MM0 Flashcards
What is the name of the process by which new glucose is synthesised?
Gluconeogenesis
0.1
What is the main site of gluconeogenesis in the body?
The liver
0.1
What are the predominant amino acids used for gluconeogenesis?
Alanine (50%) and glutamine (25%)
0.1
A patient presents with a BMI of 38. What BMI weight range would he/she be?
a. Overweight
b. Obese (class 1)
c. Obese (class 2)
d. Obese (class 3)
e. Underweight
c. Obese (class 2)
1. 3
How is obesity classified in children?
More than 20% above the healthy weight for a child of that height
(1.3)
What has 2 broad functions of metabolism?
- Generation of energy
- Synthesis of macromolecules
(0.1)
Glycolysis:
- Where does it occur (cell site)?
- Pathway equation
- Main regulatory points/ rate-limiting reactions
- In the cytosol of the cell
- Inputs:
Glucose
2 ADP
2 Pi
2 NAD+ - Outputs:
2 pyruvate
2 ATP
2 NADH
2 H+
H20 - Phosphofructokinase converting F-6-P to Fructose 1,6 Bisphosphate and pyruvate kinase converting PEP to pyruvate
(0.1)
What purpose does anaerobic lactate production serve?
What enzyme catalyses this production?
- Under anaerobic conditions NAD+ becomes rate limiting for glycolysis, as NADH isnt being used by the mitochondira for respiration
- Lactate production regenerates NAD+ allowing glycolysis to continue
- Lactate production is associated with high energy demand situations
- Lactate dehydrogenase
(0. 1)
TCA cycle:
- Where does it occur (cell site)?
- Cycle inputs and outputs
- Main regulatory mechanisms/ rate limiting steps
- Occurs in mitochondria
- Each cycle consumes:
- 1 pyruvate
- 2 H20 - Each cycle produces:
- 1 ATP
- 3 NADH
- 1 FADH2
- 2 CO2 - Pyruvate oxidation is the main regulatory mechanism.
- This is decreased by Acetyl-CoA, NADH and ATP
- It is increased by AMP
(0.1)
Beta-Oxidation
- Where does it occur?
- How is it regulated?
- Occurs in mitochondria of cells
- Regulation poorly controlled compared to other metabolic pathways. Availability of fatty acids and their transport into the mitochondria are the primary regulatory mechanisms
(0.1)
What is the respiratory quotient (RQ) used for?
- What is the RQ of glucose?
- What is the RQ of fatty acids?
The respiratory quotient can indicate where carbohydrates or fats are the predominate fuel source.
- Glucose RQ = 1
- Fatty acid RQ approx = 0.7
What is the purpose of gluconeogenesis?
- Some tissues only use glucose, such as the brain, kidneys and RBCs. Thus in fasting states GNG can produce glucose for these tissues.
- Despite using 4 ATP GNG is still an energetically favourable reactions as 32 ATP are able to be generated from the glucose formed
(0.1)
What bonds do alpha-amylase hydrolyse?
Alpha-1,4 glucosidic bonds
0.2
During carbohydrate absorption monosaccharides have to move through the intestinal mucosa to the capillaries. List the relevant transporters for:
- Glucose and galactose
- Fructose
- Glucose and glactose move from the lumen of the intestine to the mucosa via SGLT1 symporter (Na in at the same time)
- Fructose moves into the mucosa via the GLUT5 transporter
- All sugars are released to the capillaries via GLUT2 transporters
(0.2)
What is the point of no return in glycolysis?
The conversion of glucose to Glucose-6-phosphate via hexokinase
(0.2)
Describe the mechanism by which increased blood glucose leads to insulin release from beta cells
- Glucose enters the beta-cell via GLUT2
- Glucose undergoes glycolysis and produces ATP
- Increased ATP leads to closure of ATP dependant K+ channels
- Membrane depolarises, leading to opening of voltage dependant Ca2+ channels
- Increased intracellular Ca2+ leads to insulin vesicle release
(0.2)
Describe the mechanism by which increased blood glucose leads to insulin release from beta cells
- Glucose enters the beta-cell via GLUT2
- Glucose undergoes glycolysis and produces ATP
- Increased ATP leads to closure of ATP dependant K+ channels
- Membrane depolarises, leading to opening of voltage dependant Ca2+ channels
- Increased intracellular Ca2+ leads to insulin vesicle release
(0.2)
Describe the main physiological effect of insulin on the liver
Liver:
- Increased glycolysis
- Decreased GNG
- Increased glycogen synthesis/ decreased glycogenolysis
(0.2)
Describe the main physiological effect of insulin on adipose tissue
Adipose tissue:
- Increased glucose uptake
- Increased glycolysis (small amount, physiological role unknown)
- Increased triglyceride utilisation (increased activation of lipoprotein lipase)
- Decreased lipolysis
(0.2)
Describe the main physiological effect of insulin on skeletal muscle
Skeletal muscle:
- Increased glucose uptake
- Increased glycolysis
- Increased glycogen synthesis
- Increased protein synthesis
- Decreased glycogenolysis
(0.2)
Describe the mechanism of insulin-stimulated glucose uptake in muscle cells and adipocytes.
- Mediated by insulin signalling and translocation of GLUT4 to the plasma membrane of muscle and adipocytes
- Insulin binds to Insulin Receptors on the target cells causing phosphorylation and activation of secondary messengers, eventually activating PDK1 and mTORC2
- these secondary messengers phosphorylate AKT which is responsible for vesicle translocation and vesicle target ing to the membrane (vesicles containing the GLUT4 transporters)
- GLUT4 translocation to membrane increases glucose uptake into target cell.
(0.2)
Following a meal, approximately what % of glucose is consumed by the:
- brain
- kidney
What are the main glucose transporters involved?
- Brain: ~15%
- Kidney: ~8%
GLUT1, 2 and 3 (all insulin independent)
Glucose uptake is largely constitutive in both of these tissues
(0.2)
Major fates of glucose in different tissues:
- Muscle
- Liver
- Adipose tissue
Muscle:
- oxidation to generate ATP (glycolysis, TCA cycle, OxPhos)
- Storage as glycogen
Liver:
- Oxidation to generate ATP (glycolysis, TCA cycle, OxPhos)
- Storage as glycogen
Adipose tissue:
- Storage as lipids (partial metabolism and lipogenesis)
(0.2)
Describe the movements of chylomicrons in the body
- Chylomicrons are assembled in the intestinal enterocytes from fatty acids and other lipids.
- Once synthesised the chylomicrons move through the lacteals (lymphatic capillary) to join the lymphatic system. The lymphatic system carries them to the venous return of the systemic circulation.
- Note by travelling in this manner lipids do not use the hepatic portal system and thus deny the liver first access to them.
- Once in the systemic circulation the chylomicrons move to adipose, skeletal or cardiac tissue, where lipoprotein lipase releases the fatty acids for use.
- The chyomicron remnants are then recycled at the liver.
(0.3)
Describe the mechanism of insulin synthesis and processing in the Beta cell.
- produced as preproinsulin which has a signal sequence on the end
- the signal sequence is cleaved an a disulphide bond formed = proinsulin
- removal of C-peptide forms insulin
(0.2)
What determines glucose fate (oxidation vs storage)?
- Energy balance of tissue: if energy balance is low, glucose will be oxidised to normalise ATP levels before it is stored
- Availability of other substrates: lipids are preferred substrate at rest
- Hormonal signalling: Balance of storage signals vs utilisation signals
(0.2)
Explain how following feeding insulin activates glycogen synthesis in muscle and liver.
Insulin acts on Insulin receptor, leading to activation of AKT. AKT inactivates GSK3b, an inhibitor of glycogen synthase- therefore there is more glucose being stored as glycogen.
(0.2)
T or F
- Glycogen synthesis in muscle is activated by G6P
- Calcium released by active skeletal muscle activates Glycogen synthesis in muscle
- The same allosteric mechanisms control glycogen synthesis in muscle and liver
- Glycogenolysis in the liver is inhibited by glucose and ATP
- T
- F - calcium inhibits Glycogen synthesis
- F- they are different
- T
(0.2)
Glycogen synthase forms what kind of glycosidic bonds?
a-1,4 glycosidic bonds, but not the a-1,6 glycosidic bonds required for branching
(0.2)
Give a brief overview of the pathway of how glucose is stored as Triglycerides in adipose tissue
- Glucose is broken down to pyruvate then to acetyl CoA via usual glycolysis in mitochondria.
- Acetyl CoA is then converted to fatty acids that combine with glycerol also provided by glycolysis to form triglycerides.
- NADH is used up in the fatty acid synthesis process. NADH is provided by pentose phosphate pathway
- note that Acetyl CoA can’t cross the mitochondrial membrane, so it must be converted to citrate by citrate synthase to cross and then be reversed back into Acetyl CoA by citrate lyase.
(0.2)
What does insulin act on to increase the activity of the following pathways involved in lipogenesis:
- Glycolysis
- Pentose phosphate pathway
- Pyruvate oxidation to Acetyl CoA
- Fatty acid synthesis
- PFK1
- G6PDH
- PDH
- ATP citrate lyase and Acetyl CoA carboxylase
(0.2)
Describe the steps in digestion of the lipid droplet to micelles.
- Mouth: emulsion of lipids (mechanical)
- Stomach: gastric lipase begin fat digestion and large fat droplets breakdown to smaller ones
- Duodenum: pancreatic lipase and bile salts bind to fat droplets and further breakdown lipid droplet
- Duodenum, jejunum: fatty acids and MAGs form Micelles
- Small intestine: Micelles diffuse to brush border, followed by absorption of fatty acids and MAGs
(0.3)
Fatty acid uptake into tissues is mediated by which membrane proteins?
Mediated by fatty acid transport proteins (FATP) in consort with ACSL and CD36
(0.3)
TorF, fatty acids are stored in adipocytes as multiple lipid droplets.
F. Adipocytes store lipids in a single lipid droplet. Adipocytes expand through hypertrophy to accommodate storage of fatty acids.
(0.3)
TorF, Brown adipose tissue uses uncoupled respiration to generate ATP
F. Brown adipose tissue uses fatty acids (and to a lesser extent, glucose) to generate heat through uncoupled respiration.
(0.3)
Name two Adipokines released by adipose tissue. (Extra points if you can say what they do to whole body metabolism)
Leptin: increases metabolic rate and decreases appetite (satiety signals), increases whole body insulin sensitivity, Decreases visceral fat content. Elevated in obesity.
Free fatty acids: elevated in obesity and diabetes, decreases beta-cell function, decreases insulin clearance, increases visceral fat content
(0.3)
Briefly describe protein digestion in the stomach.
- Chief cells release pepsinogen into the lumen of the stomach.
- In the lumen of the stomach pepsinogen comes into contact with a low pH environment due HCl released from parietal cells. This leads to pepsinogen converting to pepsin, the active form.
- Pepsin cleaves peptides between tyrosine and phenylalanine amino acids, turning larger proteins into smaller polypeptides.
(0.4)
Describe how the body removes ammonia produced when deaminating amino acids.
- Ammonia is a neurotoxic and thus a hazardous waste.
- At the liver the body turns ammonia to urea, which is nontoxic, water soluble and easily excreted.
- The urea is then transported to the kidneys for excretion.
(0.4)
Pyruvate dehydrogenase (PDH) plays a role in regulation of substrate utilisation, particularly its inhibition. What substrate does PDH inactivation favour?
Phosphorylation (inactivation) of PDH favours beta-oxidation and thus fatty acid utilisation.
(0.4)
What are the components of lipoprotein structure?
Apoliporprotein, Phospholipids, triglyceride (core), cholesterol and cholesterol ester (in the core).
(0.3)
List the three main pancreatic proteases released into the small intestine (and their active form)
Trypsinogen (Trypsin)
Chymotrypsinogen (Chymotrypsin)
Procarboxypeptidase (Carboxypeptidase)
- activated by enterokinase present on small intestinal brush border
(0. 4)
True or false. All amino acids are taken up by the liver for metabolism
F- glutamate and glutamine are not released from the small intestine (as they are the preferred substrate for intestinal epithelial cell metabolism). Val, Leu and Ile are also not taken up by the liver.
(0.4)
List the fates of amino acids in the liver.
- Incorporated into liver proteins
- Redistribution to peripheral tissues for protein synthesis
- Deaminated so the remaining hydrocarbons can be used for metabolic pathways (Pyruvate and TCA cycle intermediates for gluconeogenesis, AcetylCoA for fatty acid synthesis, ATP production).
(0.4)
Ammonia detoxification is compartmentalised in the liver. In which cells is Urea cycle most active?
Periportal cells (nearest to vascular supply).
0.4
Which tissue/fuel type makes up the majority of body fuel reserve?
Adipose tissue/triglycerides (~75%)
Total body protein ~22% and liver/muscle glycogen/blood glucose make up less than 1%.
(0.4)
What is the preferred fuel for:
- Skeletal muscle at rest
- Skeletal muscle during exertion
- Adipose tissue
- Liver
- Fatty acids (at rest in post-absorptive state, there is an equal mix of glucose and fatty acid oxidation)
- Glucose
- Fatty acids
- Can use fatty acids, amino acids and glucose
(0.4)
What is the preferred fuel selection in fasting/starvation?
Lipid oxidation (KBs, TAGs, lipolysis)
0.4
PDK inactivates PDH, which is a key regulatory of substrate utilisation. What are some key triggers for PDK activity?
- high energy demand (low O2, high ATP)
- High [Acetyl CoA]
- Starvation and nutrient deprivation
(0.4)
How does the Randle cycle link elevated B-oxidation with reduced glucose oxidation?
Citrate produced in beta-oxidation. Citrate is an allosteric inhibitor of PFK-1, a rate limiting enzyme in glycolysis.
(0.4)
