Ch. 19 Flashcards
What are the 3 major sources of metabolic fuel? What pathways convert them into ATP?
- Proteins, carbohydrates, and lipids
- Amino acid metabolism, carbohydrate metabolism, lipid metabolism, the citrate cycle, and oxidative phosphorylation
What is the metabolic function of the liver?
Metabolic control center of the body
- Who gets what: determines what dietary nutrients and metabolic fuels are distributed to the peripheral (nonliver) tissues
- Physiologic glucose regulator that removes excess glucose from the blood when carbohydrate levels are high (glucose influx)
- Releases glucose from stored glycogen or as a product of gluconeogenesis when blood glucose levels are low (glucose efflux)
- First organ to inventory the contents of a meal
What is the metabolic function of the brain?
Control center of body
What is the metabolic function of cardiac muscle?
Maintains blood flow through circulatory system
What is the metabolic function of the stomach?
Prepares food for small intestine (food digestion) by producing chyme, secretes hormones
What is the metabolic function of the large intestine?
- Absorbs water and electrolytes
- Secretes hormones
What is the metabolic function of the small intestine?
- Absorbs nutrients
- Secretes peptide hormones that control eating behaviors through neuronal signaling in the brain
What is the metabolic function of skeletal muscle?
- Voluntary body movement
- Stores glucose as glycogen
What is the metabolic function of adipose tissue?
Fat storage and hormone secretion
What is the metabolic function of the pancreas?
- Secretes insulin and glucagon in response to changes in blood glucose levels
- Secretes digestive proteases that degrade dietary proteins in the small intestine: trypsin, chymotrypsin, elastase
What is the metabolic function of the kidneys?
Remove waste products and export glucose
What is chyme?
Slurry of food and gastric juice generated in the stomach and delivered to the small intestines to facilitate nutrient absorption
What controls blood glucose regulation by the liver?
Insulin and glucagon signaling
What is the portal vein?
Carries blood from GI tract and spleen to liver
- Directly delivers nutrients from small intestine and inactivates toxins from the diet
What is xenobiotic metabolism in the liver?
Metabolism of compounds that are foreign to the organism (drugs, pesticides, poisons)
What is an important cofactor in detoxification and elimination of many drugs and xenobiotics metabolized in the liver?
NADPH
What are the 3 phases of xenobiotic metabolism?
- Cytochrome P450 oxidases (NADPH-dependent) introduce polar or reactive groups to the foreign compound
- It is then conjugated to a polar compound (for example, glutathione, GSH) catalyzed by glutathione S-transferases to form GS-X
- Conjugated xenobiotics are pumped out by efflux transporters or pumps (for example, multiple drug resistance proteins). They are one of the major causes of anticancer drug resistance
What are the fates of glucose-6-phosphate?
Converted to 4 products
1. Glucose-1-P for glycogen synthesis
2. Glucose for release into blood
3. 6-Phosphogluconolactone for PPP
4. Fructose-6-P for glycolysis
What is skeletal muscle?
Striated muscle that attaches to the skeletal system and is responsible for voluntary movement
What is cardiac muscle?
Striated muscle that forms the contractile tissue of the heart
What does skeletal muscle use for energy?
Fatty acids, glucose, or ketone bodies
What do muscles use for short bursts of energy?
Intracellular ATP pool
What do muscles use for more sustained levels of activity?
Additional ATP is synthesized by creatine kinase
What is creatine kinase?
Enzyme that interconverts ATP and phosphocreatine using ADP and creatine as substrates
What is phosphocreatine?
Molecule in muscle cells that is used to carry out substrate-level phosphorylation to generate ATP
What is the function of the phosphocreatine shuttle?
Provides a ready supply of phosphocreatine to cells by transferring phosphate derived from mitochondrial ATP to creatine in the cytosol
What are the steps of the phosphocreatine shuttle?
- Mitochondrial ATP/ADP translocase protein exchanges ATP for ADP, resulting in the net transport of ATP out of the mitochondrial matrix and into the intermembrane space
- Mito CK converts cytosolic creatine into phosphocreatine (mitochondrial ATP as phosphate donor)
- Phosphate on cytosolic phosphocreatine is transferred to ADP by cyto CK to generate ATP
What does cardiac muscle use for energy?
Aerobic respiration using acetyl-CoA provided by fatty acids (β-oxidation and ketone bodies)
Does cardiac muscle store glycogen or fatty acids?
No
What is adipose tissue?
- Endocrine organ that secretes adipokines
- Fat storage as TGs
What are adipokines?
Peptide hormones secreted by adipose tissue that regulate metabolic homeostasis
Adipose tissue makes up what percent of an individual’s mass?
15-25%
What is subcutaneous fat?
Adipose tissue located just below the skin in the thighs, buttocks, arms, and face
What is visceral fat?
Layers of adipose tissue in the abdominal cavity; secretes adipokines
What are the relative body types that arise based on the amounts of visceral and subcutaneous fat in an overweight individual?
- More visceral fat: apple (higher risk of CVD)
- More subcutaneous fat: pear
What percent of oxygen does the brain use? (for oxidative phosphorylation)
About 20% of the oxygen consumed by the body
What does the brain use for energy?
Glucose (exclusively)
What are astrocytes?
Glial cells that surround neurons and are in close contact with the vasculature of the brain; astrocytes form the blood–brain barrier
What is the blood brain barrier?
- Physical barrier formed by astrocytes between the blood vessels and tissues of the brain
- Controls movement of substances from blood to brain
What is positron emission tomography (PET) imaging?
Neuroimaging technique that measures metabolic activity or blood flow changes in the brain by monitoring the distribution of radioactive glucose molecules
How much glucose does the brain require per day? Why is so much glucose needed?
- About 120g
- Needed to maintain electrical potential across the neuronal plasma membrane by Na+-K+-ATPase
Why can’t the brain use fatty acids?
Astrocytes lack the enzyme needed to recover fatty acids from TG in lipoproteins
What is hypoglycemia?
Medical condition in which blood glucose levels are much lower than normal, typically dropping from 80 mg/dL (4.4 mM) to less than 50 mg/dL (2.8 mM); associated with mental confusion and fainting
How much blood do 2 healthy kidneys filter per day?
6 L up to 30 times each day
- Remove 2 L of water containing concentrated levels of urea, NH4+, ketone bodies, and other soluble metabolites
What is hemodialysis?
Medical procedure in which the blood of a patient in renal failure is circulated through a machine containing a semipermeable membrane and a dialysis solution
What is metabolic homeostasis?
Process of maintaining optimal metabolite concentrations and managing chemical energy reserves in an organism
What are the 6 primary functions required to maintain metabolic homeostasis?
- Liver: export glucose, ketone bodies, and TGs to peripheral tissues to use as metabolic fuel
- Brain: requires constant input of glucose
- Cardiac muscle: uses mostly fatty acids and ketone bodies for energy needs, but also uses a little bit of glucose
- TG cycle: ongoing exchange of fatty acids and TGs between liver and adipose tissue (maintains circulation of high-energy fatty acids)
- Skeletal muscle: uses glucose and fatty acids for ATP synthesis and exports lactate back to liver
- Glutamine and alanine transport excess nitrogen from muscles to kidneys and liver for urea cycle
What affects metabolic homeostasis?
- Physical activity
- Psychological stress
- Timing and extent of feeding
- Tissue dysfunction
How is metabolic homeostasis controlled?
- Control of metabolic gene expression in response to signaling through nuclear receptors (PPARs)
- Biochemical response to insulin & glucagon
What does PPAR signaling do?
- Metabolic sensors of lipid homeostasis
- Lipid transport
- Mobilization
- Fatty acid oxidation
- Lipid synthesis
- Regulates gene expression in response to binding of low-affinity, fatty acid-derived nutrients
- Important in energy metabolism and insulin sensitivity
Where are insulin and glucagon synthesized as prohormones?
Islets of Langerhans (regions of the pancreas)
What are the 3 types of cells in the islets of Langerhans that produce?
- β cells (insulin)
- α cells (glucagon)
- δ cells (somatostatin)
What is somatostatin?
Paracrine hormone that controls secretion of insulin, glucagon, and acinar cell proteases
What are acinar cells?
Secrete digestive proteases destined for the duodenum
What triggers the release of insulin? What does insulin signaling do?
“I just ate”
- Elevated blood glucose levels
- Stimulates glucose uptake in liver, skeletal muscle, and adipose tissue and activates fatty acid uptake and TG storage in adipose tissue
- Decreases appetite through neuronal signaling in the brain
What does glucagon signaling do?
“I’m hungry”
- Stimulates glucose export as a result of increased rates of gluconeogenesis and glycogen degradation
- In adipose tissue, activates TG hydrolysis and fatty acid export
What are the effects of Insulin and glucagon signaling on metabolic pathways in major tissues?
What does epinephrine do?
Released into blood to prepare muscles, lungs, and heart for bursts of activity
What does cortisol do?
Mediates body’s response to long term stresses
How does the human body adapt to near-starvation conditions?
By altering the flux of metabolites between various tissues to extend life as long as possible
What makes up about half the volume of blood in a person?
Erythrocytes, leukocytes, and platelets
Why do erythrocytes rely on blood glucose for energy?
They lose nucleus and mitochondria during differentiation, so they get all their ATP from glycolysis
What are the 2 ways in which flux through metabolic pathways is altered to cope with starvation?
1. Gluconeogenesis occurs
2. Fatty acids are used as fuel
- High rates of fatty acid oxidation leads to build-up of acetyl-CoA
- Increased levels of acetyl-CoA leads to increased ketone bodies formation
What happens during prolonged fasting and starvation?
Metabolism shifts to provide fuel for the brain
What are the 3 types of fuel reserves in adults?
- Glycogen (in liver), and in smaller amounts in muscles
- Large amounts of TG in adipocytes
- Tissue proteins that can be degraded when necessary
What happens in the body after an overnight fast?
- Increased glucagon promotes fatty acid mobilization from adipose tissue
- Muscles switch from glucose to fatty acid metabolism for energy production
- This spares glucose for brain and RBC
What are the 4 major changes that occur in metabolic flux during starvation?
- Increased release of fatty acids from adipose tissue
- Increased gluconeogenesis in liver and kidney cells
- Increased ketogenesis in liver cells
- Protein degradation in skeletal muscle
What is energy balance defined as?
Calories consumed/day (input) = Calories expended/day (output)
- If input > output: positive energy imbalance (may cause fat storage set point changes)
- If output > input: negative energy imbalance
What are macronutrients?
Nutrient required in relatively large amounts (proteins, fats, carbs)
Explain how energy input and energy expenditure alter metabolic homeostasis (Pima Indians study).
- 2 populations of Pima Indians who have significantly different rates of obesity and insulin-resistant T2D
- Same language, culture, and are genetically related, but live in different parts of North America for ~ 1000 years
- Southern AZ population: high rates of obesity and T2D; T2D rates 10x higher than Mexican counterpart (80% of adults are overweight, obese, or diabetic)
- Northern Mexico popultion: weigh ~60 lbs less than AZ relatives
- Differences caused by different lifestyles and daily caloric intake
- AZ: live on government reservation land that doesn’t have the water supply for agricultural lifestyle (little daily physical activity, eating unhealthy foods)
- Mexico: physically demanding agricultural lifestyle; consume naturally low-cal and low-sat fat food
What is the thrifty gene hypothesis?
Certain genes may have been advantageous in a culture when times of famine were routine but have become detrimental in modern society where food is in abundance
What is the #1 killer in the U.S.?
Heart disease
What are the risk factors for heart disease?
- High plasma cholesterol and triglycerides
- High blood pressure
- Smoking
- Obesity
- Diabetes
What is metabolic syndrome?
Set of medical conditions that puts a person at risk for diabetes and cardiovascular disease
Symptoms:
1. Abdominal obesity (large amounts of visceral fat)
2. Insulin resistance (prediabetes)
3. Hypertension (high blood pressure)
4. Hyperlipidemia (high LDL and low HDL levels)
5. High risk for cardiovascular disease (blood protein profiles associated with atherosclerosis)
What is type 1 diabetes?
Disease characterized by reduced uptake of glucose from the blood into tissues due to low production of insulin in the pancreas
- Responds to insulin
What is type 2 diabetes?
Disease characterized by reduced uptake of glucose from the blood into tissues due to insulin receptors that bind insulin but fail to activate downstream signaling pathways
- Does not respond to insulin
What is a glucose tolerance test?
Medical test to measure glucose clearance kinetics in the blood of a patient
What are the symptoms of T1D and T2D?
- Excessive thirst
- Frequent urination (polyuria)
- Intake of large volumes of water (polydipsia)
- Excretion of large amounts of glucose in urine (glucosuria)
What tests are used to diagnose pre-diabetes and diabetes?
3 blood tests:
- Fasting plasma glucose (FPG)
- A1C (primary test recommended by the American Diabetes Association, ADA)
- Oral glucose tolerance test (OGTT)
What is the FPG test?
Blood test done after fasting overnight
What is the A1C test?
- Measures average blood sugar level for the past 2-3 months (instead of blood sugar level at a specific point in time)
- Better reflection of blood glucose levels
- Normal: ~ 5% of total Hb is glycated
- Untreated diabetes: as high as ~13% (dangerously high)
- The higher the A1C, the higher the average blood sugar levels over the past 2-3 months
What is glycation?
Irreversible non-enzymatic addition of glucose
What is OGTT?
- Takes a little more time than the other 2 glucose tests
- Blood is taken after an overnight fast, and then again two hours after a sugary drink (~100g sugar in a glass of water)
- Normal for blood sugar to rise after the drink (falls to below 140 mg/dL within 2 hours)
- If the blood sugar is between 140 and 199 mg/dL, it is indicative of a pre-diabetic condition; 200 mg/dL or above is diagnostic for T2D
How do we distinguish between T1D and T2D?
Administer insulin and monitor blood glucose levels
- T1D will respond, T2D won’t respond
What factors contribute to T2D?
- Genetics (gene mutations)
- Obesity
- Elevated levels of free fatty acids in serum
How can T2D be managed?
- Dietary restriction
- Accompanied by weight loss reduces overall burden of handling fatty acids
- Lipid composition of diet influences expression of genes involved in beta oxidation and energy expenditure - Regular exercise
- Activates AMPK and shifts metabolism towards beta oxidation and inhibits fatty acid synthesis
- Drugs that improve insulin sensitivity or insulin production
How is T2D treated with drugs?
- Key is to decreae blood glucose and increase insulin sensitivity
- 4 major classes of drugs
- α-glucosidase inhibitors (miglitol)
- Sulfonylurea drugs (glipizide)
- AMPK stimulators (metformin)
- Ligand agonists of the nuclear receptor PPARγ (thiazolidinediones)
How do sulfonylurea drugs work?
Inhibit pancreatic ATP-dependent K+ channel activity –> membrane depolarization, calcium release, and increased secretion of insulin from pancreatic β cells
How does metformin work?
Elevates AMP levels that then activate AMP-activated protein kinase
What are the AMPK target proteins?
