Carb metabolism

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Glycogen Degradation Metabolic Branch

Liver contains glucose 6- phosphatase Converts Glucose-6-Phosphate into free glucose Glucose 6-phosphatase is required to release free glucose from the cell

Insulin and Counter-regulatory Hormones

Liver involved with Fed state activities (A) Liver in B -> Fasted state activities

GLUT 2

Liver, kidney, panc B-cell, serosal surface of intestinal mucosa cells High-capacity, low affinity trasnporter Maybe used as the glucose sensor in pancreas

Glycolysis

Location: cytosol ➔Every cell type can perform glycolysis Especially important source of ATP for cells without mitochondria Generates NADH •Transferred across the inner mitochondrial membrane via "shuttles"

Vi/Vmax vs glucose conc for Gk vs HK

(Hepatic and pancreatic isoform): GK (lower Vi/vmax)

•Experimental studies

-Involves the investigator trying to control nature/people -can determine causality

Glycogen Degradation and Synthesis are highly and reciprocally regulated.

(S1) Glucose 6-phosphate (glucose 6-P) is formed from glucose by hexokinase in most cells, and glucokinase in the liver. It is a metabolic branch point for the pathways of glycolysis, the pentose phosphate pathway, and glycogen synthesis. (S2) Uridine diphosphate (UDP)-glucose (UDP-G) is synthesized from glucose 1-phosphate (glucose 1-P). UDP-glucose is the branch point for glycogen synthesis and other pathways that require the addition of carbohydrate units. (S3) Glycogen synthesis is catalyzed by glycogen synthase and the branching enzyme. (D1) Glycogen degradation is catalyzed by glycogen phosphorylase and a debrancher enzyme. (D2) Glucose 6-phosphatase in the liver (and, to a small extent, the kidney) generates free glucose from glucose 6-P. ATP, adenosine triphosphate; Pi, inorganic phosphate; PPi, pyrophosphate; UTP, uridine triphosphate. During Glycogen Synthesis, Insulin activates glycogen synthase a and inactivates glycogen phosphorylase a.

Getting to Pyruvate for Gluconeogenesis

*Of the 20 essential AAs, only Leucine and Lysine are unable to provide the carbon for net glucose synthesis* *Cysteine, Glycine, Serine, Threonine, and Tryptophan can also serve as carbon source for the synthesis of glucose because they also form pyruvate*

Nutrition Research Designs- •Observational studies

-Involves the investigator observing nature/people -can only define associations

•How was diet assessed? •Did the study look at real disease endpoints (e.g., myocardial infarction, hip fractures, etc)?

-Some methods of dietary assessment are better than others •A 24-hour recall is very limited, but cheaper and quicker •A Food Frequency Questionnaire (FFQ), while thorough, is often very time- consuming for respondents and burdensome •Food duplicates are costly and also burdensome for participants -Good studies will describe their tools (e.g., survey instruments) -Researchers should use instruments with strong validity for the population being studied

Gastrointestinal-Derived Hormones Directly Affecting Fuel Metabolism

A variety of peptides synthesized in the endocrine cells of the pancreatic islets, the cells of the enteric nervous system, the endocrine cells of the stomach, small bowel, and large bowel, and certain cells of the central and peripheral nervous system, influence fuel metabolism directly.

•Descriptive studies

-case reports, case series, or descriptive cohorts -document observations and experience -can establish incidence (the number of new cases of a condition developing per year) -can establish prevalence (the number of cases of a condition present in a population at any given point in time)

Describe the key steps/enzymes for gluconeogenesis.

1) Pyruvate➔Oxaloacetate (OAA) via Pyruvate carboxylase - occurs in the mitochondria, requires Biotin as a cofactor for the carboxylation reaction (biotin carries the bicarbonate) 2) OAA➔Phosphoenolpyruvate (PEP) via PEP carboxykinase (PEPCK) - cytosolic and mitochondria, requires magnesium and GTP ▪ These first two steps (which are together generally considered the first "glycolysis bypass" step in gluconeogenesis), overcome the pyruvate kinase reaction from glycolysis 3) Fructose 1,6-bisphosphate➔Fructose 6-phosphate via Fructose 1,6-bisphosphatase - cytosol ▪ This overcomes the PFK-1 reaction in glycolysis. 4) Glucose 6 phosphate➔Glucose via Glucose 6-phosphatase - cytosol ▪ This overcomes the glucokinase (liver) reaction of glycolysis.

Bypassing Pyruvate Kinase

1.Alanine and Lactate are converted into Pyruvate ▪Pyruvate to OAA and OAA to malate ▪Pyruvate from cytosol transported across the inner mitochondrial membrane by the pyruvate transporter 2.Pyruvate converted to OAA via Pyruvate Carboxylase a. OAA converted to malate/aspartate then transported across inner mitochondrial membrane via shuttle 3.Once back in cytosol, malate converted back to OAA 4.OAA converted to PEP via PEP Carboxykinase

Glycogen Synthesis Summary

1.Glucose is first phosphorylated by hexokinases (e.g. muscle) or glucokinase (liver) to glucose-6-phosphate (G6P) 2.G6P is then converted to glucose-1- phosphate (G1P) 3.G1P is then activated for glycogen synthesis via the addition of uridine nucleotide ➔ UDP-glucose 4.UDP-glucose can be used as a substrate for the self-glucosylating reaction of glycogenin, or if pre-existing glycogen polymers exist, the UDP-glucose is utilized as the substrate for glycogen synthase

Anaerobic glycolysis

1.Pyruvate is reduced to lactate in the cytosol by lactate hydrogenase 2.NADH is oxidized to NAD+ in the rxn 2.Lactate's fate is tissue-dependent Some tissues depend on anaerobic glycolysis for at least a portion of their energy needs: RBCs, WBCs, Kidney Medulla, Eye, Skeletal Muscle

Where is FADH2 produced?

3.Succinate DH

What is an Institutional Review Board?

A group of experts and lay-persons (typically at an institution like a university or hospital) that is responsible for the protection of human research subjects. All research involving human subjects needs to be evaluated by the IRB in some capacity. Not all studies will require a full-board IRB review - some will be deemed as "exempt" or "expedited". Informed Consent is also often (but not always) part of human subjects research. Informed Consent is how the researcher explains the purpose of the research, the risks/benefits, time commitment required, and that participating in research is always voluntary and research participants can stop being in a study at any time. Any research involving humans is best approached with a "ask permission first" mentality. At PNWU, our Office of Scholarly Activity (OSA) can help anyone interested in getting going on research regardless if it is involving humans or not.

The Cori Cycle (aka Lactic acid cycle)

A way to handle lactate build-up ➔ Recycling of lactic acid 1.Important during exercise •Results in production of glucose in the liver, from lactate produced in the muscle->GNG->glucose and ATP in liver and glucose goes into blood and to RBCs where it undergoes glycolysis and produces 2 lactate that can be removed from rbcs and moved into liver and repeat process 2.Removal of lactate produced from RBCs •fed or fasted •esp. important during starvation

A study is performed involving a group of 500 free-living people followed over 10 years. The purpose of the study is to examine the relationship between diet and cancer. The people return for data collection annually where they complete surveys and other measurements. The authors report that inclusion of certain foods in the diet is associated with a decreased risk for subsequent development of cancer. Which one of the following study designs is this study most likely to be? A cohort study A cell culture study A literature review study A double-blind, placebo-controlled study A meta-analysis study

A. Cohort studies are most likely to report conclusions as "associations".

Using calipers to measure subcutaneous fat tissue around several areas of the body is called: Skin fold thickness Densitometry Assessment Uncomfortable The most accurate anthropometric method

A. Skin fold thickness

Generation of phosphoenolpyruvate (PEP) from gluconeogenic precursors

A.Conversion of oxaloacetate to PEP, using PEP carboxykinase B.Interconversion of oxaloacetate and malate C.Transamination of aspartate to form oxaloacetate. Note that the cytosolic reaction is the reverse of the mitochondrial reaction as shown in Figure 28.5.

Glucose 6-phosphatase (von Gierke disease) Explain the mechanisms involved in the glycogen storage diseases including the defective enzyme and the signs/symptoms of the disorder, and the treatment involved.

ABCD: Anderson branching cori debranching TYPE: I Enzyme affected: Glucose 6-phosphatase (von Gierke disease) Primary organ involved: Liver Manifestations and Tx: Enlarged liver and kidney, growth failure, severe fasting hypoglycemia, acidosis, lipemia, thrombocyte dysfunctionTx: Special diet to maintain glucose levels, prevent hypoglycemia and maximize growth and development Increased dependence on fat metabolism Small frequent meals high in carbohydrates throughout life, nighttime enteral feedings

Galactosemia autosomal recessive disease

AR ▪Defect in galactose 1-P uridylyltransferase is more common ▪Results in very high blood concentration of galactose ▪Cells accumulate toxic levels of Gal-1-P and metabolites

Comparing Muscle and Liver response to Epinephrine/Glucagon

Activation of GTP-binding protein to epinephrine ➔ increases cAMP production ➔Activates Protein Kinase A (PKA) Sets off cascade of phosphorylations ➔PKA activates phosphorylase B kinase ➔Phosphorylase B kinase activates glycogen phosphorylase a and b This strongly AMPLIFIES the initial signal Provides muscle with energy for ATP Provides liver with glucose to be released systemically and counters low blood sugar

Activation of Muscle Glycogen Degradation During Exercise

Activation of GTP-binding protein to epinephrine ➔ increases cAMP production (ATP hydrolysis) ➔Activates Protein Kinase A (PKA) Sets off cascade of phosphorylations ➔PKA activates phosphorylase B kinase ➔Phosphorylase B kinase activates glycogen phosphorylase a and b; phosphorylase a (turned on) Sarcoplasmic reticulum Ca2+ nerve impulse binds to calmodulin- Muscle contraction ATP myosin ATPase to ADP and being converted to AMP (adenylate kinase) goes to glycogen phosphorylase b

Dephos PFK-2

Active whereas FBP2: inactive, favors formation of F2,6-bisphosphate which is a bifunctional enzyme PFK-2(active) and FBP-2 (inactive)

GLUT 4

Adipose tissue, skeletal muscle, heart muscle, Insulin-sensitive transporter, In presence of insulin, number of GLUT4 transporters increases on cell surface, high affinity system

Compare and contrast the roles of Hexokinase vs. Glucokinase in their respective tissues, including their differences in Km and binding affinity. Why are these differences important?

Advantage of hexokinase having a high affinity (low Km) for glucose? Efficient phosphorylation and metabolism of glucose even when skeletal muscle tissue concentrations of glucose are low Advantage of glucokinase having a low affinity (high Km) for glucose? Functions only when intracellular concentration of glucose in liver cells is elevated, after a meal. This results in liver using glucose for hepatic energy needs only when adequate glucose is present (in other times when glucose is not abundant, liver relies on fatty acid oxidation for energy). This also minimizes hyperglycemia during the post-absorptive phase.

Aerobic vs. Anaerobic Glycolysis

Aerobic Glycolysis: 1.Pyruvate enters the Mitochondria and is oxidized to CO2 and H20 2.Shuttles are used to get cytosolic NADH across the Inner Mitochondrial Membrane 2.Pyruvate oxidized to acetyl CoA 2.Acetyl CoA enters TCA cycle

Hereditary Fructose Intolerance

Aldolase B is defective or absent Fructose-1-Phosphate accumulates and doesnt form enough glyceraldehyde Tx: Avoid all fructose and sucrose in the diet As the rate-limiting step of glycolysis is bypassed, if fructose ingestion becomes too high it can result in an unregulated accumulation of glycolytic intermediates. e.g., fructose-1-phosphate may accumulate, which will deplete the liver stores of phosphate and thus limit ATP production. Glyceraldehyde converted to G3P using ATP hydrolysis and triose kinase DHAP and G3P are isomers of each other Glucose HK Glucose 6P can be converted to G1P in a side rxn; G1P converted to glycogen Fructose 6P Fructose-1,6, BP DHAP and G3P (converted to this using aldolase B (liver) and aldolase A(muscle)) G3P pyruvate FA's or TCA or lactate Fructose (FK (using ATP hydrolysis)) Fructose 1P As the rate-limiting step of glycolysis is bypassed, if fructose ingestion becomes too high it can result in an unregulated accumulation of glycolytic intermediates. e.g., fructose-1-phosphate may accumulate, which will deplete the liver stores of phosphate and thus limit ATP production. Glyceraldehyde and DHAP (converted to this using aldolase B in liver) Glyceraldehyde to G3P using ATP hydrolysis and triose kinase

Fates of pyruvate

Amino acids, acetyl coA or lactate

Amylin

Amylin PRIMARY CELL/TISSUE OF ORIGIN Pancreatic β-cell, endocrine cells of stomach and small intestine ACTIONS 1.Suppresses postprandial glucagon secretion (enhancing the effect of insulin), 2.Slows gastric emptying (thereby blunting a large increase in blood nutrient levels immediately after a meal), and 3.Reduces appetite SECRETORY STIMULI Co-secreted with insulin in response to oral nutrients

Different glycogen cascade

And another way to look at it: 1-Glucagon binding to the glucagon receptor or epinephrine binding to a β- receptor in the liver activates adenylate cyclase, via G-proteins, which synthesizes cAMP from ATP. 2-cAMP binds to protein kinase A (PKA; cAMP-dependent protein kinase), thereby activating the catalytic subunits. 3-PKA activates phosphorylase kinase by phosphorylation. 4-Phosphorylase kinase adds a phosphate to specific serine residues on glycogen phosphorylase b, thereby converting it to the active glycogen phosphorylase a. 5-PKA also phosphorylates glycogen synthase, thereby decreasing its activity. 6-As a result of the inhibition of glycogen synthase and the activation of glycogen phosphorylase, glycogen is degraded to glucose 1-phosphate. The red dashed lines denote reactions that are decreased in the livers of fasting individuals. ADP, adenosine; ; GTP, guanosine triphosphate; Pi, inorganic phosphate; UDP, uridine diphosphate.

Ingested glucose

As concentration of blood glucose approaches the normal fasting range of 80 to 100 mg/dL roughly 2 hours after a meal, glycogenolysis is activated in liver. Liver glycogen is the primary source of blood glucose during the first few hours of fasting.

Regulation of Pyruvate Kinase in Liver

At least 3 isoforms in humans The liver, but not muscle isoform, is regulated via phosphorylation

A common function of Thiamin, Riboflavin and Niacin is that they They all are used in synthesis of blood clotting proteins They all work as a part of a coenzyme used in energy metabolism They all help to strengthen blood vessel walls They are used to stabilize cell membranes They are readily stored in the body

B. All act as co-enzymes/co-factors in energy metabolism

Folate works together with ______________ to produce new red blood cells. Vitamin A Cobalamin Tetrahydrofolate Retinol Niacin

B. Cobalamin, aka, vitamin B12

What is the name of the process used to identify an individual who is malnourished or who is at risk for malnutrition, or to determine if more intervention is warranted? Nutrient review Nutrition screening Rapid evaluation Total assessment Full workup

B. Nutrition Screening Nutrition screening identifies characteristics known to be associated with nutritional problems. Nutrition assessment is a more in depth process that takes into account a patient's anthropometric data, biochemical methods, clinical methods, and dietary methods. Nutrition assessment will provide a much more in depth look at a patient's nutrition status and is performed by the registered dietitian nutritionist.

A 41-year-old man has had increasing dyspnea for the past year. On physical examination his temperature is 37°C, pulse 106/min, respiratory rate 20/min, and blood pressure 100/65 mm Hg. He has diffuse crackles at lung bases. A chest x-ray shows pulmonary edema and cardiomegaly. Echocardiography shows an ejection fraction of 40%. Laboratory studies show hemoglobin 14 g/dL, hematocrit 42%, and WBC count 8320/microliter. A deficiency in which of the following vitamins is most likely to produce these findings? Vitamin A Thiamin Riboflavin Vitamin K Vitamin B12

B. Thiamin deficiency can cause beri beri, which is responsible for these symptoms. Wet Beri Beri is assoc. with CHF.

A 49-yr old male is being treated for a urinary tract infection (UTI) and had a one-time brief episode of hemolysis and jaundice. He has been on antibiotics for the UTI. His peripheral blood smear revealed a normocytic anemia with Heinz bodies (Fig. 1) seen in erythrocytes. Which of the following genetic deficiencies is most likely related to his hemolytic episode? branching enzyme glucose 6 phosphate dehydrogenase glycogen phosphorylase lysosomal α-1,4 glucosidase pyruvate kinase

B. This is a case of G6PD.

On the BMI scale, what range considers an adult to be overweight? 15-18 19-24 25-29 30-35 36 and above

BMI 25-29 is considered "overweight".

Describe the major types (including their pros and cons) of nutrition assessment methods Anthropometrics:

BMI, Weight, Height, Waist Circumference

Prescribe a "healthy diet" and lifestyle for disease prevention based on the current peer-reviewed evidence. Give an example of how you would write a prescription for a "healthy diet". Is it specific enough? Is it overly general?

Being specific is important for the patient to have a clear understanding, so a healthy diet prescription should look something like this: eat 5 servings of non-starchy vegetables daily, or eat breakfast daily, or limit your tortilla intake to just two, 6-inch tortillas per meal, 3 times per day, rather than six AND Here is a handout explaining portion sizes, or Here is a list of non-starchy vegetables and the portion sizes for those, or I'm referring you to a registered dietitian nutritionist to get some more comprehensive education on what/how you should be eating

GLUT 3

Brains(neurons) Major trasnporter ub CBSm high affinity system

A 42 year old male thrill-seeker was dropped off in a remote mountainous location 5 days ago. His food supply ran out after his last meal 20 hours ago. His most likely source of blood glucose is a result of which of the following? Increasedactivityinerythrocytepyruvate dehydrogenase Increasedactivityinglucose6phosphatase Increasedactivityinglucose6phosphate dehydrogenase Increasedactivityinglucokinase Increased activity in muscle glycogen phosphorylase

By 5 days, he would be relying mostly on gluconeogenesis and ketone production. Of the choices listed, the most logical option is B, as this is needed to release glucose from gluconeogenesis (or glycogen degradation).

Describe nutrition risk and how level of nutrition risk is determined.

By a comprehensive assessment of many of the factors listed above, clinical judgement of the registered dietitian nutritionist, patient medical history and current circumstances (how are they eating? Is the appetite WNL? Have they experienced recent unintentional weight loss? Do they have a diagnosis that will impair their ability to obtain adequate/optimal nutrition - e.g., throat/GI cancer, GI surgery, malabsorption, premature infants who cannot breastfeed, new onset diabetes, chronic kidney disease, liver failure, intractable nausea/vomiting, etc).

Eating the liver of which animal can cause short-term (acute) vitamin A toxicity, and even death? A. Mule deer B. BuffaloC. Polar bear D. Pig E. Swordfish

C. There are documented cases of vitamin A toxicity due to ingestion of polar bear liver

Which is the leading cause of blindness in children worldwide? A. Protein malnutritionB. Glycogen storage diseaseC. Vitamin A deficiencyD. Vitamin B12 deficiencyE. Pyruvate dehydrogenase complex deficiency

C. Vitamin A deficiency is the leading cause of blindness in children

Digestion of Carbohydrates

Carbohydrates are primarily found in plant foods ▪Salivary and pancreatic amylases Disaccharides ➔ monosaccharides at brush border ▪Glucose taken up by intestinal epithelium cells ▪Fermentation of fiber, etc, via gut bacteria

Describe and define the major categories of common nutrition research designs, including their pros and cons: Laboratory, Case-control, Cohort, and Randomized Controlled Trial. What are the primary features/characteristics of each type of study design listed above? List the pros and cons of each:

Case-control: Looks at characteristics of a group of people who already have a certain health outcome (cases) and compares them to a similar group of people who do not have the outcome (controls) PROS: Can be done quickly; Compared to large RCTs, case-control studies are relatively inexpensiveCONS: Typically gathers information from the past; People with illnesses often recall past behaviors differently from those without illness Cohort: Follows a group of people over a long period of time (but not always, can also be cross- sectional); Can be very large, epidemiological (involving thousands of people) in nature OR smaller, community-based studies (involving tens or hundreds of people); Characteristics of people in the group are compared to test specific hypotheses; Researchers regularly gather information from the people in the study on a wide variety of variables (like meat intake, physical activity level, and weight). Once a specified amount of time has elapsed, the characteristics of people in the group are compared to test specific hypotheses (like the link between carotenoids and glaucoma, or meat intake and prostate cancer). Examples of famous cohort studies include: e.g., Nurses Health Studies, the Health Professionals Follow-up Study; Page 1 of 5 The Bogalusa Heart Study; the Lyon Heart Study; the Framingham Heart Study, The Adventist Health Study; and many others. The NHANES studies is another famous and frequently referenced cohort study that many nutrition (and all types of) researchers use and publish analyses from. PROS of Cohort Studies: good way to compare groups; test intervention methods (e.g., an educational or behavioral intervention); don't rely on recall or retrospective analysis as much as case-control.CONS of Cohort Studies: Can be costly; Time-consuming; labor intensive

Gluconeogenesis vs. Glycolysis in Liver

Cellular locations Tissue locations Hormonal Regulators Tissues most reliant on pathway Key Regulatory Enzymes Substrates of key enzymes

3 insoluble fibers and their classes of compounds and dietary sources

Cellulose: Polysaccharide composed of glucosyl residues linked β-1,4 Whole-wheat flour, unprocessed bran, vegetables Hemicelluloses Polymers of arabinoxylans or galactomannans Bran cereals, whole grains, Lignin: Noncarbohydrate, polymeric derivatives of phenylpropane Fruits and edible seeds, mature vegetables

What activates PFK-1? What dephosphorylates it?

Elev levels of Fructose 2,6-bisphosphate activates PFK-1, inc rate of glycolysis; lower PKA will dephos PFK-2 which

Coordinating Glycogen Synthesis and Degradation

Coordinated Regulation of Glycogen Synthesis and Degradation in fasted state by Glycogen Phosphorylase and Synthase ➔Activates Protein Kinase A (PKA) Sets off cascade of phosphorylations ➔PKA activates phosphorylase B kinase ➔Phosphorylase B kinase activates glycogen phosphorylase a and b; phosphorylase a (turned on) PKA to glycogen synthase a to glycogen synthase b (turned off)

Glycogen Homeostasis-glycogen synthesis (another term)

Coordinated regulation of the rate of glycogen synthesis (glycogenesis)

45 yr old male found unconscious by family member. EMS suspects pt has had a major MI. The primary source of cellular energy for cardiac tissue at this point would be: A. Fatty acid oxidation B. GluconeogenesisC. GlycolysisD. Ketone oxidation E. Krebscycle

Correct answer is C. Anaerobic energy needs would be met via glycolysis in this situation

Glycogenolysis

Cytosolic •Involves the actions of glycogen phosphorylase and the glycogen debranching enzyme •Primary pathway used for glycogen degradation in liver and muscle Lysosomal •Degradation is catalyzed by the enzyme lysosomal acid α- glucosidase (also called acid maltase) •Represents just 5% of total muscle glycogen degradation, and 10% of total liver glycogen degradation *Important to know for Glycogen Storage Disease pathology*

A 32 year old female with elevated levels of glucose, insulin, and increased activity in glucokinase and pyruvate dehyrogenase complex enzymes would be best described as which of the following? being at least 3 hours from her last meal Fasted for 24 hours likely suffering from a glycogen storage disease recently consumed a carbohydrate-rich meal recovering from a bout of exercise

D is the correct answer.Just think through this scenario.Elevated Glucose and Insulin point to fed state.Increased activity in Glucokinase and Pyruvate Dehydrogenase Complex point to fed state.All these would be reduced 3 hours after a meal (unless it was very high in fat, and I would need to tell you that!)For sure not fastedThere are no glycogen storage diseases that fit this description.If recovering from exercise, glucose would be low, not high.

An anthropometric assessment method that relies on dunking in a water tank or measuring gas exchange by having a person sit inside an enclosed device is called: Skin fold thickness DEXA Subjective Global Assessment Densitometry Indirect calorimetry

D. Densitometry Skin fold thickness uses calipers to pinch the skinDEXA uses imaging devices (dual energy x-ray absorptiometric scan)SGA uses multiple variables, but none as describedIndirect Calorimetry uses gas exchange, but not the whole-person-sitting-in- something method. Typically done on ventilated patients in the ICU, or on outpatients at exercise physiology labs, or less commonly, gyms.

We did not discuss this particular condition, but FYI for future board prep A 9 year old Amish boy is evaluated by a hematologist after his pediatrician found the boy to be anemic with splenomegaly and jaundice. Vital signs are WNL. Growth is WNL. Patient's mom reports a history of a "blood disorder" in the family, but doesn't know anything more specific. Blood smear reveals hemolysis, but no other remarkable findings. What is the most likely diagnosis? A glycogen storage disease GLUT4 transporter deficiency Heavy metal poisoning Pyruvate kinase deficiency Type 1 diabetes

D. Normochromic, normocytic, or macrocytic anemia, together with reticulocytosis in the absence of blood loss, is suggestive of hemolysis.Jaundice due to the deficient liver pyruvate kinase (LPK), an isoenzyme that is usually deficient whenever the red cell pyruvate kinase is deficient because of the common origin of both enzymes (the PKLR gene).

Outline the steps and key enzymes involved in the degradation of glycogen.

Degradation occurs during fasting in cell cytosol or lysosomes. These vary in terms of the enzymes involved in the glycogen degradation. Also see the info on the glycogen cascade.

Descriptive studies - case reports, case series, or descriptive cohorts - document observations and experience - can establish incidence (the number of new cases of a condition developing per year) - can establish prevalence (the number of cases of a condition present in a population at any given point in time) Laboratory: research done with cells, tissue, or animals. Cell-culture is a common example. PROS: Offers controlled conditions; useful for new investigations or novel topics/processes not well-understoodCONS: Requires training, equipment, and facilities, can be costly

•Watch this 4 min Video -If the above hyperlink does not work, here is the URL: •http://www.myhealthywaist.org/evaluating-cmr/clinical-tools/waist- circumference-measurement-guidelines/index.html Click on "measurement by a healthcare professional" to view the video

Disease Risk for type 2 diabetes, hypertension, and CVD Relative to Normal Weight and Waist Circumference, Extreme obesity/class

Glycogen synthesis

During Glycogen Synthesis, Insulin activates glycogen synthase a and inactivates glycogen phosphorylase a. increased compared with other physiologic states and decreased compared with other physiologic states

The synthesis of glucose from pyruvate by gluconeogenesis: occurs exclusively in the cytosol is inhibited by high levels of glucagon requires oxidation/reduction of FAD increases in muscle by PFK uses lactate and glycerol as substrates

Which of the following is a function of Vitamin B-12? Acts as a transporter of CO2 Helps maintain acid-base balance Influences the cells that build bone tissue Is essential to the formation of bone Maintains the sheaths that surround and protect nerve fibers

E. B12 is involved in nerve conduction

The PDH complex requires multiple co- factors for maximal efficiency. In the case of a patient with alcohol use disorder, the most likely co-factor with reduced function is which of the following? A. Coenzyme A (CoA) B. FADC. NADD. Lipoic acid E. Thiaminpyrophosphate(TPP)

E. Thiamin is essential for PDH complex, and often not adequately consumed in persons with EtOH use disorder.

4. Describe how blood glucose levels are maintained under a variety of conditions FASTED state

FASTED - glucagon is released in the fasted state to keep blood glucose levels within normal range, despite no active food intake. Glucagon stimulates glycogen degradation in the liver, via the glycogen cascade, which releases blood glucose via glucose-6-phosphatase. When glycogen stores have been depleted (usually with 12-24 hours), the liver begins ramping up gluconeogenesis. Simultaneously, you will learn that fats are also released from stores in adipose tissue. Fatty acids are released for beta-oxidation by the liver (yielding a lot of acetyl CoA). Glycerol is fed into gluconeogenesis. Because there is an abundance of acetyl CoA and glycerol, and acetyl CoA is an allosteric activator, Pyruvate Carboxylase is stimulated even further.

4. Describe how blood glucose levels are maintained under a variety of conditions FED state

FED - insulin is released in response to rising blood glucose levels; GLUT-4 and insulin are needed to facilitate transport of glucose into the peripheral tissues (muscle, adipose). GLUT 2 is used to transport glucose into the Hepatocyte, but unlike GLUT4, GLUT2 is independent of insulin. In addition to insulin, the incretins, GIP and GLP1, are secreted by the small intestine, and stimulate glucose-dependent insulin secretion. Incretin secretion begins when food is consumed. GIP increases insulin release via an "incretin" effect and GLP1 helps potentiate the effects of insulin. Both also help reduce or blunt the post-prandial (after meal) blood glucose rise via tamping down glucagon release as blood glucose begins to fall. As food is more fully digested and absorbed, generally within about 2 hours, blood glucose levels begin to fall back to pre-meal range and we move back into the post-prandial or "fasted" state.

Fates of G6P from Glu 1 P and Galac 1 P (Gal 1 P UT)

Forms glucose in liver and undergoes glycolysis in other tissues after forming G3P and resulting in pyruvate that can enter Krebs

Describe where (e.g., tissues, cells) synthesis and degradation of glycogen occurs.

Found in most cell types, but the bulk of our glycogen stores are located mostly in liver (10% of liver weight) and skeletal muscle (1-2% of weight) tissue, much lesser degree in kidney and intestine. Because the total mass of muscle is so much greater than that of liver, total-body glycogen stored in muscle is about twice that of liver. Synthesis and degradation occur wherever glycogen is found, so most of these activities occur in liver and muscle tissues (which is why the GSDs most often impact these tissues). As for cellular location, also see prior question to recall the cytosolic vs. lysosomal glycogen degradation processes (which is why Pompe's disease affects lysosomes).

Converting Fructose 1,6- bisphosphate to Fructose-6- Phosphate

Fructose 1,6-bisphosphatase overcomes the PFK1 reaction of glycolysis 1.Inhibited by high levels of AMP (signaling there not enough energy to perform the rxn) 2.Stimulated by high ATP and low AMP 3.Inhibited by Fructose 2,6- bisphosphate 4.Induced (increased gene transcription of the protein) during fasting

GLUT 5

Fructose transporter Intestinal epithelium Spermatozoa

What are the key steps in fructose metabolism? What causes hereditary fructose intolerance and how is it treated?

Fructose➔phosphorylated by fructokinase to fructose-1-phosphate, which is further metabolized to glyceraldehyde-3-phosphate via aldolase B to enter glycolysis

What form of glucose enters glycolysis

G3P

Glycogen breakdown gives

G6P

What is the typical presentation and treatment of glucose-6-phosphate dehydrogenase deficiency?

G6PD results in an inability to recycle glutathione via lack of NADPH It most often occurs among persons of Middle Eastern, African and Asian ancestry, and parts of the Mediterranean. It is one of the most common disease-producing enzyme deficiencies in humans. The G6PD results in chronic hemolytic anemia, but also provides increased resistance to malaria Precipitating factors: Oxidant drugs - antipyretics (aspirin), anti-malarials, anti- inflammatories (NSAIDS). The digestion and metabolism of fava beans can also increase the chance of a G6PD flare-up.

Prescribe a "healthy diet" and lifestyle for disease prevention based on the current peer-reviewed evidence. What about if you are given an example patient, e.g., a retired school teacher, 68 yr old male, mostly sedentary, with knee osteoarthritis, BMI 34 kg/m2. Waist circumference 44". What risk would this patient be at based on the NHLBI Waist Circumference and BMI risk chart? What if his BMI was just 26 and his waist circumference was 39?

It would categorize him as Very High Risk for type 2 diabetes, HTN, and CVD. It would categorize him at Increased Risk for type 2 diabetes, HTN, and CVD.

Incretin effect - what is it?

GIP (glucose-dependent insulinotropic peptide) and GLP-1 (glucagon-like peptide-1) are secreted after food ingestion, and they then stimulate glucose-dependent insulin secretion. Once released, GIP and GLP-1 are subject to degradation by DPP4 on lymphocytes and on endothelial cells of blood vessels. The red cells in the islets are insulin-containing (β) cells and the green cells are glucagon-containing (α) cells. •Both GIP and GLP-1 are rapidly deactivated by an enzyme called dipeptidyl peptidase 4 (DPP4) •The incretin effect accounts for at least 50% of the total insulin secreted after oral glucose

How many isoforms do glucose transport proteins have?

GLUT 1-5 isoforms (transporters)

GLUT 4 transporters

GLUT4 transporters, which are insulin-dependent, are also involved in muscle and adipose tissue uptake of glucose.

Metabolism of galactose (liver)

Galactose to Galactose 1 phos: Galactokinase (1) enzyme and ATP hydrolysis Gal 1 P uridyl transferase (2) Glu 1 P ->mutase-> Glu-6-phos-> glycolysis UDP galactose epimerase (3) converts from udp galactose to udp glucose UDP galactose uses glucose+udp(needs udp from glucose) and lactose synthetase to make lactose UDP glucose to glycogen from udp galactose using UDP galactose epimerase

Describe how galactose is metabolized. What is the key enzyme involved in the form discussed in class and what happens if that enzyme is not working properly? Where would an infant get galactose in his/her diet? How is this condition treated?

Galactosemia autosomal recessive disease, results in inability to convert galactose to glucose. Defect in galactose 1-P uridylyltransferase is more common. Results in very high blood concentration of galactose; cells accumulate toxic levels of Gal-1-P and metabolites➔liver failure, renal failure, cataracts, and brain damage Without treatment,75% mortality in infants Galactosemia requires lifelong avoidance of lactose/galactose, so no milk, including breastmilk.

Regulation of Liver and Muscle Glycogen stores

Glucagon in liver in high levels Muscle cells not getting enough glucose for transport and glycogen synthesis is lower in muscles

Insulin and Counter-regulatory Hormones: Glucagon

Glucagon metabolism

Compare and contrast glycolysis with gluconeogenesis including cellular locations, key enzymes involved and under what conditions each cycle would active/inactive.\ Gluconeogenic enzymes Pyruvate Carboxylase Phosphoenolpyruvate Carboxykinase (PEPCK) Fructose 1,6- bisphosphatase Glucose 6 Phosphatase

Gluconeogenic Enzymes Induced by - effecting the gene(s) responsible for making the enzymes involved in the pathway Activated or Inhibited by Pyruvate Carboxylase Induced by - effecting the gene(s) responsible for making the enzymes involved in the pathway: Glucagon, Epinephrine, and Glucocorticoids Activated or Inhibited by: Activated by acetyl CoA (acetyl CoA alters the conformation of the Pyruvate Carboxylase protein lowering the Km and increasing the affinity for pyruvate). It also allosterically activates PC and inactivates Pyruvate Kinase. *Acetyl CoA in the fasting state is generated from fatty acid oxidation Phosphoenolpyruvate Carboxykinase (PEPCK) Induced by - effecting the gene(s) responsible for making the enzymes involved in the pathway: Glucagon, Epinephrine, and Glucocorticoids, also induced via the cAMP-response element binding protein (CREB), which we did not discuss Activated or Inhibited by: Inhibited by insulin Fructose 1,6- bisphosphatase Induced by - effecting the gene(s) responsible for making the enzymes involved in the pathway: Glucagon, Epinephrine, and Glucocorticoids, Fasting also induces this enzyme Activated or Inhibited by: The ABSENCE of Fructose 2,6-bisphosphate stimulates (or activates) Fructose 1,6- bisphosphatase (recall that Fructose 2,6-bisphosphate comes from the PFK-2/FBP bifunctional enzyme reaction) Glucose 6 Phosphatase Induced by - effecting the gene(s) responsible for making the enzymes involved in the pathway: Glucagon, Epinephrine, and Glucocorticoids, Fasting also induces this enzyme

Glycogen Synthesis de novo starts with (Stage 1)

Glucose 1 Phosphate -> UDP-glucose •Glycogen is both formed from and degraded to glucose 1-P •Biosynthetic and degradative pathways are separate and involve different enzymes •Starting point is Glucose-6-phosphate (from free glucose via Hexokinase/Glucokinase reaction), which is converted to glucose 1 phosphate •Glucose 1 Phosphate is then converted into UDP-glucose •This is sometimes call "Stage 1" •To begin glycogenesis de novo, glycogenin is required

Glucokinase vs. Hexokinase

Glucose to G6P step G6P can participate in PPP, glycogen synthesis or glycolysis

Oxidative portion of the PPP is regulated by

Glucose- 6-Phosphate Dehydrogenase

What are the 3 key reactions in glycolysis (include the enzyme, product and reactant)?

Glucose➔Hexokinase/Glucokinase + ATP➔Glucose 6 Phosphate + ADPFructose 6-Phosphate➔PFK-1 + ATP➔Fructose 1,6-bisphosphate + ADP Phosphoenol pyruvate➔Pyruvate Kinase➔Pyruvate + ATP

How is glycerol derived?

Glyceraldehyde after the catalysis of F-1-P to glyceraldehyde and DHAP (with the help of aldolase-B), can be converted to glycerol by oxidizing NADH

Rate of glycogen breakdown

Glycogemolysis

Outline the steps and key enzymes involved in the synthesis of glycogen, including the role of UDP-glucose and glycogenin.

Glycogen Synthesis starts with Glucose-6-phosphate (from free glucose via Hexokinase/Glucokinase reaction), which is converted to glucose 1 phosphate via phosphoglucosemutase, which is a reversible reaction. Glucose 1 Phosphate is then converted into UDP-glucose. UDP-Glucose is an activated sugar nucleotide, which is energetically favorable and a very stable intermediate. UDP-Glucose is a precursor of glycogen and lactose; UDP- glucuronate and glucuronides; and the carbohydrate chains in proteoglycans, glycoproteins, and glycolipids (you will learn more about those in the Connective Tissue session). UDP-Glucose is required for the synthesis of many carbohydrate compounds. To make UDP-Glucose, a sugar is transferred from the nucleotide sugar to an alcohol or other nucleophilic group to form a glycosidic bond. Synthesis and degradative pathways are separate and involve different enzymes

Outline the steps and key enzymes involved in the synthesis of glycogen, including the role of UDP-glucose and glycogenin.

Glycogen is a highly branched polysaccharide - analogous to the animal version of plant starch. The chains are linked by an alpha-1,4-glycosidic bond with alpha-1,6-branches occurring about every 8-10 glucose residues.

Compare and contrast liver and muscle glycogen.

Glycogen serves as a fuel reserve for ATP synthesis, especially during early fasting (about 4-16 hrs after eating, variable depending on diet/eating habits and exercise levels). Most glycogen is utilized during early fasting or in the post-prandial state. Muscle glycogen is used to provide muscle with energy▪ Glucose derived from muscle glycogen cannot be released from muscle due to lack of glucose-6- phosphatase In muscle, AMP produced from ATP degradation allosterically activates glycogen phosphorylase b. The neural impulses that activate muscle contraction release calcium 2+ from the sarcoplasmic reticulum. Ca2+ binds to calmodulin, which activates phosphorylase kinase. Phosphorylase kinase is also activated via phosphorylation via PKA.

G6P to glycogen

Glycogen synthesis

Compare and contrast glycolysis with gluconeogenesis including cellular locations, key enzymes involved and under what conditions each cycle would active/inactive. Glycogenic enzymes Glucokinase/hexokinase PFK-1 Pyruvate Kinase

Glycogenic Enzymes Inhibited by Activated by Glucokinase/hexokinase Inhibited by: We did not discuss this so don't worry about it Activated by: Insulin; hexokinase is inhibited by Glucose-6-phosphate (glucokinase is not) PFK-1 Inhibited by: High [ATP] signals ATP production via glycolysis is outpacing demand, so high ATP lowers affinity of PFK1 for its substrate, fructose 6 phosphate High [citrate] enhances ATPs inhibitory effect Activated by: Strongly allosterically activated by Fructose 2,6-bisphosphate (which comes from the PFK-2/FBP bifunctional enzyme reaction) ADP and AMP allosterically activate Pyruvate Kinase Inhibited by ATP and alanine Inhibited by glucagon and epinephrine Activated by: Liver form is activated by Fructose 1,6-bisphosphate Liver isoform has allosteric sites. Muscle and other tissue isozymes do not contain allosteric sites.

Synthesis (S1, S2, S3) vs. Degradation (D1,D2)Summary

Glycogenolysis and gluconeogenesis in liver both supply blood glucose ➔ both pathways are activated together by glucagon High glucagon levels activate GNG and glycogenolysis

Heinz bodies

Heinz bodies: inclusions within RBCs that have denatured Hb (purple): oxidative damage to Hb in RBCs-> thalassemia and hemolytic anemia, RBC breakdown Occur due to hemolysis

Deficiency of Glucose-6-Phosphate Dehydrogenase causes/PPP oxidation portion not functioning well

Hemolytic Anemia G6P dehydrogenase cannot oxidize G6P to 6-phosphogluconate in the pentose phosphate pathway by using NADP+ and cannot synthesize glutathione downstream (2 GSH reduced form with help of glutathione reductase is imp) which are essential in avoiding heinz bodies(Met-Hb, occur only in oxidized form of glutathione(GS-SG)) and subsequently, glutathione peroxidase cannot neutralize peroxide ROS(due to oxidant stress, infections, drugs, fava beans that have impact on protein/amino acids) to water within RBCs leading to OH species with one oxygen electron that causes the hemolysis in RBCs Heinz bodies: inclusions within RBCs that have denatured Hb (purple): oxidative damage to Hb in RBCs-> thalassemia and hemolytic anemia, RBC breakdown

What is the role of Lactate Dehydrogenase in anaerobic glycolysis? Where does lactate go once it is produced in this reaction?

LDH is responsible for the conversion of pyruvate➔lactate in the absence oxygen. During that reaction, NADH is used, and NAD is produced. That NAD returns to glycolysis to help it continue. Anaerobic glycolysis is a critical source of ATP for cells that have a decreased O2 supply either because they are physiologically designed that way (e.g., cells in the kidney medulla, rapidly working muscle, red blood cells) or because their supply of O2 has been pathologically decreased (e.g., coronary artery disease).

Glucose➔Hexokinase/Glucokinase + ATP➔Glucose 6 Phosphate + ADPFructose 6-Phosphate➔PFK-1 + ATP➔Fructose 1,6-bisphosphate + ADP Phosphoenol pyruvate➔Pyruvate Kinase➔Pyruvate + ATP a. How are each of these 3 enzymes regulated? Include allosteric and covalent regulators as discussed in lecture. Hexokinase/GLUT 4

Hexokinase: regulated via tissue-specific isozymes (called Hexokinase in non-hepatic tissues, and Glucokinase in Hepatic tissues; there are 4 isozymes of hexokinase, but we really just focus on the differences between Hexokinases I-III and Glucokinase, aka Hexokinase IV). The hexokinases are primarily regulated through their affinity for glucose. Muscle Hexokinase is able to operate at a wide variety of glucose concentrations. This is because muscle hexokinase plays the primary role of providing the muscle with glucose for energy use. Because glucose entering a muscle cell from the blood stream (where glucose levels are approx. 70-90mg/dL), results in a glucose concentration within the cell high enough to saturate hexokinase, the enzyme is acting at or near its max rate. Muscle hexokinase (low Km/high affinity). This allows hexokinase in muscle to always phosphorylate glucose when glucose is present. Hexokinase has a low Km/high affinity for glucose, allowing glucose uptake (and use) by muscle cells even at "low" glucose levels. Hexokinase is also regulated in muscle through allosteric inhibition via Glucose-6- Phosphate (G6P) levels. This means that whenever G6P levels rise above normal concentrations, hexokinase in muscle is inhibited and the rate of G6P formation slows, to return balance to the production and use of G6P.

What activates PFK-1?

High conc of F-2,6-bisphosphate activates PFK-1 which leads to inc rate of glycolysis

What causes dec cAMP and low levels of active pKA?

High insulin/glucagon ratio in the cytosol

4. Describe the regulatory processes of glycogen synthesis and degradation, including the glycogen cascade.

Hormonally regulated through insulin because changes in insulin levels are much more dramatic compared to changes in glucagon levels (think of this as analogous to the cellular changes in AMP discussion). Insulin INACTIVATES glycogen degradation and STIMULATES synthesis. Glucagon (in liver only) and epinephrine ACTIVATE glycogen degradation. The Glycogen Cascade is a cascade of amplification and phosphorylation reactions. It can also be described as a G-protein stimulated second-messenger cascade.

4. Describe how blood glucose levels are maintained under a variety of conditions STARVED state

If the fasting state continues beyond a couple days, we are entering the "starved state". In the STARVED state, gluconeogenesis continues, and eventually, ketone synthesis also ramps up, preserving the amino acid precursors used in gluconeogenesis - thereby reducing body protein catabolism.

Describe the Cori Cycle in terms of tissues involved and overall purpose.

Lactate production is a normal part of metabolism. The Cori Cycle is a way for cells to recycle their lactate. In the absence of disease, elevated lactate levels in the blood are associated with anaerobic glycolysis during exercise. Exporting lactate out of the muscle cells during exercise prevents muscle tissue from becoming overly acidic. Lactate released from cells undergoing anaerobic glycolysis is taken up by other tissues (primarily the liver, heart, and skeletal muscle) and oxidized back to pyruvate. In the liver, the pyruvate is used to synthesize glucose (gluconeogenesis), which is returned to the blood. The cycling of lactate and glucose between peripheral tissues and liver is called the Cori cycle.

In contrast to muscle hexokinase, glucokinase plays a different role. The liver needs to maintain glucose homeostasis for the entire organism - not just the local organ. Glucokinase is capable of metabolizing excess glucose when liver glucose concentrations are over 180+ mg/dL, reflecting a high Km/low affinity for glucose. This allows for high glycolytic activity in liver hepatocytes only once blood glucose concentrations are elevated, such as after a meal. This means the liver metabolizes glucose through glycolysis, allowing for eventual synthesis into glycogen, and if warranted due to continued excess glucose, triglycerides for fat storage.

7. Explain the purpose of incretins and summarize the two incretins we discussed.

Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating. Incretins regulate the amount of insulin that is secreted after eating. Substantially more insulin is secreted with oral or enteral administration, a phenomenon known as the incretin effect We discussed GIP and GLP1

Review of TCA

Intermediates are precursors for biosynthetic pathways Acetyl coA: CH3 C=O SCoA TCA is an anaplerotic reaction and forms intermeds Several vitamins play key roles in TCA function FAD = riboflavin NAD = niacin Coenzyme A = pantothenic acid Alpha-KG = thiamin (and lipoic acid)

Which reactions produce NADH?

Isocitrate DH, alpha-KG, Malate DH

Normal Fructose Metabolism

Majority of metabolism occurs in liver Fructose is phosphorylated by fructokinase to fructose-1- phosphate, which is further metabolized to glyceraldehyde-3- phosphate via DHAP and glyceraldehyde to enter glycolysis Fructose (FK) +ATP/ADP Fructose 1 P Aldolase-B Results in DHAP and Glyceraldehyde Glyceraldehyde 3 P Glyceraldehyde converted to glycerol with the help of NADH oxidized to NAD+ Glyceraldehyde converted to G3P with the help fo triose kinase

Isozymes:

Mito Pepck and cytosolic pepck are 2 distinct enzymes that catalyze the same reaction. Can have different cell locations or metabolic roles. Mito PEPCK predominates in muscle (limits shuttling of reducing equiv of mitochondria) cyto pepck predominates in liver

Reminder: Function of Glycogen varies by Tissue

Muscle and Liver Glycogen serve different functions In muscle, glycogen is used to generate ATP for use in muscle In liver, glycogen is used to maintain blood glucose levels in the brain and throughout the body

Cellulose

Non digestible carb

Indirect calorimetry:

Not an anthropometric study. Often called a "Metabolic Cart" study; used more than the other methods in hospital setting; Quantifies energy expenditure based on O2 consumption, CO2 production, and heat production; Typically, only used in selected ICU patients receiving enteral or parenteral nutrition; Also used on free-living persons (e.g., athletes) in exercise physiology lab setting

Observational studies - Involves the investigator observing nature/people - can only define associations Experimental studies - Involves the investigator trying to control nature/people - can determine causality

Physical Assessment:

Orbital fat pads (eyes should not appear sunken); Triceps skinfold thickness (1 cm or less = malnourished); Temples (should not appear sunken); clavicle, shoulders (girdle structures should not be easily seen); Interosseus muscle (should bulge when pinching forefinger and thumb); Anterior lower ribs and Scapula should not be easily visible; Thigh and Calf should not look "wasted". These are all relatively easy to visually assess on most people.

Regulation of the pyruvate to phosphoenolpyruvate (PEP) step PEPCK

PEP Carboxykinase (PEPCK) a.Mg2+ dependent b.Requires GTP c.PEPCK in humans is located either in the cytosol or in mitochondria, distributed about equally in each compartment. d.Inducible

G6P to R5P + NADPH

PPP

Ghrelin

PRIMARY CELL/TISSUE OF ORIGIN Central nervous system, stomach, small intestine, and colon ACTIONS Stimulates appetite; the "hunger hormone" SECRETORY STIMULI Fasting

Glucagonlike peptide-1 (GLP-1)

PRIMARY CELL/TISSUE OF ORIGIN Enteroendocrine L-cells in ileum, colon, and central nervous system ACTIONS 1.Enhances glucose disposal after meals by inhibiting glucagon secretion and stimulating insulin secretion 2.Acts through second messengers in β-cells to increase sensitivity of these cells to glucose (an incretin) SECRETORY STIMULI 1.Oral nutrient ingestion 2.GIP

Glucose-dependent insulinotropic polypeptide (GIP)

PRIMARY CELL/TISSUE OF ORIGIN Neuroendocrine K-cells of duodenum and proximal jejunum ACTIONS 1.Increases insulin release via an "incretin" effect 2.Regulates glucose and lipid metabolism SECRETORY STIMULI Oral nutrient ingestion, especially long-chain fatty acids

3 water soluble/dispersible fibers and their classes of compounds/dietary sources

Pectic substances: Galacturonans, arabinogalactans, β-glucans, arabinoxylans Apples, strawberries, carrots, citrus Gums: Galactomannans, arabinogalactans Oats, legumes, guar, barley Mucilages: Wide range of branched and substituted galactans Flax seed, psyllium, mustard seed

Pentose Phosphate Pathway, Fructose, Galactose and Ethanol Metabolism What is the purpose of the pentose phosphate pathway and what is the key enzyme required? In what tissue type is this enzyme so critical? Are there substances that can inhibit this metabolic reaction? What happens if this enzyme fails?

Pentose Phosphate Pathway occurs primarily in cytosol of liver, lactating mammary glands, adipose tissue, adrenal cortex, and RBCs - but performed in all cells. It generates intermediates not produced elsewhere The primary purpose of the PPP is the generate NADPH, which is needed for: Synthesis of fatty acids and cholesterol; Maintains reduced form of glutathione; and Immune function

ATP Generating Phase

Phosphoenolpyruvate (PEP) ➔ Pyruvate is catalyzed by Pyruvate Kinase (PK) ▪PK is activated by Fructose-1,6-bisphosphate, the product of the PFK reaction (feed-forward regulation) ▪Also controlled via phosphorylation

Compare and contrast the current nutrition recommendations to your own self-assessment findings via the nutrition project.

a. This will be determined via your nutrition self-assessment project, so there will not be exam questions on this objective.

Explain where the precursor materials for gluconeogenesis come from.

Precursors for gluconeogenesis come primarily from Lactate and Alanine (although many other amino acids can contribute carbon to the process, alanine is most common).

Regulation of the pyruvate to phosphoenolpyruvate (PEP) step

Pyruvate Carboxylase - mitochondrial enz a.An ABC enzyme due to the roles of ATP, Biotin, and CO2 b.Allosteric activator: AcetylCoA ▪comes from the oxidation of fatty acids, being delivered to liver after release from adipose tissue in response to fasting or stress. c.Low levels of Acetyl CoA inactivates Pyruvate Carboxylase; pyruvate is oxidized thru PDH d.High levels of Acetyl CoA in mitochondria signals need for increased OAA (occurs during fasting when OAA used for gluconeogenesis)

Describe the Pyruvate Dehydrogenase (PDH) Complex. What cofactors are needed for proper functioning? How is the PDH complex regulated?

Pyruvate➔PDH➔Acetyl CoA PDH oxidizes pyruvate to acetyl-CoA, thus linking glycolysis and the TCA cycle. It is inactive with phosphorylation, and inhibited by Acetyl CoA (product inhibition). It contains the same three basic types of catalytic subunits as the α-ketoglutarate dehydrogenase complex and the branched-chain α-ketoacid dehydrogenase complex: (1) pyruvate dehydrogenase subunits that bind TPP (E1), (2) transacetylase subunits that bind lipoate (E2), and (3) dihydrolipoyl dehydrogenase subunits that bind FAD (E3).

Hypoglycemia

abnormally low level of sugar in the blood

Major Route for Ethanol Metabolism

Pyruvic acid to actealdehyde + CO2 decarboxylation: Pyruvate decarboxylase in cytoplasm and mito Process below happens in liver Ethanol using Alcohol dehydrogenase (NAD+ getting reduced) and forms acetaldehyde acetaldehyde to acetate using Acetaldehyde dehydrogenase (NAD+ getting reduced again) Acetate or acetaldehyde (product or reactant in above rxn) can go out in the blood IF acetate is present in blood will enter muscle acetate converted to acetyl coA using acetyl coA synthetase acetyl coA can then enter krebs (1 FAD, 3NADH, 1 CO2) if acetaldehyde is not converted to acetate in liver/dysfunction of ALDH, buildup of acetaldehyde in blood (cannot enter muscles?) and cannot be incorp into TCA cycle bc not converted into acetyl coA form

The NHANES studies is another famous and frequently referenced cohort study that many nutrition (and all types of) researchers use and publish analyses from.

RCT: Like cohort studies, RCTs follow a group of people over time. Follows a group (usually a large group) of people over time like cohort studies; Procedures are controlled to ensure that all participants in all study groups are treated the same except for the intervention group Intervention (where the "trial" part comes from in the description) to see how a specific behavior change (e.g., walking, eating vegetables, or meditation, etc) or treatment (e.g., drug) affects a health outcome; People in the study are randomly assigned either to receive or not receive the interventionPROS: Powerfully from a statistical standpoint; RCTs are considered the "gold standard" for pharma and medical researchCONS: Costly, difficult to do in nutrition Famous RCTs in Nutrition: The Dietary Approaches to Stop Hypertension (DASH) study involved a 3-period randomized crossover trial in free-living healthy individuals who consumed in random order a control diet, a standard DASH diet, and a higher-fat, lower-carbohydrate modification of the DASH diet (HF- DASH diet) for 3 wk each, separated by 2-wk washout periods. The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the combination of 30 mg beta- carotene and 25,000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18314 men and women at high risk of developing lung cancer. The CARET intervention was stopped 21 months early because of clear evidence of no benefit and substantial evidence of possible harm; there were 28% more lung cancers and 17% more deaths in the active intervention group (active = the daily combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate).

Rate-limiting, principal regulatory step in glycolysis . Enzyme has complex regulation with multiple binding sites for both substrates and allosteric effectors in response to the cell's needs for energy and building blocks for biosynthesis. In the liver, during the Fed State, there is a relative high level of glucose. Concurrently, there will be a relative high level of insulin and low level of glucagon. This sets up the regulation for PFK-1. The most potent allosteric effector of PFK-1 is Fructose-2,6-Bisphosphate (F-2,6-BP). F- 2,6-BP is a product of a non-glycolytic, bifunctional enzyme. One part of the bifunctional enzyme is referred to as "PFK-2" and the other part is "Fructose Bisphosphatase-2" - we generally use PFK-2 when the bifunctional enzyme is dephosphorylated (as is the case during glycolysis); we generally use Fructose Bisphosphatase-2 when the bifunctional enzyme is phosphorylated (as is the case when talking about gluconeogenesis). PFK-2 has kinase activity (which produces the Fructose 2,6-bisphosphate) and phosphatase activity. The state PFK-2 takes (e.g., kinase or phosphorylase) is regulated by the hepatic insulin:glucagon ratio.

Overview of Carbohydrate Metabolism

Ribose 5 phos: NADPH

Response to Low Blood Glucose

Signs/Symptoms of Hypoglycemia can include: Hunger Cranky Shaking Sweating Dizziness Headache followed by drowsiness and, eventually, coma ➔ death

Glycogen Synthesis Stage II

Stage II Glycogen synthase immediately transfers glucose from UDP-glucose to a pre-existing glycogen chain Glycogen synthase cannot make the alpha-1,6 bonds found at the branching points of glycogen

Glycogen Synthesis Stage III

Stage III Branching enzyme (also called amylo-1,4 to 1,6 transglycosylase, or glycogen 4,6 transferase) creates a branching point in the glycogen molecule This makes glycogen more soluble and increases the number of sites accessible to glycogen phosphorylase and glycogen synthase

Fructose-2,6-Bisphosphate (F-2,6-BP) is the most potent allosteric activator of PFK1

Step 1 happens in liver

Key Reactions of Gluconeogenesis Overview

Substrates include Glycerol, some Amino Acids (esp. alanine), and Lactate 1.Pyruvate carboxylase ▪Converts Pyruvate to Oxaloacetate (OAA) 2.PEP carboxykinase ▪Converts OAA to Phosphoenolpyruvate 3.Fructose 1,6-bisphosphatase ▪Converts Fructose-1,6-bisphosphate to Fructose-6- phosphate ▪Overcomes the PFK-1 rxn of glycolysis 4.Glucose 6-phosphatase ▪Converts Glucose-6-phosphate to Glucose

3.Where is GTP produced?

Succinyl CoA ➔ Succinate thiokinase

Stages of GLycogen synthesis

Synthesis and degradative pathways are separate and involve different enzymes This is sometimes call "Stage 1" of Glycogen Synthesis. In stage II of Glycogen Synthesis, Glycogen Synthase immediately transfers glucose from UDP-glucose to a pre- existing glycogen chain To begin glycogenesis de novo (e.g., when glycogen stores have been totally depleted), glycogenin is required. In stage III of glycogen synthesis, branches are added by the "branching enzyme" (also known as also called amylo-1,4 to 1,6 transglycosylase, or glycogen 4,6 transferase)

Lysosomal α- glucosidase (Pompe disease)

TYPE: II Enzyme affected: Lysosomal α- glucosidase (Pompe disease): may see clinical symptoms in childhood, juvenile, or adult life stages, depending on the nature of the mutation Primary organ involved: All organs with lysosomes Manifestations and Tx: Infantile form: early-onset progressive muscle hypotonia, cardiac failure, death before age 2 years. Juvenile form: later-onset myopathy with variable cardiac involvement. Adult form: limb- girdle muscular dystrophy-like features. Glycogen deposits accumulate in lysosomes. Tx: High protein diet of approx. 25-30%, proteins, 30-35% carbohydrates, and 35-40% fat. More recently treatment with enzyme therapy has been developed but this is very costly and required for life.

Amylo-1,6-glucosidase (debrancher; Cori's disease)

TYPE: III Enzyme affected:Amylo-1,6-glucosidase (debrancher; Cori's disease): form IIIa is the liver and muscle enzymes, form IIIb is a liver-specific form, and IIIc a muscle-specific form (very difficult to distinguish between the types of GSDIII that affect the same tissues. GSD types IIIa and IIIb are the most common forms of this condition). Primary organ involved: Liver, skeletal muscle, heart Manifestations and Tx: Fasting hypoglycemia; hepatomegaly in infancy and some myopathic features. Glycogen deposits have short outer branches.Tx: frequent high-protein feedings during the day and a high-protein snack at night; energy is distributed as 45% carbohydrate, 25% protein, and 30% fat.

Amylo-4,6-glucosidase (branching enzyme) (Andersen disease)

TYPE: IV Amylo-4,6-glucosidase (branching enzyme) (Andersen disease) Primary organ involved: Liver Manifestations and Tx: Hepatosplenomegaly; symptoms may arise from a hepatic reaction to the presence of a foreign body (glycogen with long outer branches); usually fatal Tx: generally supportive, but not very effective

Muscle glycogen phosphorylase (McArdle disease)

TYPE: V Muscle glycogen phosphorylase (McArdle disease) (expressed as either adult or infantile form) Primary organ involved: Skeletal muscle Manifestations and Tx: Exercise-induced muscular pain, cramps, and progressive weakness, sometimes with myoglobinuria, Tx: carbohydrate-rich diet stress/illness: glucose build up and trigger glycolysis

Glycogen cascade

The Glycogen Cascade is a cascade of amplification and phosphorylation reactions. It can also be described as a G-protein stimulated second-messenger cascade. ▪ Activation of GTP-binding protein➔increases cAMP production• Triggered by Glucagon (liver only) or epinephrine... cAMP Activates Protein Kinase A (PKA) and sets off cascade of phosphorylations ➢ PKA activates phosphorylase B (kinase)▪ Phosphorylase B (kinase) activates glycogen phosphorylase ➔This strongly AMPLIFIES the initial signal releasing large quantities of free glucose from the liver (most of which is consumed by the brain, but also other peripheral tissues), or, releasing Glucose-6-phosphate from muscle which then goes through glycolysis and TCA, etc, for energy needs locally. ▪ Provides muscle with energy for ATP ▪ Provides liver with glucose to be released systemically and counters low blood sugar (hence, why we call glucagon and epinephrine "counter regulatory hormones" in the diabetes world).

In a glucose tolerance test, an individual in the basal metabolic state ingests a large amount of glucose. If the individual is normal, this ingestion should result in which one of the following? A. An enhanced glycogen synthase activity in the liver B. An increased ratio of glycogen phosphorylase a to glycogen phosphorylase b in the liver C. An increased rate of lactate formation by red blood cells D. An inhibition of PP-1 activity in the liver E. An increase of cAMP levels in the liver

The answer is A. After ingestion of glucose, insulin levels rise, cAMP levels within the cell drop (thus, E is incorrect), and PP-1 is activated (thus, D is incorrect). Glycogen phosphorylase a is converted to glycogen phosphorylase b by the phosphatase (thus, B is incorrect), and glycogen synthase is activated by the phosphatase. Red blood cells continue to use glucose at their normal rate; hence, lactate formation will remain the same (thus, C is incorrect).

A patient went on a 3-day "cleansing" fast but did continue to consume water and vitamins. What is this patient's source of fuel to maintain blood glucose levels under these conditions? A. Fatty acidsB. GlycerolC. Liver glycogen stores D. Muscle glycogen stores E. Ketone bodies

The answer is A. During a fast, liver glycogen stores are exhausted after about 30 hours, so the only pathway through which the liver can produce glucose is via gluconeogenesis. Gluconeogenesis requires energy, which is provided by fatty acid oxidation. Glycerol is a substrate for gluconeogenesis, but it is not oxidized to provide energy for gluconeogenesis. Muscle glycogen stores can provide glucose 1-phosphate for use by the muscle, but the glucose produced from muscle glycogen cannot enter the blood to be used by any other tissue. The liver will produce ketone bodies from fatty acid oxidation, but the liver does not express the coenzyme A transferase needed to metabolize ketone bodies.

Mrs. Jones is a sedentary 83-year-old woman who is 5 ft 4 in tall and weighs 125 lb. She has been at this weight for about a year. She says that a typical diet for her includes a breakfast of toast (white bread, no butter), a boiled egg, and coffee with cream. For lunch she often has a cheese sandwich (white bread) and a glass of whole milk. For dinner she prefers cream of chicken soup and a slice of frosted cake. Mrs. Jones's diet is most likely to be inadequate in which one of the following? A. Vitamin C B. ProteinC. CalciumD. Vitamin B12 E. Calories

The answer is A. Mrs. Jones's diet lacks fruits and vegetables, both of which are good sources of vitamin C. Her diet is adequate in protein, as eggs, milk, cheese and cream contain significant levels of protein. Her calcium levels should be fine owing to the milk, cream, and cheese in her diet. Vitamin B12 is derived from foods of animal origin, such as eggs, milk, and cheese. As the patient's weight has been stable for a year, her diet contains sufficient calories to allow her to maintain this weight, which is in the normal range for a patient who is 5 ft 4 in tall, as her BMI is 21.5.

A patient presented with a bacterial infection that produced an endotoxin which inhibits phosphoenolpyruvate carboxykinase (PEPCK). In this patient, then, under these conditions, which one of the following precursors to glucose production would be inhibited? Alanine Glycerol Even-chain numbered fatty acids Phosphoenolpyruvate Galactose

The answer is A. PEPCK converts OAA to PEP. In combination with pyruvate carboxylase, it is used to bypass the pyruvate kinase reaction. Thus, compounds that enter gluconeogenesis between PEP and OAA (such as lactate, alanine, or any TCA cycle intermediate) must use PEPCK to produce PEP. Glycerol enters gluconeogenesis as glyceraldehyde 3-P, bypassing the PEPCK step. Galactose is converted to glucose 1- phosphate, then glucose 6-P, also bypassing the PEPCK step. Even-chain fatty acids can only give rise to acetyl-CoA, which cannot be used to synthesize glucose.

An athlete is competing in a 400-meter dash. Which ONE of the following is the major source of energy for the muscles used in this competition? A. Muscle glycogen storesB. Muscle triacylglycerol storesC. Muscle amino acid oxidationD. Lactic acid from the red blood cells E. Liver triacylglycerol stores

The answer is A. The 400-meter dash is primarily an anaerobic activity, and the major source of energy for the muscle is glucose from its own glycogen stores (this pathway is also the one that produces energy at the fastest rate). The muscle does not store triacylglycerol (adipose tissue does). During the exercise, the muscle will generate lactic acid, which will be secreted in the blood. The muscle will not use lactate as an energy source. The muscle will not degrade its own proteins to generate amino acids to use as an energy source.

A new patient to your practice has been diagnosed with type 2 diabetes. Your treatment plan includes prescribing a drug that would be beneficial in lowering postprandial serum glucose levels. A class of such a drug is which one of the following? A. Drugs that decrease levels of GIPB. Drugs that decrease levels of GLP-1C. Drugs that increase levels of somatostatin D. Drugs that decrease levels of DPP-4E. Drugs that increase the levels of glucagon

The answer is D. GIP and GLP-1 accentuate insulin release after a meal large enough to cause an increase in blood glucose concentration (so they should be increased as a treatment for diabetes). Both GIP and GLP-1 have a very short half-life owing to inactivation by DPP-4. Reducing the levels of DPP-4 would allow more GLP-1 and GIP to stimulate insulin release and lower postprandial blood glucose levels. Somatostatin and glucagon are counterregulatory hormones and would antagonize the effects of insulin.

Assume that an individual had a glucagon- secreting pancreatic tumor (glucagonoma). Which one of the following is most likely to result from hyperglucagonemia? A. Weight lossB. HypoglycemiaC. Increased muscle protein synthesis D. Decreased lipolysisE. Increased liver glycolytic rate

The answer is A. The high levels of glucagon will antagonize the effects of insulin and will lead to hyperglycemia because glucagon stimulates glucose export from the liver by stimulating glycogenolysis and gluconeogenesis. Owing to the overriding effects of glucagon, blood glucose cannot enter muscle and fat cells, and fat oxidation is stimulated to provide energy for these tissues. This leads to a loss of stored triglyceride, which, in turn, leads to weight loss. Insulin is required to stimulate protein synthesis in muscles (glucagon does not have this effect), and glucagon signals export of glucose from the liver, which means that the rate of glycolysis is suppressed in hepatic cells under these conditions. Glucagon also stimulates lipolysis in adipocytes to provide fatty acids as an energy source for muscle and liver.

A male patient exhibited a BMI of 33 kg/m2 and a waist circumference of 47 in. What nutrition therapy would be most helpful? A. Decreased intake of total calories because all fuels can be converted to adipose tissue triacylglycerols B. The same amount of total calories but substitution of carbohydrate calories for fat calories C. The same amount of total calories but substitution of protein calories for fat calories D. A pure-fat diet because only fatty acids synthesized by the liver can be deposited as adipose triacylglycerols E. A limited food diet such as the ice cream and waffles diet

The answer is A. The patient's BMI is in the obese range, with large abdominal fat deposits. He needs to decrease his intake of total calories because an excess of calories ingested as carbohydrate, fat, or protein results in deposition of triacylglycerols in adipose tissue. If he keeps his total caloric intake the same, substitution of one type of food for another will help very little with weight loss. (However, a decreased intake of fat may be advisable for other reasons.) Limited food diets, such as the ice cream and waffles diet or a high-protein diet of shrimp, can work if they decrease appetite and therefore ingestion of total calories. Dr. Early's additional comment: it's much more complicated than what the text book makes it seem

Assume that an individual has been eating excess calories daily such that he will gain weight. Under which one of the following conditions will the person gain weight most rapidly? A. If all the excess calories are from carbohydrate B. If all the excess calories are from triacylglycerol C. If all the excess calories are split 50%/50% between carbohydrate and triacylglycerol D. If all the excess calories are split 25%/75% between carbohydrate and triacylglycerol E. It makes no difference what form the excess calories are in.

The answer is B. Consider the energy required to convert dietary carbohydrates to triacylglycerol. Some ATP is generated from glycolysis and the PDH reaction, but energy is also lost as the fatty acids are synthesized (the synthesis of each malonyl- CoA requires ATP, and the reduction steps require two molecules of NADPH). Dietary fat, however, only requires activation and attachment to glycerol; the fatty acid chain does not need to be synthesized. Therefore, it requires less energy to package dietary fat into chylomicrons than it does to convert dietary carbohydrate into fatty acids for incorporation into VLDL. Thus, weight gain will be more rapid if all the excess calories are derived from fat as opposed to carbohydrates.

Without a steady supply of glucose to the bloodstream, a patient would become hypoglycemic and, if blood glucose levels get low enough, experience seizures or even a coma. Which one of the following is necessary for the maintenance of normal blood glucose? A. Muscle glucose 6-PB. Liver glucose 6-PC. Glycogen in the heart D. Glycogen in the brain E. Glycogen in the muscle

The answer is B. Glycogen in the liver provides glucose for the circulation. Glycogen in the heart, brain, or muscle cannot provide glucose for the circulation. In the liver, glucose 6-phosphatase hydrolyzes glucose 6-P to glucose, which is released into the bloodstream. The liver generates glucose 6-P from either glycogen degradation or gluconeogenesis. Muscle does not contain glucose 6-phosphatase.

Which one of the following is most likely to occur in a normal individual after ingesting a high-carbohydrate meal? A. Only insulin levels decrease.B. Only insulin levels increase.C. Only glucagon levels increase.D. Both insulin and glucagon levels decrease. E. Both insulin and glucagon levels increase.

The answer is B. High blood glucose levels signal the release of insulin from the pancreas; glucagon levels either stay the same or decrease slightly.

A patient with type 1 diabetes, who has forgotten to take insulin before a meal, will have difficulty assimilating blood glucose into which one of the following tissues? A. BrainB. AdiposeC. Red blood cell D. LiverE. Intestine

The answer is B. Insulin stimulates the transport of glucose into adipose and muscle cells by promoting the recruitment of GLUT 4 glucose transporters to the cell membrane. Liver, brain, intestine, and red blood cells have different types of glucose transporters that are not significantly affected by insulin.

A patient is rushed to the emergency department after a fainting episode. Blood glucose levels were extremely low; insulin levels were normal, but there was no detectable C- peptide. The cause of the fainting episode may be which one of the following? A. An insulin-producing tumor B. An overdose of insulinC. A glucagon-producing tumor D. An overdose of glucagon E. An overdose of epinephrine

The answer is B. The key to answering this question correctly relates to the absence of detectable C-peptide levels in the blood. An overproduction of insulin by the β- cells of the pancreas can lead to hypoglycemia severe enough to cause loss of consciousness, but because there was no detectable C-peptide in the blood, the loss of consciousness was most likely the result of the administration of exogenous insulin, which lacks the C-peptide (see Chapter 19). An overdose of glucagon (either through injection or from a glucagon-producing tumor), or epinephrine, would promote glucose release by the liver and not lead to hypoglycemia.

GLUT2

the insulin-independent glucose transporter, transports glucose into the hepatocytes.

A patient told her doctor that a friend told her that if she ate only carbohydrates and proteins and no fats, she would no longer store fats in adipose tissue. The doctor told the patient her friend was misinformed and then should further respond to this statement via which one of the following? A. Dietary glucose is converted into fatty acids but not glycerol by the liver. B. Dietary glucose is converted by the liver into fatty acids and glycerol. C. Dietary glucose is converted into glycerol but not fatty acids by the liver. D. Low-density lipoprotein transports the dietary converted products from the liver to the adipose tissue. E. Low-density lipoprotein transports the dietary converted products to the muscle tissue for oxidation.

The answer is B. The liver can convert dietary glucose into fatty acids and glycerol to produce triacetylglycerols, which are packaged into VLDL for transport to adipose tissue (for storage) or to the muscle for immediate oxidation if necessary. A low-fat diet, if excessive in overall calories, will lead to triglyceride formation and storage of the triglyceride in adipose tissue.

Glucose is the body's universal fuel, which can be used by virtually all tissues. A major role of glycolysis is which one of the following? A. To synthesize glucoseB. To generate energyC. To produce FAD(2H)D. To synthesize glycogenE. To use ATP to generate heat

The answer is B. The major roles of glycolysis are to generate energy and to produce precursors for other biosynthetic pathways. Gluconeogenesis is the pathway that generates glucose (thus, A is incorrect); FAD(2H) is produced in the mitochondria by a variety of reactions but not glycolysis (thus, C is incorrect); glycogen synthesis occurs under conditions in which glycolysis is inhibited (thus, D is incorrect); and glycolysis does not hydrolyze ATP to generate heat (that is caused by nonshivering thermogenesis; thus, E is incorrect). .

A prisoner has gone on a hunger strike, drinking only water. Careful monitoring of the prisoner demonstrated a drop in BUN (blood urea nitrogen) during the second week of the fast. This occurred because of which one of the following? A. Enhanced glycogenolysisB. Reduced ketone body formationC. A decrease in the rate of gluconeogenesis D. An increase in the rate of gluconeogenesis E. Enhanced glucose metabolism in the brain

The answer is C. As a fast increases in length, the liver will begin to produce ketone bodies from the oxidation of fatty acids obtained from the adipocyte. As the ketone bodies are released from the liver, the brain will begin to use them, reducing its need for glucose by approximately 40%. This, in turn, reduces the need of the liver to produce glucose by gluconeogenesis (recall that glycogen stores are depleted by 36 hours of the fast), which, in turn, reduces the rate of protein degradation in the muscle. The overall effect is to spare muscle protein (thereby producing less blood urea nitrogen as a product of protein catabolism) for as long as possible.

A patient with frequent sweating and tremors is diagnosed with "reactive hypoglycemia" and has been prescribed a small meal every 4 hours throughout the day. The patient most likely is impaired in carrying out which one of the following? A. Glycogenesis of liver glycogen storesB. Glycogenolysis of muscle glycogen storesC. Glycogenolysis of liver glycogen storesD. Glycogenesis of muscle glycogen storesE. Glycogenesis of adipose tissue glycogen stores

The answer is C. Blood glucose levels return to the fasting range about 2 hours after a meal. The decrease in blood glucose causes a decrease in insulin and an increase in glucagon production. Glucagon stimulates the liver to degrade its glycogen stores (glycogenolysis) and release glucose into the bloodstream. If the patient eats another meal within a few hours, the patient returns to the fed state. Glycogenesis is the synthesis of glycogen. While the muscle contains glycogen stores, degradation of muscle glycogen only benefits the muscle; the muscle cannot export glucose to maintain blood glucose levels. Adipose tissue does not contain significant levels of glycogen.

In a well-nourished individual, as the length of fasting increases from overnight to 1 week, which one of the following is most likely to occur? A. Blood glucose levels decrease by approximately 50%. B. Red blood cells switch to using ketone bodies. C. Muscles decrease their use of ketone bodies, which increase in the blood. D. The brain begins to use fatty acids as a major fuel. E. Adipose tissue triacylglycerols are nearly depleted.

The answer is C. The major change during prolonged fasting is that as muscles decrease their use of ketone bodies, ketone bodies increase enormously in the blood and are used by the brain as a fuel. However, even during starvation, glucose is still required by the brain, which cannot oxidize fatty acids to an appreciable extent (thus, D is incorrect). Red blood cells can use only glucose as a fuel (thus, B is incorrect). Because the brain, red blood cells, and certain other tissues are glucose-dependent, the liver continues to synthesize glucose, and blood glucose levels are maintained at only slightly less than fasting levels (thus, A is incorrect). Adipose tissue stores (~135,000 kcal) are not depleted in a well-nourished individual after 1 week of fasting (thus, E is incorrect).

An adolescent patient with a deficiency of muscle phosphorylase was examined while exercising her forearm by squeezing a rubber ball. Compared with a normal person performing the same exercise, this patient would exhibit which one of the following? A. Exercise for a longer time without fatigue B. Have increased glucose levels in blood drawn from her forearm C. Have decreased lactate levels in blood drawn from her forearm D. Have lower levels of glycogen in biopsy specimens from her forearm muscle E. Hyperglycemia

The answer is C. The patient has McArdle disease, a glycogen storage disease caused by a deficiency of muscle glycogen phosphorylase. Because she cannot degrade glycogen to produce energy for muscle contraction, she becomes fatigued more readily than a normal person (thus, A is incorrect), the glycogen levels in her muscle will be higher than normal as a result of the inability to degrade them (thus, D is incorrect), and her blood lactate levels will be lower because of the lack of glucose for entry into glycolysis. She will, however, draw on the glucose in her circulation for energy, so her forearm blood glucose levels will be decreased (thus B is incorrect), and because the liver is not affected, blood glucose levels can be maintained by liver glycogenolysis (thus, E is incorrect).

A marathon runner reaches the last mile of the race but becomes dizzy, light-headed, and confused. These symptoms arise because of which one of the following? A. Enhanced induction of GLUT 4 transporters B. Reduced blood glucose levels for GLUT 2 transport C. Inhibition of GLUT 5 transporters D. Reduced blood glucose levels for GLUT 1 transport E. Lack of induction of GLUT 4 transporters

The answer is D. GLUT 1 is the carrier for glucose across the blood brain-barrier (as well as red blood cells). When blood glucose levels drop below the Km for this transporter, then the nervous system does not receive sufficient glucose to keep functioning properly—hence, the signs of hypoglycemia. The GLUT 2 and GLUT 5 transporters are not responsible for glucose entry into the nervous system (the liver and pancreas use GLUT 2, whereas GLUT 5 primarily transports fructose, not glucose). GLUT 4 transporters are insulin-responsive transporters, expressed primarily in the muscle and fat cells. Altering the number of GLUT 4 transporters will not affect glucose entry into the nervous system.

Which of the following is a common intermediate in the conversion of glycerol and lactate to glucose? a. Pyruvateb. Oxaloacetatec. Malated. Glucose 6 phosphate e. Phosphoenolpyruvate

The answer is D. Glycerol is converted to glycerol 3-P, which is oxidized to form glyceraldehyde 3-P. The glyceraldehyde 3-P formed then follows the gluconeogenic pathway to glucose. Lactate is converted to pyruvate, which is then carboxylated to form OAA. The OAA is decarboxylated to form PEP and then run through gluconeogenesis to glucose. Because glycerol enters the gluconeogenic pathway at the glyceraldehyde 3-P step and lactate at the PEP step, the only compounds in common between these two starting points are the steps from glyceraldehyde 3-P to glucose. Of the choices listed in the question, only glucose 6-P is in that part of the pathway.

A patient has large deposits of liver glycogen, which, after an overnight fast, had shorter- than-normal branches. This abnormality could be caused by a defective form of which one of the following proteins or activities? A. Glycogen phosphorylase B. Glucagon receptorC. GlycogeninD. Amylo-1,6-glucosidase E. Amylo-4,6-transferase

The answer is D. If, after fasting, the branches were shorter than normal, glycogen phosphorylase must be functional and capable of being activated by glucagon (thus, A and B are incorrect). The branching enzyme (amylo-4,6-transferase) is also normal because branch points are present within the glycogen (thus, E is incorrect). Because glycogen is also present, glycogenin is present in order to build the carbohydrate chains, indicating that C is incorrect. If the debranching activity is abnormal (the amylo-1,6-glucosidase), glycogen phosphorylase would break the glycogen down up to four residues from branch points and would then stop. With no debranching activity, the resultant glycogen would contain the normal number of branches, but the branched chains would be shorter than normal.

A patient arrives at the hospital in an ambulance. She is currently in a coma. Before lapsing into the coma, her symptoms included vomiting, dehydration, low blood pressure, and a rapid heartbeat. She also had relatively rapid respirations, resulting in more carbon dioxide being exhaled. These symptoms are consistent with which one of the following conditions? A. The patient lacks a pancreas. B. KetoalkalosisC. Hypoglycemic comaD. DKA E. Insulin shock in a patient with diabetes

The answer is D. The hyperglycemia in an untreated diabetic creates osmotic diuresis, which means that excessive water is lost through urination. This can lead to a contraction of blood volume, leading to low blood pressure and a rapid heartbeat. It also leads to dehydration. The rapid respirations results from acidosis-induced stimulation of the respiratory center of the brain in order to reduce the amount of acid in the blood. Ketone bodies have accumulated, leading to DKA (thus, B is incorrect). A patient in a hypoglycemic coma (which can be caused by excessive insulin administration) does not exhibit dehydration, low blood pressure, or rapid respirations; in fact, the patient will sweat profusely as a result of epinephrine release (thus, C and E are incorrect). Answer A is incorrect because lack of a pancreas would be fatal.

A dietitian is counseling a patient with celiac sprue (intolerance to gluten, leading to malabsorption issues in the intestine) who has experienced steatorrhea (fatty stools caused by poor absorption of dietary lipids in the intestine) for a number of years. The dietitian, in addition to describing appropriate carbohydrates, lipids, and proteins that will not trigger the malabsorption issue, also encourages the patient to take certain vitamins. Which ONE of the following vitamins is most likely on this list? A. Vitamin C B. Folic acid C. Vitamin B12 D. Vitamin K E. Vitamin B1

The answer is D. Vitamin K is a fat-soluble vitamin, and it is absorbed from the small intestine in the presence of lipids. If lipids cannot be absorbed, the fat-soluble vitamins (vitamins A, D, E, and K) also will not be absorbed. The other vitamins listed (vitamins B1, C, folic acid, B12) are all water-soluble vitamins that do not require the presence of lipid for absorption from the intestinal lumen. During the vitamins lecture I talked about how fat soluble vitamins are likely to be of concern when there is a malabsorption issue.

Which one of the following schemes most accurately depicts the timeline of the metabolic processes of the liver after a carbohydrate meal is ingested followed by 3 hours of fasting? A. Glycolysis, glycogen synthesis, lipolysis, glycogenolysis, gluconeogenesis B. Glycogen synthesis, lipolysis, glycogenolysis, gluconeogenesis C. Glycolysis, lipolysis, glycogenolysis, gluconeogenesis, glycogen synthesis D. Glycogen synthesis, lipolysis, gluconeogenesis, glycolysis E. Glycogen synthesis, glycogenolysis, lipolysis, gluconeogenesis

The answer is E. After eating a high-carbohydrate meal, the excess carbohydrates in the liver are first stored as glycogen and then sent through glycolysis to generate pyruvate and then acetyl-CoA, for eventual fatty acid production. After time, as the blood glucose is used by tissues, its levels will drop, and glucagon will be released from the pancreas, which will stimulate glycogenolysis in the liver such that glucose can be exported to raise blood glucose levels. The glucagon release also stimulates lipolysis, and energy from fatty acid oxidation is used to produce glucose via gluconeogenesis.

You are evaluating a patient who has a mutation that hinders his ability to carry out liver glycogenolysis. One initial finding shortly after entering the fasting state in this patient would be which ONE of the following? A. HyperglycemiaB. Ketosis (elevated levels of ketone bodies) C. Significantly increased urea synthesisD. Reduced blood lactate levelsE. Hypoglycemia

The answer is E. As blood glucose levels begin to drop, glucagon is released from the pancreas, which stimulates glycogenolysis in the liver. The glucose produced from liver glycogen is used initially to maintain blood glucose levels during the early stages of a fast. Gluconeogenesis will kick in later because this process requires more energy than glycogenolysis, and fatty acid oxidation must be under way before glucose can be produced from lactate, glycerol, and amino acids. Ketone bodies will not be evident after initiating a fast (the levels of ketones will not be significant until 24 to 48 hours after a fast is initiated). Significant protein degradation will not occur until the liver runs out of glycogen, about 24 to 36 hours after the start of the fast (and without protein degradation, urea synthesis will remain normal). The red blood cells will still be metabolizing glucose, so blood lactate levels (the end product of red cell glucose metabolism) will remain relatively constant.

Fructose is the second most common sugar in the human adult diet and its metabolism parallels glycolysis. Which one of the following substances is found in both the fructose metabolic pathway and the glycolytic pathway? A. Glucose 1-PB. Fructose 1-PC. Fructose 6-PD. Fructose 1,6-bisP E. Glyceraldehyde 3-P

The answer is E. Fructose 1-P is found only in fructose metabolism. Glucose 1-P is derived from glycogen degradation. Fructose 6-P and fructose 1,6-bisP are found in glycolysis but not in fructose metabolism. Both fructose and glucose are converted to glyceraldehyde 3-P, and this is where the two pathways intersect. Their continued metabolism is identical from this point on.

A person is training for a half-marathon. After running 5 miles, which one of the following is providing most of the products for ATP generation in the muscles? A. Muscle glycogen B. Liver glycogenC. Blood glucoseD. Ketone bodies E. Fatty acids

The answer is E. Initially, muscles use glucose from muscle glycogen, and fatty acids provided by the adipocyte. As the run continues, the levels of AMP increase in the muscle, which leads to activation of the AMP-activated protein kinase. This kinase leads to a reduction of malonyl-CoA levels in the muscle (by inhibiting, via phosphorylation, acetyl-CoA carboxylase and activating, via phosphorylation, MCD), which allows for fatty acid entrance into the mitochondria. The muscle does not contain sufficient glycogen to provide energy for the entire marathon, so a mixture of fatty acids and glucose (from glycogen) is used by the muscle for optimal performance. In an adult, there is no ketone-body production during the race. Blood glucose can be taken up by the muscle (the activation of the AMP-activated protein kinase stimulates the fusion of GLUT4 containing vesicles with the plasma membrane), but the runner will race at a pace that allows some of the blood glucose to be used by the nervous system, which requires that the muscles use fatty acids to generate energy.

A 4-week-old baby is being seen by the pediatrician because of frequent vomiting after meals and tenderness in the abdomen. Upon examination, the physician noted an enlarged liver and a hint of cataract formation in both of the child's eyes. A urine dipstick test for a reducing sugar gave a positive result. Blood glucose levels were slightly below normal. The compound that reacted with the urine dipstick test was most likely which one of the following? A. Glucose B. Fructose C. Lactose D. Maltose E. Galactose

The answer is E. The child has a form of galactosemia in which galactose cannot be metabolized, such that free galactose enters the blood and is excreted via the urine. The below-normal blood glucose levels indicate that glucose is not being excreted in the urine. The high levels of galactose lead to galactose entering the lens of the eye, where it is converted to galactitol via aldose reductase, trapping the galactitol in the lens. This leads to an osmotic imbalance across the lens, resulting in swelling and cataract formation. High levels of fructose do not lead to cataract formation. Lactose is a disaccharide that is cleaved to glucose and galactose in the small intestine, such that lactose does not enter the blood. Maltose is another disaccharide (glucose- glucose) that does not enter the blood.

Proportional Cardiometabolic Disease Mortality Associated With Suboptimal Dietary Habits Among US Men and Women in 2012 JAMA, 2017

The bars represent the estimated percentage of cardiometabolic deaths related to 10 dietary factors compared with optimal intakes. The dietary factors are listed in rank order of total mortality in men and women combined. Error bars indicate 95% uncertainty intervals. CHD indicates coronary heart disease; CVD, cardiovascular disease; PUFA, polyunsaturated fat.

A 45-year-old woman has developed red, roughened skin in sun- exposed areas over the past 2 years. She also has a chronic, watery diarrhea. On physical examination she exhibits memory loss with confusion. These findings are most consistent with which of the following vitamin deficiencies? Vitamin A Thiamin Niacin Pyridoxine Vitamin E

This description is most consistent with niacin deficiency, Diarrhea, Dermatitis, Dementia

Which assessment tool would be in use if a patient was asked to recount everything they ate yesterday? Rote memory FFQ Food Journal Total Recall 24-hr recall

This is an example of E, a 24-hr recall

GLUT1

Tissue dist: Human RBC's, BBB, Blood-retinal barrier, blood-placental barrier, blood-testis barrier Expressed in cell types with barrier functions, high affinity for glucose transport system

Conversion of Glucose-6-Phosphate to Glucose via Glucose-6-phosphatase

Used in both gluconeogenesis and glycogenolysis Muscle lacks Glucose-6-phosphatase ➔ only liver glycogen can be used for blood glucose maintenance Hepatic deficiency of this enzyme leads to a specific type of glycogen storage disease Glucose 6-phosphate travels on a transporter into the endoplasmic reticulum (ER), where it is hydrolyzed by glucose 6-phosphatase to glucose and inorganic phosphate (Pi). These products travel back to the cytosol on transporters

Prescribe a "healthy diet" and lifestyle for disease prevention based on the current peer-reviewed evidence.How would you prescribe a healthy diet and physical activity plan for this patient?

You would want to know more about his cultural background, social situation (does he live alone or have family at home? Who prepares the meals?), Is access to a variety of foods difficult? What are his overall food preferences - e.g., does he eat a wide variety of foods? Does he eat animal protein, dairy, etc? Does he follow a certain diet for religious or cultural reasons? What are his options for physical activity that can accommodate his knee pain? Let's presume this patient is a Black American Muslim and follows the dietary practices in accordance with his religious beliefs (e.g., avoids pork and any foods that are not considered halal, or lawful). He observes Ramadan annually. He also prefers to avoid dairy products. Let's also presume that upon further discussion with him, you learn that he is married (for 40 years!) and his wife does most of the food preparation. Their 3 children are grown and out of the house. Review of his medical record reveals that patient also has new onset hypertension.

Describe the major types (including their pros and cons) of nutrition assessment methods Diet assessment

asking the person how/what they eat/ate. Often relies on recalling the past, like in the case of a "diet recall" or a Food Frequency Questionnaire (FFQ). There are prospective methods like food duplicates that are more accurate, but also more costly because they rely on the participant collecting exact duplicates of what they eat, which are then provided to the research team for analysis.

G6P to pyruvate vs pyruvate to G6P

glycolysis vs GNG

Functional Assessment:

grip strength, ability to do activities of daily living, etc.

Incretins

gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating.

Glucose taken up by which cells

intestinal epithelium cells and gut bacteria ferments fiber

Biochemical assessment methods:

labs like Comprehensive Metabolic Panel (CMP) which include things like Albumin, electrolytes, renal function indicators (BUN, Creatinine), and liver function tests (liver enzymes like Alanine transaminase (ALT), Aspartate transaminase (AST), and Alkaline phosphatase (ALP). C-reactive protein is also helpful to better understand a patient's inflammatory state.

Body fat/lean body mass methods:

skin calipers (requires experienced user, but affordable), densitometry (requires special costly equipment, some patients cannot tolerate the water or small space required). Densitometry has been considered the gold standard for assessing body composition. Bioelectrical Impedance Analysis is easy for the participant and affordable (hundreds or few thousand dollars), but also dependent on hydration status. Other body composition tests are costly too, such as MRI or dual-energy X-ray absorptiometry (DEXA), but can also very accurately assess lean and fat mass.

Functional Assessment

•Activities of Daily Living (ADL's) •Strength -e.g., grip strength •Hospitalized patients with poor grip strength ➔ increased LOS (length of stay), reduced ability to return home, and increased mortality -Nutritional Assessment Techniques

Effects of Carbohydrate Intake

•After a high-carbohydrate meal, blood glucose rises from a fasting level of approximately 80 to 100 mg/dL (~5 mM) to a level of approximately 120 to 140 mg/dL (8 mM) within a period of 30 minutes to 1 hour • •Concentration of glucose in the blood begins to decrease, returning to fasting range by approximately 2 hours after the meal

Assessing Nutrition Research

•Are the authors reporting the results of a single study? If so, where does it fit in with other studies on the topic? •How large is the study? •Are the findings related to the research question(s)? •Where and when was it published? •Was the study done in animals or humans?

G6PD preventative tx

•Avoid oxidant stresses - •Certain medications (oxidant drugs such as Antibiotics, Antimalarials, Antipyretics) can exacerbate the condition •Favism •Blood transfusions if symptomatic •For acute attack: oxygen and bed rest

Subjective Global Assessment - SGA

•Based on the clinical judgment of 4 subscales 1.recent weight changes 2.dietary intake 3.GI symptoms 4.loss of subcutaneous fat and signs of muscle wasting •Most often used in Hemodialysis patients, but occasionally used in other populations (put a pin in this for the Renal System)

Glycogen Storage Disease 3: Cori's (GSD TypeIII)

•Cannot be distinguished from von Gierke disease (type I) by physical examination alone •Lacking the debranching enzyme (α-1,6-glucosidase), and so only the outermost branches of glycogen can be effectively utilized •Structure of liver and muscle glycogen is abnormal and the amount is markedly increased •Outer branches of the glycogen are very short ➔only a small fraction of this abnormal glycogen is functionally active as an accessible store of glucose

Glycogenolysis and glycogenesis

•Coordinated regulation of the rate of glycogen synthesis (glycogenesis) and the rate of glycogen breakdown (glycogenolysis) •Reciprocally regulated •Hormones that stimulate glycogenolysis (e.g. glucagon, cortisol, epinephrine, norepinephrine) simultaneously inhibit glycogenesis •Conversely, insulin stimulates glycogenesis while simultaneously inhibiting glycogenolysis

Glycogen Storage Disease 1 Von Gierke's (GSD Type I) question

•Deficiency in glucose 6 phosphatase •Inability to release phosphate from glucose- 6-phopsphate results in diversion into glycolysis + pyruvate + increased diversion into the pentose phosphate pathway •Production of excess pyruvate, at levels above of the capacity of the TCA cycle to completely oxidize it, results in its reduction to lactate resulting in lactic acidemia

Glycogen Storage Disease 4: Anderson's Disease(GSD4)

•Deficient glycogen-branching enzyme •Classic hepatic form typically becomes apparent during the first months of life •Disease course varies, including age of onset, associated signs/symptoms, degree of abnormal glycogen accumulation in various tissues, and specific organs affected •Symptoms: failure to grow at the expected rate (failure to thrive) and abnormal enlargement of the liver and spleen (hepatosplenomegaly)

How To Help Your Patients

•Don't promote things that are costly, dangerous or ineffective •Anecdotes are not equal to evidence •Don't be afraid to say I Don't Know •Target what changes patients need to make for CVD health by doing a quick assessment of diet and exercise patterns •Focus on the reasons why change is needed, rather than how they should make the change •Avoid "Red Flag Claims" •USE COMMON SENSE •Refer to your local Registered Dietitian Nutritionist

Dz associated with Nutrition status

•Edema -In ambulatory patients, no impression should remain following pressure application •Ascites -Should not be present in healthy individuals -Degree of fluid accumulation in abdominal cavity can be indicative of nutrition status

Energy vs. Nutrient Density

•Energy dense ➔ more calories compared to nutrients •Nutrient dense ➔ more nutrients compared to calories • •Excess portion sizes with an energy dense diet is a very common contributor to the obesity epidemic.

The Registered Dietitian Nutritionist (RDN)

•Estimates nutritional needs based on individual goals •Assesses usual intake/lifestyle and suggests individualized, appropriate action •Provides the patient with education, support and encouragement to achieve desired goals •Provides patient, family and health care team education/instruction •Works as a part of the medical team » Minimum Qualifications: Bachelors degree + complete a min. 900 hour internship, and pass a national registration exam to practice, plus continuing ed •Where will you see RDNs?

Common Nutrition Research Designs: RCT (randomized controlled trial)

•Follows a group (usually a large group) of people over time like cohort studies •Procedures are controlled to ensure that all participants in all study groups are treated the same except for the intervention group •Intervention ("trial") to see how a specific behavior change (e.g., walking, eating vegetables, or meditation, etc) or treatment (e.g., drug) affects a health outcome •People in the study are randomly assigned either to receive or not receive the intervention

Common Nutrition Research Designs: Cohort Studies

•Follows a group of people over a long period of time •Can be very large, epidemiological (involving thousands of people) in nature OR smaller, community-based studies (involving tens or hundreds of people) •Characteristics of people in the group are compared to test specific hypotheses •Time-consuming •The larger the sample size, the more costly the study •Provides more reliable information than case-control studies because they don't rely as much on information from the past - e.g., Nurses Health Studies, The Framingham Heart Study, The Adventist Health Study and many others

Human Research Participants

•Free-living human research is not easy -Lots of variables to consider - socioeconomic status, diet, activity, co- morbid conditions, environmental factors, etc •Requires Institutional Review Board (IRB) approval •Usually involves some type of incentive to participants - gym memberships, gift cards, free food, etc •Informed Consent -Requires researcher training and experience -Can be a lengthy process, but it's a must!

Glucocorticoids

•GCs stimulate lipolysis in adipose tissue and the release of amino acids from muscle protein • •In liver, glucocorticoids stimulate gluconeogenesis and the synthesis of glycogen • •The breakdown of liver glycogen is stimulated by epinephrine

Nutrition History

•General vs. Specific - specific is more useful •Adequate variety? •Difficulty obtaining adequate food/calories? •Consuming enough or too many calories? •Any obvious signs/symptoms for deficiencies? •Food allergies/intolerances? •Social influences?

Glucagon Release from Pancreas

•Glucagon is released rapidly when blood glucose is low •Glucagon exerts effects on cells by binding to a receptor located on the plasma membrane of target cells for this hormone •Binding to these specific receptors by glucagon stimulates the synthesis of the intracellular second messenger, cyclic adenosine monophosphate (cAMP)

Densitometry

•Gold standard for assessing body composition •Works off the principle of displacement •Underwater Weighing Watch this 5 min. video Pros: very accurate Cons: limited availability, expensive (capital), not appropriate for patients not comfortable under water, modest patients may feel uneasy •Bod Pod Watch this 2 min. video Pros: very accurate Cons: limited availability, expensive, not appropriate for patients not comfortable in tight spaces, modest patients may feel uneasy, larger patients may not fit

Common Nutrition Research Designs: RCT (randomized controlled trial) Pros and Cons

•Good for looking at topics like vitamin supplements (or drugs) and a disease end-point •When the change in diet is more involved than taking a pill, participants may have trouble sticking to the prescribed diets (DASH was a RCT Feeding Trial) •Harder to do with dietary factors; no practical placebos for foods •Can also be very expensive and challenging to coordinate and manage

Anthropometrics: the scientific study of measurements of the humanbody

•Height •Weight •Recent weight loss = marker of nutritional status •More than 5% in 1 month or 10% in 6 months before hospitalization = clinically significant •Waist Circumference •Weight for height •BMI •Body fat assessment •Skin calipers - user-dependent •Bioelectrical Impedance •Hydrostatic weighing, Bod Pod •Other methods

Incretin Effect

•IV-obtained glucose has a different effect compared to GI-obtained glucose •Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating. •Incretins regulate the amount of insulin that is secreted after eating. •If IV glucose infusion is adjusted so that the resulting plasma glucose concentrations are identical to those after oral or small intestinal administration of glucose, substantially more insulin is secreted with oral or enteral administration, a phenomenon known as the incretin effect

Glucose 6-Phosphate Dehydrogenase Deficiency

•Inability to recycle glutathione via lack of NADPH •Highest prevalence in Middle East, tropical Africa and Asia, and parts of the Mediterranean •Inherited x-linked deficiency •Most common disease-producing enzyme deficiency in humans - affects more than 400 million people worldwide •Chronic hemolytic anemia, but increased resistance to malaria

Concentration of ATP vs. ADP vs. AMP in Skeletal Muscle

•Large pool of ATP in cytosol •During exercise... •[ATP] decreases by 20% •[ADP] increases by 50% •[AMP] increases by 300% ➔ •AMP is a very sensitive energy status indicator for the cell •AMP levels activate multiple pathways

Glycogen Storage Disease 4: Anderson's Disease(GSD4) treatment

•Leads to a generalized accumulation of structurally abnormal glycogen (e.g., long, unbranched outer chains) in various body tissues •Can affect the liver, skeletal muscles, heart, nervous system, and/or other bodily tissues •Treatment •Symptomatic and supportive •Includes long-term management of cirrhosis/liver function; neuromuscular disease; and/or heart dysfunction. •May require dietary measures to maintain normal levels of glucose in the blood (normoglycemia) and provide sufficient nutritional intake in order to improve liver function and muscular strength.

Liver Glycogen

•Liver glycogen is used to regulate systemic blood glucose levels •Glucose reserve in between meals and during fasting •Used especially for neural tissue energy needs •Depleted within 12-24 hours

Common Nutrition Research Designs: Case-control Studies

•Looks at characteristics of a group of people who already have a certain health outcome (cases) and compares them to a similar group of people who do not have the outcome (controls) •PROS: -Can be done quickly -Compared to large RCTs, case-control studies are relatively inexpensive •CONS: -Typically gathers information from the past -People with illnesses often recall past behaviors differently from those without illness

Summary of Major Regulatory Points of Glycolysis

•Major function of glycolysis is ATP generation •In resting skeletal muscle, HIGH ATP and low AMP inhibit glycolysis •In working skeletal muscle, lower ATP and higher AMP stimulate glycolysis during exercise, inc glycolysis •Liver glycolysis requires stimulati•Major function of glycolysis is ATP generation •In resting skeletal muscle, HIGH ATP and low AMP inhibit glycolysis •In working skeletal muscle, lower ATP and higher AMP stimulate glycolysis •Liver glycolysis requires stimulation by insulin and F-2,6-Bisphosphateon by insulin and F-2,6-Bisphosphate

Recognizing and Preventing Malnutrition: Why We Assess Nutrition Status

•Malnutrition is associated with unfavorable outcomes: -higher infection rates -poor wound healing -longer lengths of stay -higher frequency of readmission •Nutrition Assessment is step #1 in preventing malnutrition in your patients!

Body Composition Assessment

•Measures lean body mass (muscle) •Measures fat mass (adipose) •Influences energy needs -More lean body mass ➔ more energy burned/used -More fat mass ➔ less energy burned/used •Informs nutrition assessment •Informs overall health risk

Glycogen Storage Disease 2, Pompe's Disease (GSDII)-lysosomal functions disrupted

•Missing α-1,4-glucosidase •Unable to break down glycogen in the lysosome •Disables the heart and skeletal muscles •Glycogen accumulates in lysosomes & muscles •Classic form is infantile-onset •Non-classic form still usually appears by age 1 •Delayed motor skills, failure to thrive •Can be treated with enzyme replacement therapy, which requires periodic enzyme infusions for life - without it, the disorder is fatal. Picture: Glycogen-Engorged Lysosome in skeletal muscle from an infant with type II glycogen- storage disease (Pompe disease)

Pyruvate Dehydrogenase (PDH) complex

•Multi-enzyme complex •Pyruvate dehydrogenase (E1): TPP, thiamin TPP to acyl-TPP (pyr to CO2) •Dihydrolipoyl transacetylase (E2): acyl-lipoate to Lip-S-S and Lip-SH-SH (coASH to ac-coA) coenzymeA helps catalyze disulfide bond formation •Dihydrolipoyl dehydrogenase (E3): Riboflavin FADH to FAD (using NAD+ niacin to NADH+H+) •Regulation •Inactive with phosphorylation •level of Acetyl CoA inhibits PDH (product inhibition) catalyzes conversion of pyruvate to ac-coA with coenzyme A, NAD+ and production of CO2

Muscle glycogen serves two distinct purposes

•Muscle glycogen is used to provide muscle with energy •Glucose derived from muscle glycogen cannot be released from muscle due to lack of glucose-6- phosphatase

Pentose Phosphate Pathway (PPP)

•No ATP produced or used •Occurs primarily in cytosol of liver, lactating mammary glands, adipose tissue, adrenal cortex, and RBCs - but performed in all cells •Generates intermediates not produced elsewhere 1.Pentose phosphates (5-ribose phosphate) 2.NADPH •Synthesis of fatty acids and cholesterol •Maintains reduced form of glutathione •Immune function Oxidative portion of the PPP is regulated by Glucose- 6-Phosphate Dehydrogenase

Indirect Calorimetry (IC)

•Not an anthropometric study •"Metabolic Cart" study •Feeding a critically ill patient 3 min •Clinical example 6 minutes •Outpatient exercise physiology example 2 min •Clinical utility - used more than the other methods in hospital setting •Quantifies energy expenditure based on O2 consumption, CO2 production, and heat production •Uses different equations than free-living energy estimations •Typically only used in selected ICU patients receiving enteral or parenteral nutrition •Also used on free-living persons (e.g., athletes) in exercise physiology lab setting

Glycolysis vs Gluconeogenesis in the liver

•Not identical •Gluconeogenesis shares 7 of the 10 glycolytic rxns

Confusion Abounds

•Nutrition and diet are always a "hot topic" and your patients will ask you about it •Conflicting ideas and studies reported in the media •Confusing information •Confusing food labels •Media "experts" espousing one view or another

Common Nutrition Research Designs: Lab and Animal Studies

•Offers controlled conditions; useful for new investigations or novel topics/processes not well-understood -Cell culture •e.g., Role of nutrients and mTOR signaling in the regulation of pancreatic progenitors development. Molecular Metabolism. 2017 Mar 28;6(6):560-573. doi: 10.1016/j.molmet.2017.03.010. eCollection 2017 Jun. •e.g., Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice. Hepatology. 2018 Jun;67(6):2150-2166. doi: 10.1002/hep.29676. Epub 2018 Apr 16.

Common Nutrition Research Designs: Prospective vs. Retrospective

•Often diet and lifestyle is assessed retrospectively -e.g. Tell me what you ate in the past 24 hours or "How much exercise did you get in the past week?" -While convenient, there is a higher chance of inaccuracies •Prospective diet and activity tracking takes more diligence (and sometimes technology), but can be well worth the effort in the quality of data collected -looks to the future

Physical Assessment of Nutrition Status

•Orbital fat pads •Triceps skinfold thickness - 1 cm or less = malnourished •Temples •Clavicle •Shoulders •Interosseus muscle •Anterior lower ribs •Scapula •Thigh and Calf

G6PD precipitating factors/causes and sx

•Precipitating factors •Oxidant drugs - aspirin, anti-malarials, anti-inflammatories •Fava beans •Infection Neonatal jaundice •Most common clinical feature is a lack of symptoms •Acute life-threatening hemolysis •Fever, abdominal pain, nausea, diarrhea, and hemoglobinuria Enlarged, tender spleen

Glycogen Storage Disease 1 Von Gierke's (GSD Type I) symptoms and tx

•Primary symptom of GSDI in infancy is low blood sugar level (hypoglycemia) •In untreated patients: failure to thrive, stunted growth, hepatomegaly •Shaking, sweating, inconsolable/crying, loss of motor function , lethargy, confusion (often more noticeable in older children) •Doll-like faces with fat cheeks, relatively thin extremities, short stature, and protuberant abdomen (due to hepatomegaly) • Treatment •Special diet to maintain glucose levels, prevent hypoglycemia and maximize growth and development •Increased dependence on fat metabolism •Small frequent meals high in carbohydrates throughout life, nighttime enteral feedings

Nutrition Risk Assessment

•Pulls all the assessment pieces together •Allows the clinician to anticipate issues related to nutrition Examples: -If a patient is extremely underweight with poor dentition, they would likely benefit from a mechanically soft, high calorie diet with frequent monitoring by the clinical dietitian. This person would likely be considered at higher nutrition risk. -Premature babies; children with new onset diabetes; very elderly or frail people; persons with no oral intake for prolonged periods of time (NPO); severe weight loss; cachexia; requiring nutrition support ➔ all of these are examples of patients at higher nutrition risk -A patient eating a normal diet, in normal weight range, recovering from a broken leg or appendectomy (for example), most likely would be at low nutrition risk

Glycolysis vs. Gluconeogenesis

•Reciprocally regulated to avoid a futile cycle •Negative effectors of glycolysis are positive effectors of gluconeogenesis = reciprocal regulation •Gluconeogenesis requires 3 bypass steps to overcome Glycolysis •Regulation involves: covalent modifications, allosteric mechanisms and substrate availability •gluconeogenic precursors (lactate, amino acids, glycerol), strongly influence the rate of gluconeogenesis •Regulation of the activity of PFK-1 and Fructose 1,6-Bisphosphatase is the most significant site for controlling the flux toward glucose oxidation or glucose synthesis

Blood Glucose Levels at Various Stages of Fasting

•Regulatory mechanisms control the conversion of glucose to stored fuels •As glucose concentration increases in the hepatic portal vein, concentration of glucose in the liver may increase from the fasting level of 80 to 100 mg/dL (~5 mM) to a concentration of 180 to 360 mg/dL (10 to 20 mM). Stage of Fasting Glucose (mg/dL) Glucose, 700 g/d IV* 100 Fasting, 12 h 80 Starvation, 3 d 70 Starvation, 5-6 wk 65

Evidence-Based Strategies to Enhance Adherence to Changes in Diet and Eating Behaviors

•Self-monitor behaviors •Set realistic, measurable goals •Enhance self-efficacy •Prevent relapse •Reinforce with positive feedback •Control stimuli to limit undesirable behaviors •Promote adequate social support •Provide ongoing contact Tailor or personalize the regimen for that patient

Other Methods of Assessing Body Composition

•Skin Fold Testing (multiple sites are used for increased accuracy of the measurement) Watch this 2 min. video Pros: fairly quick and easy Cons: accuracy varies depending on person performing the measurements, requires training and practice, quality calipers are pricey, modest patients may feel uneasy •Bioelectrical Impedance Analysis (BIA) (same technology as used in standing scales with hand-holds, but different accuracy; depends on proper hydration of the subject) Watch this 2 min. video Pros: fairly quick and easy Cons: accuracy varies depending on hydration status

Nutrition Assessment In-depth evaluation of both objective and subjective data related to a person's food/nutrient intake, lifestyle, and medical history. Collected and organized by the practitioner to permit assessment and evaluation of the nutritional status of the person.

•Social situation •Socioeconomic situation •Medical History - Including medications, supplements, herbs, etc •Dietary history, usual eating habits •Dieting history •Appetite •Anthropometrics •Functional assessment •Labs

How should we (medical professionals) prescribe a healthy diet?

•THIS: "eat 5 servings of non-starchy vegetables daily" or "eat breakfast daily" or "limit your tortilla intake to just two 6-inch tortillas per meal rather than six" • AND •"Here is a handout explaining portion sizes" or "Here is a list of non- starchy vegetables" or "I'm referring you to a registered dietitian nutritionist to get some more comprehensive education on what/how you should be eating"

Glycogen Storage Disease 5: McArdle's Disease(GSDV)

•The metabolism of glycogen to glucose in muscle does not occur as it should •Inadequate/Defective/Missing muscle glycogen phosphorylase •Model explaining the physiology of this disorder can be found here •Significant physical limitations - exercise intolerance •painful cramping that can occur during moderate to intense physical activity •Not directly life-threatening •Regular physical activity at appropriate intensity and duration can improve symptoms and make muscles less susceptible to injury •Consume carbohydrates prior to exercise

How should we (medical professionals) prescribe a healthy diet?

•The same way drugs are prescribed •Based on evidence - not anecdote or opinion •Provide specific instruction •NOT THIS: "eat healthier" or "watch what you eat" or "eat fewer carbs" or "eat less fat" or "exercise more" But, Why Not??? •All of those examples are too general and vague. •Would you tell your patient to just "take aspirin" or "take X medication"? No! •You would tell a select patient, based on risk level, to take a specific amount of aspirin (e.g., 81mg), for a specific frequency (e.g., every morning) and for a specific amount of time (e.g., indefinitely)

Biochemical Assessment

•There is no one lab test to indicate nutrition status •Lab tests used might include -Serum protein levels •Albumin levels are not reliable for hospitalized patients or anyone with an acute injury -C-reactive protein (a marker of inflammation) -Renal and liver function -Immune competence

Glycogen Storage Diseases (Normal vs Hepatic vs Myopathic types)

•Typically impact either liver's ability to regulate blood glucose levels OR •Muscle ability to keep itself energized ➔Accumulation of glycogen OR ➔Inability to release stored glycogen

Uridine Diphosphate-Glucose

•UDP-Glucose is an activated sugar nucleotide •Energetically favorable and very stable intermediate •Precursor of glycogen and lactose; UDP- glucuronate and glucuronides; and the carbohydrate chains in proteoglycans, glycoproteins, and glycolipids •Required for the synthesis of many carbohydrate portions of those compounds, a sugar is transferred from the nucleotide sugar to an alcohol or other nucleophilic group to form a glycosidic bond

Glycogen Storage Diseases

•Understand the enzyme defect involved and how that produces the signs/symptoms of the condition 1.Type I, von Gierke's ➔ glucose 6-phosphatase (liver) 2.Type II, Pompe's ➔ α-1,4-Glucosidase (lysosomal) 3.Type III, Cori's ➔ debranching enzyme (liver and muscle) 4.Type IV, Andersen's ➔branching enzyme (liver and muscle) 5.Type V, McArdle's ➔glycogen phosphorylase (muscle)

Thought Questions

•What is a healthy diet? -Any diet based on sound nutritional principles -A belief that organic and/or unprocessed foods-i.e., produced without pesticides and chemical preservatives, are superior to adulterated foods -Aids in maintaining a healthy weight -Prevents chronic disease -Promotes general well-being •How do you define a healthy diet? •How should we (medical professionals) prescribe a healthy diet? A "healthy diet" varies greatly depending upon who you ask, their cultural background, and life experiences

Fed vs. Fasting Reminders

•Why gluconeogenesis? •Heavy reliance on glucose for some tissues •Brain and nervous system, RBCs, testes, kidney, embryonic tissue •To supply the body with glucose during times of fasting •Glycogen stores are not always sufficient to meet needs •Locations of gluconeogenesis •Liver, kidney •Epithelial cells lining the small intestine

Amylopectin

•contains 10,000 to 100,000 glucose units and is highly branched

Amylose/starch

•contains 100 to 10,000 glucose units and is less heavily branched compared to amylopectin. •Linear shape allows amylose to pack more tightly into the less accessible regions of starch granules; can be more difficult to digest.

Glycogen Structure Overview

•the bulk of our glycogen stores are located in our liver and skeletal muscle •Synthesis requires energy inputs •Glycogen is a highly branched glucose storage polymer ➔Permits rapid degradation •Stored as cytoplasmic granules •Also contains most of the enzymes necessary for synthesis and degradation •Can be exhausted in less than an hour during vigorous physical activity

More specifically, here is how pyruvate gets from cytosol into the mitochondria. Look at the bottom right corner of this picture.

▪ (I won't ask you the name of this transporter, but it is sometimes called the monocarboxylic acid transporter 1, MCT1) ▪ Transport across the outer mitochondrial membrane involves a voltage-dependent porin transporter ▪ Because the mitochondrial membrane has no OAA transporter, OAA formed from pyruvate must be converted into malate by mitochondrial malate dehydrogenase before exporting from the mitochondria. ▪ Following reduction of OAA to malate, the malate is transported to the cytosol by the malate transporter (labeled as SLC25A11 in this image - a detail you do not need to know), and then converted back into OAA by cytosolic malate dehydrogenase. Now, gluconeogenesis can proceed to the next bypass step. You WILL NOT need to know all the details of this image. However, you should know that Lactate Dehydrogenase converts Lactate into Pyruvate, and Alanine Aminotransferase converts Alanine into Pyruvate. AND that getting from Pyruvate to OAA and PEP requires extra steps as described above.

Prescribe a "healthy diet" and lifestyle for disease prevention based on the current peer-reviewed evidence.How would you prescribe a healthy diet and physical activity plan for this patient? Therefore, a healthy diet and physical activity plan for this patient might look something like this:

▪ Education about the DASH diet (which you can read more about, if you're curious: https://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/in- depth/dash-diet/art-20048456), easily modified to encompass his avoidance of dairy ▪ Agreement from the patient that he is willing to eat 7-9 servings of fruits/vegetables daily with the help of his wife's grocery shopping and food preparation/meal planning skills. ▪ Agreement from the patient that he will ride the stationary bike that they have in their garage for 10-15 minutes, three days per week for 1 month. After that month, reassess knee pain and overall tolerance of cycling, and increase to 20 minutes per session if tolerated. ▪ May also consider starting an antihypertensive medication, but that will be influenced by degree of hypertension and is beyond the scope of this scenario. ▪ Ask the patient to call in to speak to medical assistant/nursing staff if he is unable to increase cycling, or if the meal plan is not working/not tolerated. Follow up as needed, but probably in about 3-6 months with a provider visit (depending on if medications are started for HTN)

Regulation of Blood Glucose Summary

▪"normal" blood glucose for persons without diabetes ranges between approx. 80-100mg/dL ▪For persons without diabetes, hypoglycemia is when blood glucose gets low enough to cause signs/symptoms, which can (but don't always) include: ▪Hunger ▪Cranky ▪Shaking ▪Sweating ▪Dizziness ▪Headache, followed by drowsiness and, eventually, coma ➔ death

Anaerobic glycolysis

▪Anaerobic glycolysis generates energy in cells with a limited supply of oxygen or few mitochondria. ▪Under anaerobic conditions, pyruvate is reduced to lactate by NADH, thereby regenerating the NAD+ required for glycolysis to continue. ▪Glycolysis is regulated to ensure that ATP homeostasis is maintained. ▪The key regulatory enzymes of glycolysis are hexokinase/glucokinase, phosphofructokinase-1, and pyruvate kinase.

appetite and fuel metabolism

▪Aside from insulin and glucagon, many other proteins influence appetite and fuel metabolism. ▪Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating ▪GIP and GLP1 are two incretins that reduce post-prandial blood glucose elevation ▪Ghrelin stimulates appetite; the "hunger hormone" ▪Amylin is a co-secreted with insulin in response to oral nutrients, it "helps" the effects of insulin, reduces appetite ▪Glucocorticoids increase fuel availability; stimulate glucose production via glycogenolysis and gluconeogenesis; and stimulate lipolysis in adipose tissue and the release of amino acids from muscle protein

The Glycogen Cascade

▪Epinephrine/Glucagon trigger a G-protein stimulated second- messenger cascade ▪Glycogen Phosphorylase is phosphorylated (making it ACTIVE) and Glycogen Synthase is also phosphorylated (but making it INACTIVE) ▪PLP (vitamin B6) is a cofactor in Glycogen Phosphorylase activity

Precursors for gluconeogenesis are supplied by peripheral tissues:

▪Exercising muscle and red blood cells provide lactate through glycolysis, ▪muscle provides amino acids by degradation of protein, and ▪glycerol is released from adipose tissue as triacylglycerol stores are mobilized

Misc. Carb Metabolism: Fructose

▪Fructose is ingested principally as the monosaccharide, or as part of sucrose. ▪Fructose metabolism generates fructose 1-phosphate, which is then converted to intermediates of the glycolytic pathway. ▪Lack of aldolase B, leading to an accumulation of fructose 1-P after fructose ingestion. The increased levels of fructose 1-P interfere with glycogen metabolism and can lead to hypoglycemia, ➔requires avoidance of fructose (and sucrose), very limited fruit/veg intake

Galactose

▪Galactose is ingested principally as lactose, which is converted to glucose and galactose in the intestine. ▪Galactose metabolism generates, first, galactose 1-phosphate, which is converted to UDP-galactose. ▪The end product is glucose 1-phosphate, which is isomerized to glucose 6-phosphate, which then enters glycolysis. ▪Mutations in either galactokinase or galactose 1-P uridylyltransferase, leads to elevated galactose and/or galactose 1-P levels ➔ requires lifelong avoidance of lactose

Gluconeogenesis Summary

▪Gluconeogenesis occurs primarily in the liver. ▪The major precursors for glucose production are lactate, glycerol, and amino acids. ▪The gluconeogenic pathway uses the reversible reactions of glycolysis, plus additional reactions to bypass the irreversible steps of glycolysis. ▪Pyruvate carboxylase (pyruvate to oxaloacetate [OAA]) and phosphoenolpyruvate carboxykinase (PEPCK, OAA to phosphoenolpyruvate [PEP]) bypass the pyruvate kinase step ▪Fructose 1,6-bisphosphatase (fructose 1,6-bisphosphate to fructose 6-phosphate) bypasses the phosphofructokinase-1 step ▪Glucose 6-phosphatase (glucose 6-phosphate to glucose) bypasses the glucokinase step. ▪Gluconeogenesis and glycogenolysis are carefully regulated so that blood glucose levels can be maintained at a constant level during fasting. ▪The regulation of triglyceride metabolism is also linked to the regulation of blood glucose levels.

Glycolysis Summary

▪Glucose is oxidized and cleaved to form pyruvate during Glycolysis. ▪Glycolytic enzymes are in the cytosol. ▪Glucose is the primary carbohydrate in our diet; all cells can use glucose for energy and some cells rely on it heavily (red blood cells, neural tissue, etc). ▪Cytosolic NADH generated via glycolysis transfers its reducing equivalents to mitochondrial NAD+ via shuttle systems across the inner mitochondrial membrane. ▪The pyruvate generated during glycolysis can enter the mitochondria and be oxidized completely to CO2 by the pyruvate dehydrogenase complex and the TCA cycle

Liver glycogen is used to regulate systemic blood glucose levels

▪Glucose reserve in between meals and during fasting▪Used especially for neural tissue energy needs ▪Depleted within 12-24 hours, depending on diet and physical activity levels

Glycogen Summary

▪Glycogen is the storage form of glucose, composed of glucosyl units linked by α-1,4-glycosidic bonds with α-1,6-branches occurring about every 8 to 10 glucosyl units. Highly branched! ▪Glycogen synthesis requires energy. ▪Glycogen synthase transfers a glucosyl residue from the activated intermediate UDP-glucose to existing glycogen chains during glycogen synthesis. Branching enzyme creates α-1,6-linkages in the glycogen chain. ▪Glycogenolysis is the degradation of glycogen. Glycogen phosphorylase catalyzes a phosphorolysis reaction, using exogenous inorganic phosphate to break α-1,4-linkages at the ends of glycogen chains, releasing glucose 1- phosphate. Debranching enzyme hydrolyzes the α-1,6-linkages in glycogen, releasing free glucose. ▪Liver glycogen supplies blood glucose. Muscle glycogen supplies muscle with glucose which is oxidized through glycolysis for energy.

Glycogen synthesis

▪Glycogen synthesis and degradation are regulated in the liver by hormonal changes that signify either a deficiency of or an excess of blood glucose. ▪Lack of dietary glucose, signaled by a decrease of the insulin/glucagon ratio, simultaneously activates liver glycogenolysis and inhibits glycogen synthesis. Epinephrine and glucagon activate liver glycogenolysis. Epinephrine activates muscle glycogenolysis. ▪Glucagon and epinephrine release lead to phosphorylation of glycogen synthase (inactivating it) and glycogen phosphorylase (activating it). ▪Glycogenolysis in muscle supplies glucose 6-phosphate for ATP synthesis in the glycolytic pathway. ▪Muscle glycogen phosphorylase is allosterically activated by AMP and by phosphorylation. ▪Increases in sarcoplasmic Ca2+ (from muscle contraction) stimulate phosphorylation of muscle glycogen phosphorylase. ▪There are many Glycogen Storage Diseases, but we focused on 5.

PFK-1 Reaction - complex regulation and principle regulatory step

▪Involved in F6P to F-1,6,-bisphosphate (ATP hydrolysis) and Mg cofactor Multiple substrate binding sites ▪Multiple allosteric binding sites ▪Activity is increased with reduced [ATP] or elevated [AMP] via allosteric modification ▪Complex, allosteric activation via PFK-2 and Fructose-2,6- bisphosphate

1.Which enzymes release CO2?

▪Isocitrate Dehydrogenase and α-KG

▪Glucose 6-phosphate dehydrogenase deficiency

▪Lacks of glucose 6-phosphate dehydrogenase leads to hemolytic anemia in the presence of strong oxidizing agents

1.How many OAA are consumed for each CO2 produced?

▪No net consumption of OAA ▪First step uses OAA but the last step produces OAA ➔anaplerotic

PPP

▪Pentose phosphate pathway consists of both oxidative and nonoxidative reactions ▪ The oxidative steps of the pentose phosphate pathway generate reduced nicotinamide adenine dinucleotide phosphate (NADPH) and ribulose 5- phosphate from glucose 6-phosphate. ▪Ribulose 5-phosphate is converted to ribose 5-phosphate for nucleotide biosynthesis. ▪NADPH is used as reducing power for biosynthetic pathways. ▪Uridine diphosphate (UDP)-glucose and UDP-galactose are substrates for many glycosyltransferase reactions.

Galactosemia autosomal recessive disease symptoms

➔liver failure, renal failure, cataracts, and brain damage ▪Without treatment,75% mortality in infants ▪Treatment: no milk, including breastmilk

Carb metabolism

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