A Day at the Beach
By Cathleen Erin McGreal Michigan State University
Topic Pre-requisites: Students should have exposure to the topics of Chapters 14–18 and ideally Sections 23.2 and 23.3 of Lehninger, 6th ed.
Overview
This capstone-type case is designed to help students understand the importance of gluconeogenic 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 of Chapters 14–18 and ideally Sections 23.2 and 23.3 of the textbook (Lehninger POB,6th ed.) before beginning this case. These latter two sections could be assigned as preliminary reading before initiating the case if they have not been explicitly covered in the class; in that case, we recommend allowing students additional time to complete this case study.
Students may work individually or in groups to complete this case study. Students are constantly encouraged to refer to their textbook throughout the case, and internet access is permitted, although it is not necessary for the completion of the case. Students are required to iteratively acquire, analyze, and integrate data as they progress through the case and answer assessment questions found throughout the case. All assessment questions are automatically scored.
For this case, students will need to explore all investigative options to complete the case, and so, unlike some other cases in this collection, the number of investigations that students make use of will not be reported.
Learning Objectives
This case is intended for remediating or extending student capabilities in these difficult topics:
Some questions are designed to address areas of difficulty for students
Suggested implementation
Below we describe two options for course implementation. The hybrid Online/In-class approach is recommended. Time required for students to complete the online case will vary by group depending on their level of discussion between each investigation. The case study can be started and stopped, and so it is recommended to give students a window of 3 to 5 days in which to complete the assignment.
Hybrid: Online/In-class: (recommended approach; ~30 minutes of class-time expected)
Online only approach: (minimal in-class time required)
Suggestions for in-class discussions (these questions may also be used in summative assessments-- i.e., exams, scored quizzes, etc.):
You may be missing vital information needed to sufficiently explain this incident. You must complete all investigations before proceeding to the final assessment questions.
You may be missing vital information needed to sufficiently explain this incident. You must complete all investigations before proceeding to the final assessment questions.
This activity has already been completed, however feel free to review the information contained within.
You are about to leave the investigation and proceed to the final assessment. Are you sure you wish you to proceed?
Jessie knew she was late for the family reunion, probably too late for the big picnic lunch at Forest Lake Beach, but too early for the barbecue dinner. “Too bad” she thought, because she had skipped breakfast as well, trying to get out of the city and on the road to the lake. Perhaps there would be some leftovers; she hoped so, because she was beginning to get that slightly dizzy feeling that meant she was pushing her limits.
No leftovers, but the whole extended family was there: sitting and talking on the beach, playing Frisbee golf, and throwing a football. Some of the younger cousins were having swimming contests out from the floating platform at the edge of the swimming area. Jessie watched the kids swimming, and smiled sadly. She had been a competitive swimmer as a teenager and still missed it. As she watched the group of splashing children, Jessie began to think that something wasn’t right about a little boy off to the right of all the others. She put her hand up to shade her eyes from the sun and squinted; the kid was in trouble! He was throwing his arms around randomly, and thrashing the water into froth. None of the other children were close enough to notice, and there didn’t seem to be any other adults near enough to raise the alarm.
Without any further thought, Jessie ran into the lake, and after the first few lunges through the water, dove shallowly and began swimming towards the now sinking child. Her muscle memory kicked in and her strokes became fast, efficient, and powerful. With each stroke she raised her head enough to keep the small head in sight; she was making progress, but he was going down! She pushed harder, picked up speed, and then she saw him, underwater, sinking quickly despite his frenzied paddling. Jessie took a breath and dove; she grabbed the little guy’s surfer swim shorts, and kicked hard back toward the surface. She began the one-sided stroke that allowed her to keep his head above the water, and swam toward the beach, which seemed, strangely, to be disappearing into a haze. Jessie felt exhausted, but kept swimming, breathing in short gasps. Her vision narrowed, and she barely felt the sand under her knees as reached the shallow water. As the little boy was taken from her arms, Jessie lost consciousness.
Jessie woke up in the hospital emergency room, very weak and confused. She tried to sit up, but her arms and legs felt heavy, completely without strength. She was dizzy, disoriented, and exhausted. A gray-haired woman in a short white coat came into view, as well as a younger person dressed in scrubs.
“Hello, Jessie. Glad to see you’re finally awake. You were out for a pretty long time. I understand you are a hero; saved the day and your little cousin. Can you tell me what happened to make you faint? Did you hit your head, or swallow too much water? Everyone said that you were a really good swimmer, and so no one understood why you fainted.”
Jessie took a deep and unsteady breath. “I haven’t tried to swim that hard since I had a head injury, 5 years ago." When the ER doctor asked Jessie if anything like this had happened to before, she looked sheepish and said “yes”. She recalled similar episodes, all under similar circumstances—"pushing herself too hard".
You are a biochemistry student who is shadowing the ER doctor. With the assistance of the physician, you may conduct additional investigations to determine the cause of Jessie’s incident. The goal of this exercise is to correctly solve the biochemical case without carrying out completely unnecessary investigations; hence, you are encouraged to carefully consider the information you receive with each investigation and avoid haphazard guessing. 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.
Please note that there is a minimum set of investigations that must be conducted in order to have all the necessary information to fully understand the case. The number of investigations you select will be recorded and reported to your instructor, so randomly guessing could adversely affect your score. You should be both thorough and thoughtful in conducting your investigation. Hint: we recommend that you first thoroughly exhaust the use of broader initial investigation options, like interviewing someone, before proceeding to test specific hypotheses by doing more specific tests for particular enzyme activities, for example. After completing these initial investigations, ask yourself, what further investigations or lab tests would you like to conduct based on the information gathered so far? For starters, you might also consider what, metabolically, might make a person lose consciousness…
RECOMMENDED INITIAL INVESTIGATIONS
Evaluate overall physical appearance including the presence of insect bites or other injuries
Results: Subject is a young, adult female with a slim, athletic frame but otherwise appears normal.
Fecal analysis – Look for blood, intestinal parasites, high levels of fat in stool
Results: No blood or intestinal parasites were found. Levels of fat in the stool were normal considering the subject’s recent food intake.
Interview patient to determine dietary habits and look for neurological problems
Results: No abnormalities in cognitive function were found. Jessie reported being a strict vegan for many years; however, she claims to get a large amount of protein from plant sources. She also reports eating a high calorie diet and occasional, moderate alcohol consumption. She says that she is a non-smoker, does not use illegal drugs, and does not recall eating anything unusual recently; in fact, she had not eaten anything yet on the day of the fainting episode because she was in a rush. You ask whether she knows whether she might be diabetic or has had any trouble in the past controlling her blood sugar levels and she responds by saying “I really don’t know.”
Investigate past medical history
Results: Jessie explained that she was on the verge of gaining a swimming scholarship to college when she injured her head in a rock climbing accident. Her head injury led to epileptic episodes that were now controlled by regularly taking anticonvulsant drugs. Swimming was one of the activities she gave up because of the fear of seizures. She reports that, since the accident, she has had less endurance, which she had always ascribed to the fact that she was no longer working out regularly. She sighed and said longingly, “I don’t swim anymore… don’t really do much of anything in terms of hard exercise. I am just miserably out of shape, I guess.” You ask whether she has had a blood test to look at her blood lipid profile recently and she responds that she has not had a full physical since she was dismissed from the hospital five years ago.
SECONDARY INVESTIGATIONS
Determine Blood Serum Concentrations
Common electrolytes: Ca2+, K+, Na+, Cl-, PO43-
Results: All values are in normal ranges. (normal ranges: [Ca2+] = 8.5-10.5 gm/dL; [K+] = 3.5-5.0 meq/L; [Na+] = 135-145 meq/L; [Cl-] = 100-106 meq/L; total phosphorus = 2.6 – 4.5 mg/dL)
Common lipids: free fatty acids (FFAs), triacylglycerides (TAGs), total cholesterol, and ketone bodies (acetoacetate as a marker)
Results: [FFAs] = 500 mg/dL (normal range: 190-420 mg/dL); [TAGs] = 175mg/dL (normal range: 40-150 mg/dL); [Total cholesterol] = 140 mg/dL (normal range: 120-200 mg/dL); acetoacetate was undetectable
Which of the following would you expect to be elevated in the blood of a person who has been fasting for 12 hours, compared to a person who has recently eaten a large meal with carbohydrate, protein, and fat? (Select ALL that apply!)
a. TAGs | Fd/yhwSeUQ6ZqQj4 |
b. Free Fatty Acids (FFAs) | uS+xJY+rPntALoOB |
c. Ketone bodies | uS+xJY+rPntALoOB |
e. Glucose | Fd/yhwSeUQ6ZqQj4 |
f. Insulin | Fd/yhwSeUQ6ZqQj4 |
g. Glucagon | uS+xJY+rPntALoOB |
Glucose
Results: [Glc] = 60 mg/dL (normal range: 70-110 mg/dL)
H3O+ ions: blood pH
Results: pH = 7.41 (normal range: 7.35 – 7.45)
Lactate and pyruvate
Results: [lactate] = 1.0 meq/L (normal range: 0.5-2.2 meq/L); [pyruvate] = 0.05 meq/L (normal range: 0 – 0.11 meq/L)
NH4+ (total ammonia)
Results: [NH4+] = 45 mmol/L (normal range: 12-48mmol/L)
O2 and CO2
Results: PO2 = 88 mmHg (normal range: 75-100mmHg); PCO2 = 41 mmHg (normal range: 35-45 mmHg)
Total protein (mostly albumin)
Results: [total protein] = 4.9 g/dL (normal range: 6.0-8.0 g/dL)
Specific enzyme tests
Asp amino-transaminases (AST) and Ala amino-transferase (ALT)
Results: Both enzymes are within normal range (normal range: 7-55 U/L)
Aldolase
Results: [Aldolase] = 1.0 U/mL (normal range: 0-7 U/mL)
Carnitine acyltransferases I & II (CAT I & CAT II)
Results: The activity of both transporters was found to be well below normal. Expression levels of both proteins were actually slightly elevated, however.
Test cells for Electron Transport Chain enzyme activities
Results: ETC enzyme activities were normal
Creatine kinase (CK)
Results: CK] = 100 U/L (normal range: 40-150 U/L)
Glucose 6-phosphate dehydrogenase (G6PD)
Results: [G6PD] = 8 U/g Hb (normal range: 5-13 U/g Hb)
Lactate dehydrogenase (LDH)
Results: [LDH] = 150 U/L (normal range: 110-210 U/L)
Pyruvate dehydrogenase (PDH)
Results: PDH complex activity= 2.5 nmol/min*mg (normal range: 2-2.5 nmol/min*mg)
Measure blood levels of glycated Hb (HbA 1c as a marker)
Results: HbA1c = 3.2 % (normal range: 4 - 6.5%)
Which of the following factors can affect the concentration of glucose in the blood? (Select ALL that apply!)
a. Ability to release insulin | uS+xJY+rPntALoOB |
b. Ability to respond to insulin (insulin sensitivity) | uS+xJY+rPntALoOB |
c. Ability to release and respond to glucagon | uS+xJY+rPntALoOB |
d. The availability of glycogen in the liver | uS+xJY+rPntALoOB |
e. The availability of gluconeogenic (also called glucogenic) substrates to fuel gluconeogenesis and glucose export in the liver | uS+xJY+rPntALoOB |
f. The ability of the liver to produce ketone bodies when necessary | uS+xJY+rPntALoOB |
Conduct an oral glucose tolerance test to measure changes in insulin, glucagon, and blood glucose when oral glucose is administered.
Results: Jessie fasted for 12 hours prior to the test, and her glucose, glucagon, and insulin levels were measured just before the test began. She was then given 75 grams of glucose in water to drink, and her blood was drawn and tested every 60 minutes for 5 hours. Results were as follows: She was hypoglycemic when the test began but otherwise showed completely normal responses to the glucose challenge (to be explained in greater detail in the following assessment questions!). In the very last hour, her blood glucose slowly decreased to below normal levels (hypoglycemia).
When a person has fasted for 12 hours before a test like this, blood glucose is still being used by the brain and other tissues. How is that glucose being replenished? (Select ALL that apply!)
A. Muscles run gluconeogenesis and export glucose into the blood. | Fd/yhwSeUQ6ZqQj4 |
B. Muscles run glycogenolysis and export glucose into the blood. | Fd/yhwSeUQ6ZqQj4 |
C. Large amounts of dietary glucose are still being absorbed from the digestive tract. | Fd/yhwSeUQ6ZqQj4 |
D. The liver runs gluconeogenesis and exports glucose into the blood. | uS+xJY+rPntALoOB |
E. The liver runs glycogenolysis and exports glucose into the blood | uS+xJY+rPntALoOB |
F. The brain makes its own glucose from large amounts of glycogen stored in the brain. | Fd/yhwSeUQ6ZqQj4 |
G. Adipocytes breakdown TAGs to fatty acids and then convert those fatty acids to glucose, which is then exported by the adipocyte | Fd/yhwSeUQ6ZqQj4 |
What is happening in a healthy individual about an hour into a glucose tolerance test? (Note: At this early time-point, blood glucose levels are still high. Also, remember that a person who is taking a glucose tolerance test was fasting for 12 hours prior to the test!) (Select ALL that apply!)
A. Glucose is being exported by the liver | AD2YBdbb6x3kfgtembjVpQ== |
B. Glucose is being taken up by the liver | Efx3eLtX1Ia8xzC/fjL6GA== |
C. Glucose is being taken up by adipocytes | Efx3eLtX1Ia8xzC/fjL6GA== |
D. Glycogen is being synthesized by adipocytes | AD2YBdbb6x3kfgtembjVpQ== |
E. Triacylglycerides are being synthesized by adipocytes | Efx3eLtX1Ia8xzC/fjL6GA== |
F. Glycogen is being synthesized by the liver | Efx3eLtX1Ia8xzC/fjL6GA== |
G. Glucose is being taken up by muscle cells that are deficient in glycogen | Efx3eLtX1Ia8xzC/fjL6GA== |
H. Glycogen is being synthesized by muscle cells where it is needed | Efx3eLtX1Ia8xzC/fjL6GA== |
I. Glucose is being taken up by the brain | Efx3eLtX1Ia8xzC/fjL6GA== |
J. Large amounts of glycogen are being synthesized by the brain | AD2YBdbb6x3kfgtembjVpQ== |
In a healthy individual, glucose concentrations will spike but then return to normal levels during a glucose tolerance test. In a Type I diabetic, they will spike dramatically, due to a lack of insulin release and remain high. In a Type II diabetic, they will also spike dramatically, but due to a lack of insulin response (reduced sensitivity to insulin) and remain high. Jessie had normal glucose levels throughout the glucose tolerance test except that she was more hypoglycemic than normal at the beginning and the end of the test. Which of the following could explain her test results? (Select ALL that apply!)
A. Jessie is a Type I diabetic | AD2YBdbb6x3kfgtembjVpQ== |
B. Jessie is a Type II diabetic | AD2YBdbb6x3kfgtembjVpQ== |
C. Jessie may have a problem with gluconeogenesis in the liver resulting in lower than normal glucose production during fasting | Efx3eLtX1Ia8xzC/fjL6GA== |
D. Jessie may have a problem with the production of ATP from other sources, i.e., beta-oxidation of fatty acids, which results in increased glucose uptake by tissues from the blood to compensate. | Efx3eLtX1Ia8xzC/fjL6GA== |
E. Jessie may have glucagon levels that are too high when fasting | AD2YBdbb6x3kfgtembjVpQ== |
F. Jessie may have glucagon levels that are too low when fasting | Efx3eLtX1Ia8xzC/fjL6GA== |
Conduct a fasting metabolism study to monitor subject’s FFAs and ketone bodies in response to fasting
Results: A 40-hr fasting study was performed. Refer to the figure below to see how Jessie’s blood FFAs, and acetoacetate and γ-hydroxybutyrate levels changed during the fasting study. (Note that at the beginning of the study, she had just eaten!)
<GRAPH IMAGES>
The physician who oversaw the study noted two things that were abnormal compared to a normal person who participates in the same fasting study:
1. Healthy individuals produce significant levels of ketone bodies by the end of the 36-hour fast whereas Jessie produced barely any.
2. The study was abruptly halted after only 36 hours because Jessie fainted again! Fasting for 36 hours is clearly not safe for Jessie! Depending on what other investigations you have already conducted, it may or may not be clear why Jessie would faint during this study but her glucose levels are something that would be important to investigate if you have not already…
Continue the case
There are multiple possible explanations for how and why beta-oxidation might be blocked. Consider that there could be an inborn error in metabolism (a polymorphism in a gene coding for an enzyme in the pathway), a vitamin deficiency leading to the lack of enzyme action, or a problem with the transport of fatty acids into the mitochondria among other possibilities.
Investigate short-chain (12 carbons or less) fatty acid metabolism: Monitor ketone body formation in the bloo
Results: Interestingly, when Jessie was fed a solution containing short-chain fatty acids and again fasted, plasma acetoacetate and γ-hydroxybutyrate concentrations increased.
Conduct an MRI to determine liver fat levels.
Results: Concentrations of liver fat were found to be 12%. (normal range = 3-5.5%)
These results confirm that fat is indeed being deposited in Jessie’s liver, a health hazard that Jessie was completely unaware of! Jessie’s liver fat concentration supports the hypothesis that fatty acid oxidation is impaired. Jessie is very grateful for your help so far. In a previous investigation you also found evidence that the specific problem is likely to be the inability to transport long-chain fatty acids into the mitochondria, since short-chain acids are processed normally. The exact problem and cause still remain to be determined, so you must continue with your investigations. Consider this question before returning to additional investigations: Which of the following proteins are involved in the transport of long-chain fatty acids into the mitochondria? (Select ALL that apply!)
A. Pyruvate dehydrogenase | AD2YBdbb6x3kfgtembjVpQ== |
B. Carnitine acyltransferase I (CAT I) | Efx3eLtX1Ia8xzC/fjL6GA== |
C. Citrate synthase | AD2YBdbb6x3kfgtembjVpQ== |
D. Carnitine acyltransferase II (CAT II) | Efx3eLtX1Ia8xzC/fjL6GA== |
E. Aldolase | AD2YBdbb6x3kfgtembjVpQ== |
F. Acyl-CoA dehydrogenase | AD2YBdbb6x3kfgtembjVpQ== |
You have uncovered almost all the information necessary to explain Jessie’s health issues, but something still does not add up: specifically, why is she having these problems now and not all of her life? For example, if she has an inborn error of one of the genes encoding for CAT I or CAT II, you would expect that she would have always suffered from bouts of hypoglycemia. You discuss all the results with the physician you are working with and she suggests that you never actually asked Jessie what medication she was taking for the seizures she was having! It may be nothing, but what an oversight! The following new investigation is now available:
Ask again about past medical history including a list of current medications
Results: She reported, “I take an anticonvulsant drug, valproic acid, to control the seizures. Why, what does that have to do with anything?”
Investigate the physiological side effects of valproic acid
You quickly look up the side effects of valproic acid on your smart phone; it can cause nausea and vomiting, anorexia, carnitine deficiency, and abnormal bleeding, in patients on certain diets. You ask Jessie, and she says that she has experienced none of these—as far as she knows…
The investigation into the potential side effects of valproic acid has opened up seven new investigation options! Review your previous results so far in this case and consider whether this new information provides any logical explanation for Jessie’s odd metabolic limitations. What would you like to investigate next? The new options opened are:
Ask Jessie to think hard about whether she has been vomiting recently
Result: Jessie restates that she has not had any bouts of nausea or vomiting recently. She is mildly annoyed by this question.
Ask Jessie to think hard about whether she might have a carnitine deficiency
Result: Jessie responds with a puzzled look and says: “Umm… I don’t think so…but what is carnitine anyway?”. The physician you are shadowing steps in and clarifies that Jessie would not know whether she has a carnitine deficiency or not.
Measure blood levels of carnitine
Result: [Carnitine] = 5 µmol/L (normal range: 24-64 µmol/L)
Jessie has a severe carnitine deficiency! Carnitine is synthesized in humans from the amino acids methionine and lysine, but it is also acquired in the diet. As the name implies, carnitine is especially abundant in meat and dairy products. Because a typical omnivorous diet provides ~75% of a person’s carnitine, carnitine is sometimes considered a vitamin. However, since it can be synthesized de novo means that it is not a true vitamin. Valproic acid depletes carnitine stores in the body by multiple mechanisms but rarely results in true carnitine deficiency in most people. Something to consider: Why is Jessie experiencing carnitine deficiency? Is there any other aspect about her that might make her particularly sensitive to this side-effect of valproic acid?
Measure blood levels of CoA
Result: Levels of Coenzyme A are normal
Measure blood levels of valproic acid
Result: Valproic acid and its metabolites are detected in the blood. Levels are normal and appropriate for the dose that Jessie is taking to control her seizures
Look for abnormal bleeding in the GI tract
Result: You request that Jessie submit to an endoscopy and a colonoscopy. However, the physician you are shadowing disagrees with you - this is not a necessary set of procedures since Jessie does not report any bleeding and does not have any other apparent symptoms that would justify doing these procedures. She also notes that bleeding in the GI tract, even if it is found, does not explain the symptoms that Jessie is exhibiting.
Send Jessie to a councilor to discuss the possibility that she might be anorexic
Result: Jessie is deeply insulted by the insinuation; she has already stated that she eats a high calorie, but vegan, diet and takes your suggestion as an insinuation that she has been lying to you. She restates that she eats regularly and abundantly.
Which of the following metabolic changes will occur in a typical human after a meal balanced in carbohydrates, protein, and fat is consumed? (Select ALL that apply!)
A. Liver glycogen synthesis increases | Efx3eLtX1Ia8xzC/fjL6GA== |
B. Muscle glycogenolysis increases | AD2YBdbb6x3kfgtembjVpQ== |
C. Liver gluconeogenesis decreases | Efx3eLtX1Ia8xzC/fjL6GA== |
D. Insulin levels in the blood decrease | AD2YBdbb6x3kfgtembjVpQ== |
E. Ketone body production in the liver is increased | AD2YBdbb6x3kfgtembjVpQ== |
Which of the following metabolic changes will occur in a typical human during 12 hours of fasting? (Select ALL that apply.)
A. Liver glycogen synthesis decreases | Efx3eLtX1Ia8xzC/fjL6GA== |
B. Liver glycogenolysis decreases | AD2YBdbb6x3kfgtembjVpQ== |
C. Liver gluconeogenesis increases | Efx3eLtX1Ia8xzC/fjL6GA== |
D. Liver fatty acid oxidation increases | Efx3eLtX1Ia8xzC/fjL6GA== |
E. Ketone body formation increases | Efx3eLtX1Ia8xzC/fjL6GA== |
Fatty acids in the bloodstream that are NOT part of TAGs or phospholipids: (Select ALL that apply!)
A. Are present at levels that are independent of epinephrine, glucagon, or insulin levels | AD2YBdbb6x3kfgtembjVpQ== |
B. Are carried by the protein serum albumin | Efx3eLtX1Ia8xzC/fjL6GA== |
C. Are soluble in the aqueous phase of the blood in free form | AD2YBdbb6x3kfgtembjVpQ== |
D. Are nonexistent; the blood only carries ketone bodies | AD2YBdbb6x3kfgtembjVpQ== |
E. Are carried as part of the lipid bilayer of LDLs and chylomicrons | AD2YBdbb6x3kfgtembjVpQ== |
F. Originate primarily from stored TAGs in adipose tissue | Efx3eLtX1Ia8xzC/fjL6GA== |
G. Originate primarily from dietary fats that have just been released into the bloodstream from intestinal endothelial cells | AD2YBdbb6x3kfgtembjVpQ== |
Which of the following statements about ketone bodies is/are true? (Select ALL that are true.)
A. One cause of ketone body formation can be that oxaloacetate is scarce due to its use as a gluconeogenic substrate | Efx3eLtX1Ia8xzC/fjL6GA== |
B. The production of ketone bodies frees up molecules of CoA so that β-oxidation can continue | Efx3eLtX1Ia8xzC/fjL6GA== |
C. Ketone bodies are produced only during vigorous exercise | AD2YBdbb6x3kfgtembjVpQ== |
D. Ketone bodies provide an alternate substrate for glycolysis in the brain | AD2YBdbb6x3kfgtembjVpQ== |
E. Ketone bodies are formed in the brain when β-oxidation is interrupted | AD2YBdbb6x3kfgtembjVpQ== |
Marasmus is the medical term for the condition that results from overall calorie starvation. In developed countries like the U.S., it is relatively uncommon. However, there is a common psychological illness, anorexia nervosa that results in the same symptoms and problems as marasmus. Both conditions result in high ratios of glucagon to insulin. Having a high ratio of glucagon to insulin would do which of the following in most healthy people? (Select ALL that apply!)
A. Promote mobilization of fatty acids from adipose tissue | Efx3eLtX1Ia8xzC/fjL6GA== |
B. Result in increased glycogen storage by the liver | AD2YBdbb6x3kfgtembjVpQ== |
C. Stimulate β-oxidation by inhibiting the production of malonyl-CoA | Efx3eLtX1Ia8xzC/fjL6GA== |
D. Lead to increased concentrations of ketone bodies in the blood | Efx3eLtX1Ia8xzC/fjL6GA== |
What are some of the expected physiological consequences of a carnitine deficiency? (Select ALL that apply!)
A. Depletion of stored fat in adipocytes | Efx3eLtX1Ia8xzC/fjL6GA== |
B. Inability to metabolize short-chain fatty acids | AD2YBdbb6x3kfgtembjVpQ== |
C. High levels of circulating fatty acids | Efx3eLtX1Ia8xzC/fjL6GA== |
D. Chronic hypoglycemia when fasted | Efx3eLtX1Ia8xzC/fjL6GA== |
F. Impaired ability to produce ketone bodies | Efx3eLtX1Ia8xzC/fjL6GA== |
G. Inability to catabolize glucose to pyruvate | AD2YBdbb6x3kfgtembjVpQ== |
Based on all the evidence you have gathered in this case, and your answers to previous questions, what do you think caused Jessie’s fainting episode? (Select ALL the relevant factors that should be included in a complete explanation of her biochemical/medical issues!)
A. Jessie’s medication | Efx3eLtX1Ia8xzC/fjL6GA== |
B. Jessie’s diet in the days leading up to the episode | Efx3eLtX1Ia8xzC/fjL6GA== |
C. Jessie is a Type II diabetic | AD2YBdbb6x3kfgtembjVpQ== |
D. Jessie’s diet the day of the episode | Efx3eLtX1Ia8xzC/fjL6GA== |
E. Jessie has an inborn error of metabolism that affects lipid transport | AD2YBdbb6x3kfgtembjVpQ== |
F. Jessie is a type I diabetic | AD2YBdbb6x3kfgtembjVpQ== |
G. Jessie has chronic hypoglycemia as a result her inability to adequately metabolize most fatty acids | Efx3eLtX1Ia8xzC/fjL6GA== |
H. Jessie lost consciousness due to severe hypoglycemia because the overexertion from her swim further depleted her blood glucose | Efx3eLtX1Ia8xzC/fjL6GA== |
In your personal investigation of the case, you may or may not have discovered that Jessie had decreased levels of total blood protein and elevated levels of ammonia. Considering the metabolic consequences of her carnitine deficiency, why might this be? (Select ALL answers that would be part of a complete explanation!)
A. Ammonia is produced from short-chain fatty acid oxidation and inhibits protein synthesis | AD2YBdbb6x3kfgtembjVpQ== |
B. Because Jessie has reduced glycogen stores and hypoglycemia, her liver must run gluconeogenesis to provide glucose for the brain | Efx3eLtX1Ia8xzC/fjL6GA== |
C. Deamination of amino acids produces ammonia | Efx3eLtX1Ia8xzC/fjL6GA== |
D. Because Jessie cannot produce ketone bodies, her brain must rely solely on blood glucose as its source of energy | Efx3eLtX1Ia8xzC/fjL6GA== |
E. Normally, ketone bodies may be converted into glucose to feed the brain, but Jessie cannot make ketone bodies, so she cannot make glucose from this source and has to degrade proteins in order to do so | AD2YBdbb6x3kfgtembjVpQ== |
F. Under starvation conditions, non-essential proteins are catabolized to release glucogenic amino acids which can be deaminated to provide carbon skeletons that serve as gluconeogenic substrates | Efx3eLtX1Ia8xzC/fjL6GA== |
Congratulations on completing this Case Study! The following Case Summary gives a full explanation of Jessie's condition.
Case Summary
Jessie was suffering from a deficiency of carnitine, caused by a combination of her vegan diet and her long-term use of the anticonvulsant drug valproic acid, which depletes the body’s stores of carnitine. Carnitine is synthesized in the liver and kidney from amino acid precursors, especially lysine. Carnitine deficiencies can also occur in people undergoing regular renal hemodialysis (which increases excretion of carnitine) or in people taking drugs for AIDS or long-term bacterial infections, which can deliver toxic insults to liver or kidneys. Dietary sources of carnitine include meat and dairy products; Jessie, as a vegan, was taking in little carnitine from her diet.
Lack of carnitine caused Jessie’s muscles to lose the ability to use fatty acids as substrates for β-oxidation; without sufficient carnitine, the fatty acids cannot be converted from fatty acyl-CoA to fatty acyl-carnitine, which can enter the mitochondrial matrix, where the enzymes of β-oxidation are located. The result is a decrease in ATP made from oxidative metabolism. The unused fatty acids are stored (in the form of triglycerides) in liver and muscle tissue. Short-chain fatty acids of 12 carbons or less, do not require a carrier to enter the matrix, so such fatty acids can serve as β-oxidation substrates, and ketone bodies can be generated from the acetyl-CoA generated from this catabolic process. However, these fatty acids are relatively rare in the human diet and the majority of fatty acids stored in triglycerides are long-chain fatty acids. The inability to use long-chain fatty acids as fuel leads to higher use of glucose. Secretion of glucagon, as glucose is depleted, causes triacylglycerol stores to be mobilized, leading to an increase in fatty acids in the blood (carried by serum albumin.) With a carnitine deficiency, ketones are not made from the breakdown of fatty acids, so there is no increase in ketones seen during the fasting. In normal patients, ketones increase as glucose levels drop and fatty acids become the primary fuel for muscle. Finally, without the ATP generated from β-oxidation, there may be a lack of energy to generate glucose through the process of liver gluconeogenesis.
That fateful day, Jessie had also skipped breakfast and lunch, and so she was particularly hypoglycemic, and glycogen-depleted, before she started her heroic swim. The strenuous swim triggered glucose uptake by her muscles. The glucose used by her muscles could not be supplemented or replaced by stored glycogen, fatty acid metabolism, or ketone body formation, and therefore her blood glucose dropped to levels that cause loss of consciousness.
Finally, there are also genetic conditions that can lead to carnitine deficiencies. Examples are the lack of a functional enzyme in the carnitine biosynthesis pathway, defective transport proteins to allow entry of carnitine into the heart and muscle cells, and defective reabsorption of carnitine at the renal tubule. However, until her head injury and pharmacological intervention via valproic acid to prevent seizures, Jessie showed no symptoms, and was in fact a high-end athlete, making genetic conditions less likely as the basis for her carnitine deficiency.