necessary fuel in the human body and what organs or cell types rely most heavily on glucose? A. Most human tissues cannot use glucose as an energy source. B. Glucose is necessary for the continued function of the Na+/K+ pump, and the brain is the only organ that uses glucose as an energy source. C. During exercise, the brain stops using glucose so that it can be used by the muscles. D. Glucose is necessary because it is used by almost all tissues for energy and biosynthesis, and the brain relies almost entirely on glucose as an energy source. E. Glucose is necessary because it is the only source of energy that can fully be oxidized to produce ATP, and the liver relies heavily on glucose as its sole energy source.

14. During their three-week, pre-marathon self-experiment, both Dave’s and Michael’s livers had to produce some glucose. Which of the following molecules could be used by the liver to create the glucose that is needed to supply the brain and other tissues in a healthy person on a normal diet? (Select ALL that apply) A. Pyruvate B. Lactate C. Glycerol D. Any citric acid cycle intermediate (this excludes acetyl-CoA!) E. Even-chain fatty acids F. Alanine G. Acetyl-CoA 8

15. Which of the following statements about even-chain fatty acids is/are FALSE? (Select ALL that apply) A. The product of the oxidation of even-numbered fatty acid chains is multiple acetyl groups bound to CoA molecules. B. Humans have all the appropriate enzymes necessary to use even-chain fatty acids as glucogenic precursors through their conversion to acetyl-CoA. C. A difference between even-chain and odd-chain fatty acids is that only odd-chain fatty acids produce propionyl groups bound to CoA. D. The products of the oxidation of an odd-numbered fatty acid chain are multiple 3-carbon propionyl groups bound to CoA. E. The products of the oxidation of an odd-numbered fatty acid chain are acetyl groups and a final propionyl group attached to CoA.

16. What is happening to Dave and Michael in regard to their metabolisms? (Select ALL that apply) A. Because the human body cannot create glucose from even-chain fatty acid oxidation, both runners are starving their bodies of glucose due to their restrictive diets. B. Most of their energy is coming from fatty acid oxidation, so ketone bodies are being produced to free up CoA for continued β-oxidation. C. The brothers have compromised immune systems because of a genetic disorder that affects their metabolism. D. Their diet high in fatty acids resulted in a large build-up of glycogen in their livers and muscles. E. Excessive fatty acid oxidation resulted in protein wasting, which led to acidification of the blood.

17. What are the functions of Asp aminotransferase (AST) and Ala aminotransferase (ALT)? And why are they elevated in Michael? A. These enzymes function in glucose catabolism, catalyzing the transfer of an amino group; levels of these enzymes would be elevated due to the excessive protein wasting occurring in Michael’s body to meet his need to produce glucose in the absence of other dietary gluconeogenic substrates. B. These enzymes function in fatty acid catabolism, catalyzing the transfer of a hydroxyl group; levels of these enzymes would be elevated due to excessive glycogenolysis occurring in Michael’s body to meet his need to produce glucose in the absence of other dietary gluconeogenic substrates. C. These enzymes function in protein catabolism, catalyzing the transfer of an amino group; levels of these enzymes would be elevated due to the excessive protein wasting occurring in Michael’s body to meet his need to produce glucose in the absence of other dietary gluconeogenic substrates. D. These enzymes function in protein catabolism, catalyzing the transfer of an amino group; levels of these enzymes would be elevated due to the excessive ketone body production that is occurring in Michael’s body to meet his need for energy sources in the absence of other dietary gluconeogenic substrates. E. These enzymes function in ketone body catabolism, catalyzing the transfer of an amino group; levels of these enzymes would be elevated due to the excessive ketone body production that is occurring in Michael’s body to meet his need for energy sources in the absence of other dietary gluconeogenic substrates.

18. Why are Michael’s blood ammonia levels elevated and why are high levels of ammonia dangerous? A. Ammonia levels in the blood are high due to the rapid degradation of proteins; high levels of ammonia lead to dangerous levels of ketone bodies in muscle. B. Ammonia levels in the blood are high because of burning calories from vigorous exercise; high levels of ammonia lead to dangerous levels of ketone bodies in muscle. C. Michael’s blood ammonia is high due to the rate of ketone body production in his body; high levels of ammonia are dangerous because ammonia passes easily through the blood-brain barrier and is highly toxic to the brain. D. Ammonia levels are high because it is a byproduct of β-oxidation of fatty acids; high levels of ammonia lead to dangerous levels of ketone bodies. E. Michael’s blood ammonia is high due to the rate of protein wasting (catabolism of non-essential proteins to provide glucogenic carbon skeletons) in his body; high levels of ammonia are dangerous because ammonia passes easily through the blood-brain barrier and is highly toxic to the brain.

19. What is/are the source(s) of the excessively high levels of ketone bodies in Michael but not Dave? (Select ALL that apply) A. Ketone bodies are being formed from catabolism of carbohydrates for energy metabolism. B. Ketone bodies are being formed as a byproduct of excessive glycogenolysis. C. Ketone bodies are being formed from ketogenic amino acids released from protein catabolism. D. Ketone bodies are being formed from the products of β-oxidation of fatty acids from both stored triglycerides and the ingested fish oil. E. Ketone bodies are being produced in Michael’s brain to provide energy for the liver. F. Michael is producing large amounts of ketone bodies because he is severely hypoglycemic and has likely been hypoglycemic for most of the past few weeks.

20. Why are the two twins experiencing such different symptoms? (Select ALL that apply) A. Michael probably has a genetic inborn error in metabolism that Dave does not. B. One brother is in much better shape for the run than the other because of training. C. Michael’s case is more severe because he relies on glycolysis (by way of lactic acid fermentation) for energy. D. Michael’s supplement has almost no odd-numbered fatty acids, so his body is undergoing more protein wasting, and producing dangerous levels of ketones. E. Dave’s case is milder because the supplement he is taking contains a significant amount of odd- numbered fatty acids, some of which may be used to produce glucose. F. The twins exhibit minor variations in metabolic adaptation to dietary changes based on their genetics.

21. Which of the following would likely be true if the brothers were NOT identical twins? A. Carnitine levels would be higher in Dave than in Michael. B. Their bodies would have used different sources of energy to respond to a long term run. C. They would not have overexerted their bodies because they would be less competitive if they were not identical twins. D. The brothers would have had the same amount of ketone production. E. It would be more difficult to determine the impact of diet in this case because there would have been a greater chance that their differing symptoms were due to genetic variation in metabolism.

22. What is causing Michael’s neurological issues and what is the cause of this problem? (Select ALL that apply) A. Michael is exhibiting the first signs of diabetes, trigged by the vigorous run. B. Michael has depleted his main stores of glucose and is therefore experiencing neurological effects from hypoglycemia. C. Michael has severe hypoglycemia and ketoacidosis because of metabolic failures, both which are known to affect mental status. D. As a result of excessive protein and amino acid degradation, Michael is also experiencing mild ammonia toxicity, which is likely exacerbating his neurological issues. E. Michael is experiencing side effects of extreme dehydration.