CASE: The Runners’ Experiment, Integration of Metabolism Case Study Overview Thi

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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) 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? (Hint: Before answering this question, consider answers to previous questions and the important molecules that connect metabolic pathways)

2) A defect in the urea cycle would obviously cause an increase in blood ammonia concentrations. Which of the following might also cause the concentration of ammonium ions found in the blood to increase?

A. An increase in the rate of glucose oxidation through the pentose phosphate pathway

B. An increase in the rate of fatty acid catabolism by ?-oxidation

C. An increase in the rate of glucose oxidation through glycolysis and the citric acid cycle

D. Galactosemia

E. An increase in the rate of protein and amino acid catabolism

F. Lactose intolerance

3) When a typical person runs a marathon, he or she does 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, when dietary carbohydrates are not consumed during the race, how does the body of a healthy marathon runner maintain adequate levels of blood glucose? Hint: You may wish to review pages 445, 446, and 450-451 from Chapter 24 about glycogen, pages 497-501 from Chapter 27 about ketone bodies ,and pages 559-562 from Chapter 30 about amino acid degradation in Tymoczko Biochemistry: A Short Course, 3rd, ed., before attempting the next two questions! In addition remember to consider the sources of glucose, not ATP.

Most blood glucose will come from the breakdown of liver glycogen (glycogenolysis) that is then exported from the liver to the blood.

4) When are ketone bodies produced in an otherwise healthy human being?

Explanation / Answer

2. E. An increase in the rate of protein and amino acid catabolism

Ammonium ions are formed in the breakdown of amino acids. When excessive amounts of protein are ingested, the excess amino acids produced from digesting proteins which are transported to the liver from the small intestine. In liver, through a series of chemical reactions amino acid is oxidised and the amine group, -NH2, and a hydrogen atom, H, are removed from the main structure of the amino acid. Thus the important product of this reaction is ammonia. So, if the rate of protein and amino acid catabolism has increased the concentration of ammonium ions in the blood will also increase.

3. C. Most blood glucose will come from the breakdown of muscle glycogen (glycogenolysis) that is then exported from the muscles to the blood.

Because, muscle glycogen is the main source of energy during intense endurance events. Thus, greater amount of stored muscle glycogen produce greater potential of the body.

4. Ketone bodies produced in an otherwise healthy human being – D. When glucose levels in the blood are low.

Ketone bodies are produced from acetyl CoA when carbohydrates are so scarce that energy must be obtained from breaking down of fatty acids.

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