1
Q
What is homeostasis?
A
describes the maintenance of a dynamic, steady state by regulatory mechanisms that compensate for changes in external circumstances. in this steady state, the rate of synthesis of a metabolite equals the rate of the metabolite’s breakdown. after a disturbance, a new steady state must be established to maintain homeostasis.
2
Q
What is glucose homeostasis?
A
The entry of glucose into the blood from various sources must be balanced by the uptake of glucose from the blood into various tissues to ensure the concentration of blood glucose remains at a near constant 5 mM. In diabetes, the regulation of blood glucose concentration is defective as a result of the lack of/insensitivity to insulin, leading to complications.
3
Q
How does glucose homeostasis work?
A
Through the regulation of glycolysis/gluconeogenesis and glycogen metabolism, involving intracellular control using allosteric regulation and covalent modification. Intracellularly hormones like insulin, glucagon and epinephrine
are used.
4
Q
What is glycogenolysis?
A
Glycogenolysis is the metabolic breakdown of glycogen into glucose-1-phosphate and glucose, which primarily occurs in the liver and muscles to provide rapid energy. Glycogenolysis is more active around 4 hours after a meal but won’t be active until glycogen stores are depleted. Glycogenolysis and gluconeogenesis are the only pathways capable of increasing blood glucose levels
5
Q
What is Glycolysis?
A
A chain of reactions utilised by cells to release the energy stored in glucose that occurs in the cytosol of most eukaryotic cells. Glycolysis consists of 10 enzyme catalysed reactions that ultimately results in the production of of 2 molecules of pyruvate and 1 molecule of glucose, whilst expending ATP + NADH (energy) in the process.
However, the fate of pyruvate following glycolysis does depend on the presence of oxygen. Pyruvate will either be used in the citric acid cycle for the electron transport chain or it will undergo fermentation. This can be described as a highly regulated process that occurs when cells need energy.
6
Q
Does glycolysis require oxygen?
A
Glycolysis doesn’t utilise oxygen so it can occur in anaerobic and aerobic organisms
7
Q
Stages of Glycolysis?
A
There are 3 irreversible steps of glycolysis
The first five reactions are called the preparatory phase whilst the final 5 are known as the payoff
The preparatory phase requires energy whilst the payoff phase produces it
Net Equation: Glucose + 2 NAD+ + 2 ADP + 2 Pi -> 2 Pyruvate + 2 NADH + 2 H+ + 2 ATP + 2 H2O
8
Q
What is the Preparatory Phase?
A
Involves 2 molecules of ATP being used, ultimately leading to the production of 2 molecules of glyceraldehyde 3-phosphate. ATP provides phosphate groups for phosphorylation reactions and supplies energy through hydrolysis to drive metabolic processes.
9
Q
What is the Payoff phase?
A
This process releases energy in the form of 4 molecules of ATP and produces 2 molecules of NADH. It results in the conversion of 2 glyceraldehyde 3-phosphate molecules into 2 molecules of pyruvate. In summary, 1 glucose molecule enters the glycolytic pathway and 2 molecules of pyruvate are produced. The pathway results in the overall production of 2 ATP, and 2 NADP molecules. Both ADP and NADP+ are required for the pathway to proceed
10
Q
When is Glycolysis active?
A
When [ATP] is low, when [ADP] is high (up to 5-fold), when [AMP] is relatively high (up to 20-fold), and when the [NADH] to [NAD+] ratio is low
11
Q
What is Gluconeogenesis?
A
It occurs predominantly in the liver and uses precursors like amino acids, lactate, oxaloacetate & pyruvate to synthesis new molecules of glucose. It involves 7 reversible reactions + 3 exergonic glycolytic reactions which are irreversible. Different enzymes are required to drive the reaction in the opposite direction to glycolysis (bypassed reactions). Gluconeogenesis and glycolysis are reciprocal pathways. It involves the generation of glucose from non-carbohydrate precursors. When one is active in the cell, the other is turned off (e.g. when glycolysis is active, gluconeogenesis is not).
12
Q
What is the energy source of Gluconeogenesis?
A
Uses ATP with a net usage of 4 ATP molecules. At these points, if both reactions proceed simultaneously, ATP is consumed without any net productive outcome. This results in what is known as a futile cycle, where energy is expended without generating useful work and this contributes to the regulation of these processes.
13
Q
Balance of Gluconeogenesis and Glycolysis during Fed state
A
The balance of pathways is dependant on the state of the body immediately after a meal. Fed state scenario: after eating, glucose levels are high so it may be taken up and utilised in cells or stored in the liver as glycogen
14
Q
Balance of Gluconeogenesis and Glycolysis during Fasting state
A
Fasting state scenario (in-between meals or after vigorous exercise): cells in the body will begin to deplete the levels of glucose in the blood and gluconeogenesis is the anabolic pathway which builds glucose from non-carbohydrate sources so it is crucial in these moments. Fasting will most likely trigger gluconeogenesis in the liver.
15
Q
Gluconeogenesis: Bypass Reaction 1 -> Futile Cycle 3
A
This encompasses the last step of glycolysis which involves the conversion of 2 molecules of phosphophenyl pyruvate to 2 molecules of pyruvate, and the reverse reaction which is the 1st step of gluconeogenesis. Thus process involves 2 reactions to convert Pyruvate to Phosphoenolpyruvate. The 1st reaction occurs in the mitochondria and begins with the conversion of 2 pyruvate molecules into 2 oxalate acetate molecules, catalysed by pyruvate carboxylase (all this uses 2 ATP molecules). The 2nd can occur either in the cytosol or the mitochondria, and involves the conversion of 2 molecules of oxalate acetate into 2 molecules of phosphonyl-pyruvate and uses energy from GTP
16
Q
What is pyruvate kinase?
A
Involves 3 isozymes that are allosterically activated by fructose-1,6-bisphosphate.
Allosterically inhibited by signs of abundant energy supply (all tissues) observed through ATP, Acetyl-CoA and long-chain fatty acids along with alanine (enough amino acids). It’s activated by the glycolytic intermediate fructose 1,6-biphosphate, an intermediate from the earlier stages of glycolysis. As there is a higher flow through the glycolytic pathway, pyruvate kinase is activated.
17
Q
How does fructose-1,6-bisphosphate regulate pyruvate kinase?
A
Fructose-1,6-bisphosphate allosterically activates pyruvate kinase, increasing the rate of the final step of glycolysis and thus increasing the overall rate of glucose conversion to pyruvate
18
Q
How is pyruvate kinase regulated in the liver vs muscle?
A
There are also isozymes of pyruvate kinase, the one present in the liver but not the muscles is inhibited by phosphorylation in response to signs of glucose depletion signalled by glucagon. When blood glucose levels drop, the hormone glucagon is released resulting in increased cAMP levels (signalling molecule that activates cAMP dependent kinase - protein kinase A or pKa). This phosphorylates and inactivates the liver isoform of pyruvate kinase, causing a decrease in the use of glucose in the liver and ensures that glucose can be exported from the liver to tissues that have high glucose requirements (e.g. the brain). In contrast, the isoform of pyruvate kinase that’s present in the muscles is regulated by the hormone epinephrine which is released when additional energy is required and produces an increase in cAMP, activating glycolysis
19
Q
What are the metabolic fates of pyruvate?
A
In addition to being a substrate for gluconeogenesis, cells can use pyruvate for other purposes. Pyruvate can either enter gluconeogenesis to form oxoacetate catalysed by the enzyme pyruvate carboxylate or if not it can be converted to acetyl coA and enter the citric acid cycle.
20
Q
Gluconeogenesis: Bypass Reaction 2 -> Futile Cycle 2
A
In Glycolysis: fructose 6-phosphate is phosphorylated to Fructose 1,6-biphosphate by phosphofructokinase-1 which is a complex allosteric enzyme that has both substrate + regulatory binding sites. Phospho-fructokinase-1 is inhibited when ATP concentrations are too high, by acting as an allosteric inhibitor that lowers the affinity of phospho-fructokinase-1 for its substrate fructose 6-phosphate. In contrast, when the consumption of ATP outpaces its production and concentrations of AMP + ATP increase, they will both act allosterically to relieve the inhibition of phospho-fructokinase-1 by ATP, increasing the activity of phospho-fructokinase-1. Another allosteric regulator is citrate, which is a key intermediate in aerobic metabolism. At high concentrations, it increases the inhibitory action of ATP and signals to the cell that it’s meeting its current energy needs and glycolysis is not required. In gluconeogenesis: fructose 1,6-biphosphate is hydrolysed by Fructose 1,6-biphosphate-1, generating Fructose 6-phosphate. An activator of Phospho-fructokinase-1 is fructose 2,6-biphosphate which increases the affinity of PFK-1 for Fructose 6-phosphate and decreases its affinity for ATP & citrate. This in itself is not an intermediate in glycolysis. Fructose 2,6-biphosphate is produced specifically to regulate glycolysis and gluconeogenesis. Therefore, it promotes glycolysis, reduces the activity of gluconeogenesis and is hormonally regulated by insulin + glucagon.
21
Q
Gluconeogenesis: Bypass Reaction 2 -> Futile Cycle 1 (comparison between glycolysis & gluconeogenesis bypass)
A
In glycolysis: glucose is phosphorylated to glucose 6-phosphate by hexokinase and this requires ATP. In gluconeogenesis: glucose 6-phosphate is hydrolysed by glucose 6-phosphatase, generating glucose
22
Q
What is Fructose 1,6-biphosphatase-1?
A
This is allosterically regulated. This is inhibited by increased AMP (by-product of ATP consumption) and by Fructose 2,6-bisphosphate. To understand when it is inhibited, must known that AMP levels are high when ATP is low. Glycolysis is active when AMP is high and ATP is low, similarly gluconeogenesis is active when ATP is low, so these pathways are operated in a coordinated manner.
23
Q
Gluconeogenesis: Bypass Reaction 3 -> Futile Cycle 1
A
Encompasses the 1st step of glycolysis which catalyses the entry of glucose in the glycolytic pathway by the conversion of glucose to glucose-6 phosphate. In gluconeogenesis, it’s the final step which results in the production of glucose. Under cellular conditions, these 2 reactions are catalysed by enzymes that have large negative delta g values which are not readily reversible and require different enzymes to catalyse each reaction. The enzyme hexokinase catalyses the 1st step in glycolysis which involves the phosphorylation of glucose to glucose 6-phosphate, using ATP as the source of the phosphate group. Hexokinase is found in all cells with glycolytic activity so nearly all cell types.
Glucose 6-phosphatase is the enzyme which catalyses the dephosphorylation of glucose-6 phosphate to glucose in the last step of gluconeogenesis. Gluconeogenesis is prevented in cells without this enzyme and it is only found in hepatocytes (liver cells) but not in muscles cells or many other cell types. One way these enzymes are regulated is by controlling the level of transcription
24
Q
What is Hexokinase?
A
4 isozymes for hexokinase exist (I to IV), and differents types exist in different tissues. Isozymes perform the same reaction but are regulated differently. The liver plays an important role in maintaining blood glucose homeostasis by either using/ producing glucose whereas muscle cells don’t contribute to the maintenance of blood glucose homeostasis in the same way, creating the need for various forms of the enzyme to exist. Therefore, there must be different forms of the enzyme. Hexokinase is regulated allosterically, through its existence as isozymes, compartmentally and due to its inducible nature.
25
What is Hexokinase I & II?
This is found in muscle cells, and is allosterically inhibited by their product, Glucose 6-Phosphate. It has a high affinity for Glucose (low Km), meaning that the enzyme binds to glucose tightly at low concentrations. It is half saturated at approx 0.1 mM of glucose, therefore when glucose enters the muscle cells via the blood where the concentration of glucose is higher, and where the intracellular concentration of glucose is high enough to saturate the muscle hexokinase.
26
What is Hexokinase IV (Glucokinase)?
It is found in the liver and inhibited by binding to a protein specific only to the liver or a nuclear binding protein. It has a low affinity for Glucose (High Km), therefore it needs a high concentration of glucose for the reaction to take place, so it will be half saturated at around 10 mM. When blood glucose levels, like after a meal, glucose is transported to liver cells and because of the low affinity of hexokinase IV to glucose its activity continues to rise as blood glucose levels rise even above 10 mM. When blood glucose levels are low, too low to activate hexokinase IV, the glucose produced in the liver via gluconeogenesis will be protected and won’t be phosphorylated to glucose 6-phosphate, enabling it to leave the liver and increase blood glucose levels. It's not inhibited by its product, glucose 6-phosphate so these can be produced whilst inhibiting other forms of hexokinase. When glycolytic intermediates downstream of the hexokinase reaction, such as fructose-6-phosphate, are high, fructose-6-phosphate promotes binding of glucokinase (hexokinase IV) to its regulatory protein (GKRP), preventing it from catalysing glucose phosphorylation.
In contrast, when the concentration of glucose levels increase, this regulatory protein releases hexokinase IV back into the cytosol where it can perform its activity
27
What is Glycogen?
It is a branched molecule made up of glucose-residue chains with polymers originating from a central point at the very end of each branch. It is primarily stored in the liver but can also be stored in muscle. Its protein core is a glycogenein. In the fed state, glucose can be converted into glycogen. Types of linkages involved include residues within a branch joined by a1->4 linkages and residues at branch points joined by a1->6 linkages
28
What is Glycogenesis?
Metabolic process of converting excess glucose into glycogen for short-term energy storage, primarily occurring in the liver and skeletal muscles.
29
What are the key processes and steps in glycogenesis?
This process can occur in the liver, but also in the muscles under tight regulation. There are 2 processes that occur in the formation of glycogen elongation when new residues are added to the polymer chain, and branching. Glucose is added to glycogen chains in the form of UDP glucose. To form UDP glucose, glucose is first converted to glucose-6 phosphate by hexokinase. From here, phosphoglucomutase converts glucose 6 phosphate to glucose 1 phosphate, then UDP-glucose pyrophosphorylase utilises the nucleotide UTP to add UDP to the residue, releasing pyrophosphate (PPi - molecule with 2 phosphate groups). The product of this reaction is UDP glucose, which can then be added to a glycogen branch. Afterwards, UDP is released and the glycogen chain elongates
30
How does branching occur in glycogenesis?
The second process in glycogenesis is branching where any chain/ residues branch off from an existing one. The branching enzyme begins by cleaving a 1->4 linkage. Branches are formed as the glycogen chain extends, once a chain is at least 11 residues long, a branching enzyme will cleave the 1->4 bond 6/7 residues from the non-reducing end and transfer the chain to a glucosal group closer to the glycogen core. This forms a new 1->6 linkage. The branching enzyme will then transfer the terminal residues to an earlier point in the chain
31
How is glycogen broken down in the process of glycogenolysis?
To break down glycogen 2 enzymes are required. Firstly, glycogen must be broken down with the help of enzymes glycogen phosphorylase and a glycogen debranching enzyme. Glycogen phosphorylase acts on the non-reducing ends of glycogen branches, cleaving individual residues from the branch and releasing them in the form of glucose 1-phosphate in a phosphorylysis reaction. Glycogen phosphorylation will continue to act on the non-reducing ends of glycogen branches until it reaches a residue/s from a branch point. Then, a debranching enzyme will catalyse 2 reactions, the first being a transferase reaction transferring all but 1 of the remaining residues to the non-reducing end of another. The 2nd is a glucosidase reaction where the enzyme cleaves the remaining residue, removing the branch point. Unlike residues released by glycogen phosphorylase, this residue is cleaved and released in the form of glucose
32
What is the fate of glucose 1-phosphate?
In the liver, the glucose 1-phosphate molecules are first converted to glucose 6-phosphate by phosphoglucomutase and then to glucose. The enzyme responsible for this step is glucose 6-phosphatase located in the membrane of the endoplasmic reticulum. The active site of this enzyme is within the ER so despite the enzyme being located in the membrane of the ER, the reaction must occur in the ER itself.
33
Can muscle cells convert glucose-6-phosphate into glucose?
Muscle cells can break down their own glycogen to glucose-6-phosphate for energy, but cannot convert it to free glucose for release into the blood. Muscle cells don’t have the enzyme glucose 6-phosphatase so it cannot convert the glucose of residues broken down from glycogen to glucose and therefore cannot contribute to blood glucose concentrations. Instead, glucosyl groups broken down to glucose 6-phosphate in muscle cells are used directly for glycolysis. The majority of glucosyl residues are cleaved from glycogen in Glucose 1-phosphate form
34
What is metabolism?
describes the entire set of enzyme-catalysed transformations of organic molecules in living cells; the sum of anabolism and catabolism
35
Hormones involved in Hormone Regulation (3)
Insulin, glucagon and epinephrine
36
How do hormones regulate glucose metabolism and glucose homeostasis?
Involve chemical signals that are released into the blood and only target cells that respond to the given hormone. Hormones combine with receptor proteins.
37
Can hormones be quickly eliminated from the blood?
Yes
38
How do insulin and glucagon regulate glucose?
Insulin and glucagon are both released from the pancreas in response to blood glucose levels, insulin for when they’re high and glucagon for when they’re low
39
How does epinephrine regulate glucose?
Epinephrine/adrenaline is released from the adrenal gland and is released in order to prepare the body for action (prepares muscles, lungs + heart for a burst of activity). Epinephrine is released in order to boost blood glucose levels. However, this hormone is not released solely because blood glucose levels are low but are released to help prepare the body for action by ensuring there’s enough glucose in the blood for tissues that may require it to undergo their respective processes.
40
Difference between hormonal and intracellular regulation?
Once a hormone reaches a cell it triggers an intracellular response which is an intracellular signalling cascade so once it reaches the cell it can trigger a quick response. Insulin, glucagon, and epinephrine are the primary determinants of metabolic activity in liver, muscle, and adipose tissue.
Hormonal control (intracellular) is slower than regulation by allosteric activation/inhibition + covalent modification (intracellular), as the effects can result in 10-20 fold increases in enzyme activity
41
What does a catabolic enzyme do?
breaks down molecules and the catalytic subunit of an enzyme contains the active site
42
what does an anabolic enzyme do?
forms larger molecules
43
what does the active site do?
binds to the substrate
44
what is the regulatory site?
the binding site for regulatory molecules (e.g. allosteric regulators that cause conformational changes that increase/ decrease the protein’s activity)
45
Why do biochemical reactions need to be regulated?
The flow of metabolites through the pathways is regulated to maintain homeostasis. Homeostasis occurs when concentrations of metabolites are kept at a steady state in the body.
When disrupted, a new steady state is achieved.
Sometimes, the levels of required metabolites must be altered very rapidly.
This need to regulate biochemical reactions could arise through an increase in the capacity of glycolysis during action, like a decrease in glycolysis following an increase in gluconeogenesis after hormonal activation.
46
What is the lifespan of enzymes?
all proteins have finite lifespans, different proteins in the same tissue have different half-lives (e.g. liver 0.9 days, kidney 1.7 days, heart 4.1 days, brain 4.6 and muscle10.7 day half-lives).
Stability correlates with the sequence at N-terminus. The specific amino acid sequence of a protein is what ultimately determines its lifespan before it’s degraded by proteases within a cell. Some proteins are as old as you are (e.g. Crystallins in the eye lens). Constitutive enzymes links lifespan to function. Inducible enzymes are only needed for short periods of times so they have short lifespans
47
what are the characteristics of constitutive enzymes?
long lifespans (days to months), the rate of synthesis = rate of degradation, these are required in constant concentrations and an example of this is glycolytic enzymes.
48
what are the characteristics of inducible/repressible enzymes?
short lifespans as they're only synthesised when required, rate of synthesis & degradation can increase or decrease and examples include hormones + growth factors
49
what is induced or repressed synthesis?
The synthesis of an enzyme can be controlled, either by increasing its expression or decreasing it. It requires the transcription of the genes encoding these enzymes to be under hormonal control
Hence, it involves a reciprocal relationship.
50
What are examples of induced/repressed synthesis?
Example: 1 Hormones induced by insulin are hexokinase II & glucokinase (Glu→G-6-P) and liver phosphofructokinase (PFK-1) which in-turn increase glycolysis
Example 2: Hormones repressed by insulin include PEP Carboxykinase, and Glucose 6-phosphatase, therefore Gluconeogenic enzymes will cause the inhibition of Gluconeogenesis, the metabolic process of synthesizing glucose from non-carbohydrate precursors. By inhibiting the product of these enzymes, the liver is prevented from generating additional glucose, which is unnecessary when blood glucose levels are high.
51
What are compartmentalisations?
Enzyme concentration can by regulated by compartmentalisation of enzymes in organelles of certain cell types. Example 1: Red blood cells don’t contain mitochondria therefore they don't have the enzymes for CAC & ETC.
Example 2: Hexokinase is sequestered to the nucleus under conditions that favour glycolysis in the liver during periods of high glucose (preventing glycolysis)
52
Is Glucose 6-phosphatase an example of compartmentalision?
Yes, glucose-6-phosphatase is present in liver and kidney but absent in muscle, brain and adipose, demonstrating how metabolic pathways are compartmentalised between glucose-producing and glucose-utilising tissues to prevent futile cycling and ensure blood glucose is maintained for essential organs
53
Can enzymes exist as isozymes?
Different cells have different isozymes, enzymes that perform the same functions each other but differ in structure so it can be regulated independently of each other may exist within a single cell/tissue. Multiple forms of an enzyme that catalyse the same reaction can differ in amino acid sequence, substrate affinity, Vmax and/or regulatory properties. These are often the products of different genes and catalyse the same reaction yet have different primary structures. Example: Hexokinase with I version having a higher rate of relative enzyme activity per glucose conc (mM) than Hexokinase IV.
54
What is the key difference between liver and muscle forms of hexokinase?
The key difference between liver and muscle forms of hexokinase is their affinity for glucose, as the liver is only active when glucose levels are high (stores glucose as glycogen)
55
What is the significance of the concentration of substrates?
The rate of a reaction depends on the concentration of substrates with the rate being more sensitive to low concentrations. The rate becomes insensitive at high substrate concentrations as the enzyme here is nearly saturated with substrate.
56
What is chemical kinetics?
The frequency of substrate meeting the enzyme matter
57
What are the characteristics of facilitated transport of the glucose transporter, GLUT 1-5?
Concentration of glucose in blood plasma is ~ 4.5 mM. Concentration of glucose in cytoplasm is much lower. Glucose enters cells through specific transporters. Glucose uptake by brain and red blood cells is insulin-independent whereas glucose uptake by muscle & adipose tissue is insulin-dependent
58
What are the characteristics of glucose uptake by muscle & adipose tissue?
Insulin stimulates the movement of GLUT-4 glucose transporters to the surface of myocytes (synthesising glycogen) and adipocytes (synthesising triacylglycerols). Results in an increase of glucose uptake to 15-fold or more.
In type I diabetes: there is no insulin released and therefore no mobilisation of GLUT-4. When the GLUT-4 transporter is synthesised it’s packaged into the membrane of vesicles and when insulin reaches the cell, it triggers an intracellular signalling cascade that promotes the movement of these vesicles to the membrane. Eventually, GLUT-4 transporters are embedded into the membrane so that glucose can be transported into the cell. Upon signalling from insulin, GLUT transporters are put into the membrane, thus controlling the activity of enzymes
59
What is allosteric modulation?
It describes the reversible, non-covalent binding of a modulator (compounds that regulate enzyme activity) at a site other than the active site, and this pertains to enzymes with 2 active sites.
60
What are allosteric enzymes?
They have a separate binding site for their modulators (inhibitors or
activators). They have a quaternary structure and are composed of subunits.
Their subunits can adopt more than 1 conformation. Binding of substrate occurs more readily to one conformation. The binding of a modulator brings about a conformational change in the enzyme.
61
What is phosphorylation?
This describes the rapid process of adding a phosphate group + involves covalent modification. This process is catalysed by protein kinases. Whereas, dephosphorylation is catalysed by protein phosphates or can be spontaneous. Typically, proteins are phosphorylated on the hydroxyl groups of Ser, The or Tyr. Phosphorylation may activate or inactivate an enzyme so it has a switch-like effect. When insulin reaches a cell, it induces a series of phosphorylation events that propagate the insulin signal throughout the cell
62
When and Where is Glycogen made?
Made when blood glucose levels are high and when glucose is plentiful. Made and stored in liver + muscle cells. The general mechanism for storing and mobilising glycogen are the same in the muscle and the liver, but the enzymes differ reflecting the different roles of glycogen in the 2 tissues.
63
Why is Muscle Glycogen used?
It is required to provide a rapid source of energy for either aerobic or anaerobic metabolism. It can be used up in less that 1 hour during vigorous activity.
64
Why is liver glycogen used?
It serves as a reservoir of glucose for other tissues when dietary glucose is not available. This is especially important for the brain.
This source can be depleted in 12-24 hours. Glycogen phosphorylate is the enzyme responsible for cleaving off individual residues from the glycogen branches and a debranching enzyme is required for breaking down glycogen at the branch points
65
How is glycogen metabolism regulated?
The synthesis and degradation of glycogen is highly regulated. It is controlled at the hormonal level, enzyme level, through allosteric regulation and covalent regulation of glycogen synthase + glycogen phosphorylase
66
How is glycogen synthase regulated?
Glycogen synthesis can be controlled hormonally (phosphorylation and dephosphorylation) through insulin-signalling pathways as it increases glucose import into muscle, stimulates the activity of muscle hexokinase and activates glycogen synthase. It can also be controlled through hexokinase activity as an increase of this enables the activation of glucose. When glycogen synthase is phosphorylated it becomes inactive. Dephosphorylation activates glycogen synthase (active form = glycogen synthase a). Glycogen synthase is inactive when phosphorylated and must be dephosphorylated for glycogenesis to occur
67
What enzymes regulate glycogen synthase activity?
PP1 is modulated by insulin, glucose, and glucose 6-phosphate which all activate the enzyme but glucagon or epinephrine inhibits it. GSK3 is turned off in the presence of insulin, preventing the deactivation of glycogen synthase. Inactivation of glycogen synthesis involves glycogen synthase kinase 3 which is tightly regulated by insulin. Hence, the covalent modification and regulation of glycogen synthase is under hormonal and allosteric control
68
What is the role of glycogen phosphorylase?
Glycogen phosphorylase is the enzyme that cleaves glucose-1 phosphate from the end of glycogen branches
69
What enzymes regulate phosphorylation in glycogen metabolism?
The 2 enzymes responsible for adding and removing the phosphate groups are PP1 and phosphorylase B kinase. A kinase adds a phosphate group and a phosphatase removes one. The phosphate groups are then removed by PP1 which returns it to its less active form and ceasing glycogenolysis
70
How is phosphorylase B kinase and glycogenolysis activated?
Phosphorylase B kinase is activated by glucagon in the liver and epinephrine in the muscle. In muscles, phosphorylase B kinase is also activated by increasing calcium concentrations along with increasing AMP which both accumulate in contracting muscles. In both muscle and liver, an external signal activates cAMP and protein kinase, leading to the activation of phosphorylase B kinase and subsequently glycogen phosphorylase for glycogenolysis
71
How is glycogen phosphorylase regulated in the liver vs muscle?
The liver form of glycogen phosphorylase is strictly controlled by glucose
When glucose levels increase, glucose binds to an allosteric site, causing a conformational change that exposes phosphate groups and increases the affinity of PP1, leading to dephosphorylation and conversion to a less active form. The phosphorylase present in muscle and liver are isozymes which are regulated differently. In myocytes, calcium and AMP stimulate glycogen breakdown, but this is not the case in the liver
72
What are the roles of glycogenolysis in liver vs muscle?
Since muscle cells lack glucose-6-phosphatase, glucose-6-phosphate cannot be converted to free glucose and is used directly in glycolysis. In the liver, glycogen breakdown increases blood glucose levels, with glucose residues converted to glucose and released into the bloodstream
73
How do hormones regulate glycogenolysis in the liver vs muscle?
Glucagon initiates glycogenolysis in the liver. Epinephrine initiates glycogenolysis in muscle cells. Glucagon does not directly target muscle tissue. Insulin targets both liver and muscle and affects carbohydrate metabolism
74
How does the regulation of glycogen synthesis & breakdown overlap?
Glucagon and epinephrine both activate glycogen phosphorylation and inhibit glycogen synthesis thereby promoting the breakdown of glycogen (glycogenolysis). PP1 is involved in both pathways, when PP1 is active it activates synthase whilst inhibiting phosphorylation
75
What occurs when glucagon or epinephrine is present in the liver?
Glycogen is broken down into glucose-6-phosphate. Glucose-6-phosphate is converted into free glucose. Free glucose is released into the bloodstream → This raises blood glucose levels
At the same time: Glycolysis is inhibited (liver does not use glucose itself). Gluconeogenesis is stimulated (makes more glucose). Overall role of liver: Maintain blood glucose for the whole body
76
Key differences of the liver and muscle's use of glucose?
Liver → exports glucose → regulates blood glucose.
Muscle → uses glucose → produces energy
77
What occurs in a high blood glucose state in accordance with the insulin pathway?
When blood glucose is high:
Insulin is released which promotes storage and utilisation of glucose
Effects on glycogen metabolism: Glycogen synthase is activated
→ increases glycogen synthesis. Phosphorylase kinase is inhibited. Glycogen phosphorylase is inhibited
→ decreases glycogen breakdown.
Effects on glycolysis: Insulin increases activity of Hexokinase II, PFK-1, & Pyruvate kinase. Insulin activates PFK-2 → increases fructose-2,6-bisphosphate which in-turn strongly activates glycolysis +
inhibits gluconeogenesis.
Net effect of insulin:
Insulin increases glucose entry into cells via GLUT transporters, glycogen synthesis and glycolysis. BUT, this decreases glycogen breakdown,
gluconeogenesis, and blood glucose levels.
78
What occurs in a low blood glucose state in accordance with the insulin pathway?
When blood glucose is low:
Glucagon is released, which promotes glucose production and release.
Glucagon activates adenylate cyclase which increases cAMP, then
cAMP activates Protein Kinase A (PKA) and PKA causes the phosphorylation of enzymes.
Effects on glycogen metabolism:
Phosphorylase kinase is activated → activates glycogen phosphorylase.
Glycogen phosphorylase is activated → increases glycogen breakdown.
Glycogen synthase is inhibited → decreases glycogen synthesis.
Effects on glycolysis vs gluconeogenesis:PKA inhibits PFK-2, decreasing fructose-2,6-bisphosphate, & inhibiting glycolysis, whilst promoting gluconeogenesis
Net effect of glucagon:
Increased glycogen breakdown, blood glucose levels, and increased gluconeogenesis but
decreased glycolysis, glycogen synthesis.
79
What occurs during the phosphorylation state?
Phosphorylated state (PKA active) → glycogen breakdown ON but glycogen synthesis OFF.
Dephosphorylated state (PP1 active) → glycogen synthesis ON but glycogen breakdown OFF
80
What is the role of epinephrine?
Epinephrine acts similarly to glucagon, it activates the PKA pathway and stimulates glycogen breakdown
81
Why is protein needed in our diet?
The body cannot store excess essential amino acids or nitrogen. Hence, they must come from our diets. There is a limited ability of our body to synthesise the carbon skeleton of non-essential amino acids. There is a constant turnover of protein as our enzymes are being synthesised, and degraded in a continuous cycle in the body’s pursuit of stability. Nitrogen is used in proteins, nucleotides and nucleic acids.
82
Fate of Carbon Skeleton of Amino Acids?
When amino acids are not required to synthesise new proteins, the amino acid breaks down and the nitrogen group is separated from the carbon skeleton. Once the nitrogen is cleaved off, it can be used to synthesise other nitrogen containing molecules. It could be used to synthesise non-essential amino acids as well as our nucleotides + nucleic acids. The fate of the carbon skeleton is that it can actually be used for energy, so it’s a carbon hydrogen backbone that can be modified slightly + ultimately enter the citric acid cycle
83
What is the fate of nitrogen?
Nitrogen and ammonia as an ion in our bloodstream is actually very toxic. The fate of this nitrogen is that if it’s not recycled into another molecule, it’ll be transferred to the Urea cycle where the nitrogen will be repackaged into a molecule that’s safe + non-toxic to our tissues and easily excreted through the kidneys.
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What is transamination?
The transfer of an amino acid group from an amino acid to a-Keto acid (carbon skeleton formed from the amino acids). This process is catalysed by enzymes called amino transferase or transaminase. The amino group from a given amino acid is transferred to the a-Keto glutamate forming Glutamate, leading to another a-Keto acid. Many types of amino transferases exist which are specific for the amino acid involved. Transamination is involved in the synthesis +catabolism of amino acids. This acts as the 1st step in catabolism of most amino acids once they have reached the liver. Hence, there's no net loss of the amine group
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What is deamination?
The release/cleavage of an amino group in the liver, producing a-ketoglutarate and ammonium (NH4+). It is a reversible process, requiring a mitochondrial enzyme, and this enzyme involved is Glutamate dehydrogenase which releases/cleaves the nitrogen containing/amino group of glutamate. It is closely liked with the citric acid cycle and reduces NAD+ to NADH (or NADP+/NADPH).
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How is ammonia transported to the liver?
Glutamine transports ammonia from non-liver tissues like the brain to the liver. When it enters the liver, it undergoes deamination forming glutamate
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What is the glucose-alanine cycle?
The glucose-alanine cycle transports ammonia from muscle to liver via alanine. Glutamate and pyruvate undergo transamination to form alanine. Alanine travels in blood to the liver. In the liver, alanine undergoes transamination forming pyruvate and glutamate. Glutamate undergoes deamination, and the amino group enters the urea cycle. Pyruvate can undergo gluconeogenesis to form glucose for energy
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How are amino acids synthesised from metabolic pathways?
Many intermediates of glycolysis and the citric acid cycle are used to synthesise non-essential amino acids
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What are major nitrogen-containing molecules?
Amino acids, nucleotides, proteins, and uric acid
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What is excretion in these terms?
Nitrogen is removed mainly in the form of urea in humans. Ammonium ions are formed following deamination. It is toxic in humans because it affects ion transport across cell membranes . Ammonia is converted to urea in the liver to then undergo the urea cycle. Our bodies cannot store amino acids so excess amino acids from the diet are broken down, the carbon skeleton is re-purposed and the nitrogen excreted in the form of urea
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What is the liver urea cycle?
Urea is produced from ammonia in 5 enzymatic steps. NH4+ is removed through deamination. It's an energy dependant pathway. Nitrogen is released from the cycle in the form of Urea. Urea contains 2 amine groups which come from glutamine/glutamate and aspartate. Fumarate is released to avoid a large pool being created as a by-product of this reaction in the form of waste. Instead, it is recycled and through a series of enzymatic steps it is converted to malate which can be inputted in the Citric Acid Cycle. The cycle produces fumarate, it doesn’t require it but it does requires 1 molecule of aspartate per cycle
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Where does the urea cycle occur?
first part in the mitochondria and second part in the cytosol
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What are the links between the Urea and CAC cycle?
Fumate is a product that is released in step 3 of the urea cycle, once released it is no longer present + required. It returns to the mitochondria as malate where it enters the CAC.
Aspartate is one of the substrates used in step 2 to donate the 2nd amine group which forms arginine succinate in the Urea cycle. However, it is formed from the Citric Acid Cycle intermediate, oxaloacetate, through a transamination reaction. By continuing to add to the Citric Acid Cycle with malate, it contributes to the pool of NADH required for the ETC. Energy is required to fuel the Urea cycle as it's an ATP requiring reaction. Hence, a protein rich diet may actually be somewhat wasteful if a huge amount of those amino acids being taken up are just being converted to urea, so plenty of energy is wasted.
However, the interconnectedness between the citric acid cycle and the urea cycle does help to offset energy loss
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What are the energetics of the Urea Cycle?
4 high energy phosphates are consumed per urea formed. However, the fumarate to oxaloacetate conversion yields 1 NADH. The pathway interconnectedness reduce energetic costs of urea synthesis.
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Amino Acid Classification?
Amino acids can be classed as glucogenic or ketogenic, however some are both and this depends on the metabolic pathways followed. Only 2 amino acids are strictly ketogenic: Leucine and Lysine
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What are Glucogenic amino acids?
They’re metabolised into intermediates for the Citric Acid Cycle. They can enter the CAC independently. It ultimately forms oxaloacetate for gluconeogenesis in the pursuit of glucose production
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what are Ketogenic amino acids
They’re metabolised to Acetyl CoA or Acetoacetyl CoA but ultimately form ketone bodies. There's no gain of oxalacetate as it’s taken away from the beginning and reformed into citrate. Hence, there is no net production of oxaloacetate and it cannot contribute to the formation of glucose. Acetyl CoA cannot directly enter into the Citric Acid Cycle, hence it must form citrate by combining with oxaloacetate to form citrate. Instead, these molecules are used when energy levels are low and more fuel is required
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What is the nitrogen balance?
An indicator of balance between catabolism and anabolism of proteins with nitrogen consumed = nitrogen excreted,
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What is a positive nitrogen balance?
Positive Nitrogen Balance: nitrogen consumed > nitrogen excreted. Associated with: growth in childhood, pregnancy, convalescence (adding new protein)
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What is a negative nitrogen balance?
Negative Nitrogen Balance: nitrogen consumed < nitrogen excreted. Associated with: starvation, malnutrition, illness, burns, trauma, surgery, fever, infection (loss of protein). This can be measured with urine urea and protein intake by estimating the amount of protein taken in and comparing that with the amount of nitrogen present in our urine. In this urine analysis, all 3 molecules need to be considered, urea, uric acid and creatinine.
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How does nitrogen loss transpire?
Predominantly lost as urea and a small amount is lost as uric acid as well and through creatinine. Phosphocreatine assists in generating ATP during periods of heavy exercise or activity. Phosphocreatine is constantly broken down to become the molecule, creatine. Phosphocreatine, creatine, and creatinine all contain nitrogen. Protein contains 16% of nitrogen.
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What is Creatinine?
Creatinine is present in urea as a molecule that contains nitrogen which contributes to our overall nitrogen balance. Creatinine is the breakdown product of creatine phosphate and is excreted in the urine. It provides energy for muscle contraction
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How is nitrogen metabolised?
Amino acids are supplied from diet (protein hydrolysis). The body can synthesise 10 amino acids whilst the others must come from diet. Amino Acids in excess are deaminated. Most amino acids are deaminated through transamination with α- ketoglutarate; the glutamate formed is deaminated by glutamate dehydrogenase, releasing ammonia. Ammonia is converted to urea and excreted. Free ammonia (toxic) from deamination in tissues is transported to the liver as the amide group of glutamine which is hydrolysed to ammonium ion for urea synthesis. The glucose-alanine cycle is responsible for transporting amino nitrogen from muscles (from protein breakdown) to the liver. The carbon-hydrogen skeletons are oxidised to release energy or converted to fat/glycogen
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How do different tissues use and store energy?
All tissues need energy but some require more than others. Liver provides fuel, stores glycogen and triglycerides, and synthesises glucose and ketone bodies. Muscle has high energy demand, uses fatty acids at rest and glucose after meals or during activity. Muscle uses its own glycogen and glucose released by the liver. Muscle can use ketone bodies, mainly during starvation or prolonged fasting. Brain has high energy demand, does not store energy, relies mainly on glucose. Brain can use ketone bodies in extreme conditions. Adipose tissue stores triacylglycerides and is insulin-sensitive, so storage and release are hormonally regulated
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How do tissues regulate blood glucose
The pancreas acts as a glucose sensor, in response to high glucose it’ll secrete insulin and in response to low glucose it’ll secrete glucagon. Our bodies must regulate blood glucose levels. Blood glucose is ideally kept at around 4.5mM (60-90 mg/dL), with some fluctuation occurring after a meal.
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What fuels the brain?
The brain is incredibly selective when it comes to the fuels that it will actually use, it prefers glucose. However, when our bodies are pushed into starvation mode, our liver will synthesise ketone bodies for the brain to use. Fatty acids cannot cross the blood brain barrier
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When are hormones released in response to blood glucose levels?
Insulin is released when blood glucose is high from the pancreas. Glucagon is released from the pancreas when blood glucose is low. Epinephrine (adrenaline) is released from the adrenal glands in periods of immediate stress or activity to prepare the body for action + for muscles to move
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What is insulin?
Is a hormone secreted by Beta-cells of islets of Langerhans from the pancreas. This secretion is stimulated by glucose, amino acids, and fatty acids. It binds to insulin receptors on cells and stimulates the uptake and storage of fuels. It inhibits the mobilisation of stored fuels and both the production + export of glucose by the liver. It is secreted almost immediately after a meal as blood glucose will spike then with insulin secretion following shortly after. The presence of insulin helps to bring blood glucose levels down. As blood glucose levels drop, so does insulin, and it will continue to do so until the next meal. In individuals with type 1 diabetes, they fail to produce insulin so there will be no change whatsoever to insulin secretion between meals, causing blood glucose levels to go about unmanaged. Major targets are liver, adipose, and muscle. It stimulates pathways for the uptake of fuels, particularly glucose from the blood, and storage of excess energy
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What is Glucagon?
Glucagon is a hormone produced by the pancreas that raises blood sugar levels by triggering the liver to release stored glucose (glycogenolysis). Its major targets are liver and adipose and it stimulates the mobilisation of stored fuels (fatty acids) along with the production + export of glucose by liver. It also increases the activity of ketogenesis in the synthesis of ketone bodies. BUT, it inhibits pathways for glucose utilisation and the storage of energy sources. The glycogen stored in the muscle is only used for the muscle tissue itself so it cannot be converted back to glucose and for that reason glucagon has no effect on muscle tissue. It's used as an emergency medication for severe hypoglycemia (very low blood sugar).
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What is epinephrine?
It stimulates pathways for mobilisation of stored fuels (fatty acids), glucose utilisation and production & export of glucose by liver. Its major targets are liver, muscle, and adipose. It inhibits pathways for the storage of energy sources. It works to promote glycogen breakdown,gluconeogenesis and glycogen synthesis. It's the only hormone that stimulates glucogenolysis in muscle cells
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What is the fed state?
Fed: less than 4 hours after a meal and is referred to as the lipogenic liver
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what is the fasting state?
Fasting: more than 4 hours after a meal, and is referred to as the ‘glucogenic’ liver
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what is the prolonged fasting or starvation state?
describes days after a meal and in this period diabetes may present effects or symptoms of starvation.
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how is fuel used in 4 hours of normal human metabolism?
Immediately after a meal, glucose increases -> Insulin stimulates glycolysis and glycogen synthesis. 2-4 hours following a meal, blood glucose begins to drop so glucagon is secreted, and liver glycogen releases glucose. 4 hours post-meal (early fasting) -> More glucagon secreted, more TAG hydrolysis, and fatty acids are released to become fuel for muscle and the liver.
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What is the lipogenic liver?
Lipogenic refers to processes or substances that stimulate lipogenesis, the metabolic synthesis of fatty acids and triglycerides from non-fat sources like carbohydrates.mKey macromolecules are absorbed like glucose, amino acids, and fats taken up by our lymphatic system. This results in an increase of our blood glucose levels, and the levels of amino acids + fats. A large amount of glucose is stored in the form of glycogen and is exported to the brain for energy. Concurrently, a large amount of glucose is broken down by glycolysis to pyruvate, and then ultimately stored in the form of triacylglycerides
Acetyl CoA can both fuel the citric acid cycle and store/synthesise triacylglycerides. Some amino acids will be immediately used for protein synthesis, but the vast majority will be transaminated/broken down to alpha keto acids to be repurposed or utilised for further energy production. Fatty acids become the fuel source for mostly muscles but also the liver. Many are stored as triglycerides to be stored in the adipose tissue.
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What are the effects of prolonged fasting/starvation?
Causes muscle to be used for fuel. To do this, the liver deaminates or transaminates amino acids, which are converted to urea, as the C skeletons of glucogenic amino acids are converted to pyruvate before becoming glucose via gluconeogenesis, and finally this glucose provides energy for the brain. Fatty acids can be oxidised to acetyl CoA but oxaloacetate is depleted to make glucose as it's needed in gluconeogenesis, so ketone bodies are formed. These will be exported to other tissues like the brain and contribute to a reduction in blood pH via ketoacidosis. Oxalacetate is needed to allow for the cycling of CAC. Without fuel sources incoming into the liver, the glucogenic liver relies on already present fuel sources like glucagon. Glucagon aids in mobilising stores of triacylglycerides and transforming them into fatty acids to be taken to the liver. The liver/muscles (but not the brain) can use fatty acids for energy so there is a need to convert fatty acids to ketone bodies to generate energy for the brain. Eventually, muscle protein is utilised for energy, so both the proteins in our muscles + non-essential proteins in the liver can be broken down to their amino acids.
Depending on whether the proteins are glucogenic or ketogenic, they will either be used to synthesise further ketone bodies or be broken down into pyruvate and used for gluconeogenesis to synthesise new glucose.
In addition to this, any remaining glycogen stores are broken down for glucose. Mostly likely the first to be depleted would be glycogen stores, then all fat stores would be exhausted and only then would the body look to protein for energy as they’re essential for cell function. As the body transitions from a fast to a starvation mode, there is a small period of time where some non-essential proteins may be used. Muscle and liver proteins will initially be broken down to provide glucose for the brain through gluconeogenesis
Once ketone bodies are synthesised, the glucose demand decreases. However, once ketogenesis commences and ketone bodies are being synthesised the usage of protein diminishes until the body reaches a point where it’s the only remaining fuel source. Oxidation rate is relative to the rate the fuel sources are being used
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How are ketone bodies produced?
Increases during starvation and diabetes and released by the liver to the bloodstream. It is
synthesised only in the liver
so other organs can use ketone bodies (e.g. acetone) as fuels. High levels of acetoacetate and B-hydroxybutyrate (ketones) lowers blood pH dangerously through acidosis. Importantly, for CAC to progress, a constant supply of oxaloacetate is required to be available
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What is diabetes mellitus?
A metabolic disease characterised by elevated fasting blood glucose levels (hyperglycemia), resulting from relative or absolute deficiency of insulin. Chronic hyperglycaemia leads to damage of most body organs like the eyes, kidneys, nerves, heart, and blood vessels. This is characterised by hyperglycaemia, thirst + dehydration, and excess urination. Many symptoms of chronic diabetes stems from the prolonged nature of the high blood glucose levels
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Summarise Type 1 Diabetes Definition
Type 1 Diabetes: juvenile diabetes, the insulin dependent version (IDDM). The destruction of insulin-producing B-cells in the pancreas that synthesis insulin and it is an autoimmune disease. The body simply doesn’t synthesise insulin.
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Summarise Type 2 Diabetes Definition
Type 2: non-insulin dependent diabetes (NIDDM), the adult onset version. Here, insulin is being synthesised but it either has impaired function or the body has developed a resistance to it. Therefore, insulin is being produced but the body isn’t responding in the way it should.
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What is type 1 diabetes and what are its features?
The autoimmune destruction of islet β-cells causing an absolute insulin deficiency so it must be taken in the form of medication. Onset usually under 40 years, particularly associated with children, acute onset and weight loss
~10% of diabetes in AUS.
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What are the symptoms of type 1 diabetes?
Symptoms include thirst, frequent urination, weight loss, lack of energy, hunger, elevated blood glucose, increased fatty acid mobilisation and the breakdown of elevated ketone levels
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How is metabolism altered in type 1 diabetes?
Normally, after a meal glucose is taken up by adipose tissue muscles & the liver where it’s either utilised immediately for glycolysis or stored in the form of glycogen. In type 1 diabetics, despite glucose levels being really high, those tissue cells without the presence of insulin are unable to take up glucose as glucose is used as a GLUT-1 transporter. Insulin and glucagon would be released with insulin stimulating protein synthesis whilst inhibiting breakdown. However, in type-1 diabetics only glucagon is released which leads to protein breakdown. Type 1 diabetes leads to elevated blood lipid levels as their triacylglycerides are broken down so that both glycerol + fatty acids are released. This means that glycerol could contribute to glucose production through gluconeogenesis. Glycerol from the fatty acids are used to synthesise glucose. None of the glucose is being taken up in the diabetic model
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What is “starving amidst plenty” in type 1 diabetes?
This phenomena is known as starving amidst plenty as type 1 diabetes leads to the activation of pathways that are usually active during starvation. These refer to protein mobilisation, TAG mobilisation, glucose synthesis and ketone synthesis. Despite the concentration of nutrients in the blood being extremely high, a type 1 diabetic body cannot use them being insulin isn’t present to signal to those tissues to take up that glucose and the pathways that should be active to store glucose + use glucose are not being turned on so it simply remains in the bloodstream. Furthermore, without insulin, these tissues will continue to mobilise other fuel stores despite there being lots of glucose present in the bloodstream
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What are the long-term effects of type 1 diabetes (hyperglycaemia)?
The long term effect of an elevated blood sugar is that proteins can be glycosylated, especially at free amino groups. This increases the risk of cardiovascular disease, renal failure, and damage to small blood vessels + nerves
Example: Hemoglobin is abundant, and has many exposed amino groups during formation, so entry of glucose into erythrocytes is not regulated. Hence, Hb is easily glycosylated which compromises O2 delivery, especially in extremities (feet, etc.). Glycosylation is a complex, enzyme-controlled, post-translational modification process where carbohydrate moieties (glycans) are covalently attached to proteins or lipids in the endoplasmic reticulum and Golgi apparatus.
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What is type 2 diabetes?
Describes insulin resistance or impaired production. Is
onset gradual and usually present in individuals over 40 (but increased incidence of earlier onset) so it is the most common form of diabetes with over 85% of the population having it.
Associated with obesity, lack of exercise. Treatment: diet, exercise, oral medication, and insulin. The development of insulin resistance is somewhat unknown as it is very unique /variable. The need for these genetic defects to accumulate temporally before issues present, could explain why type 2 diabetes cannot be observed until later in life
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What is type 2 diabetes caused by?
It can be caused by genetic defects to the metabolism of carbohydrate, fat, and protein through GLUT4 transporters of glucokinase..It could be caused by defects to the production of hormones like insulin/leptin and insulin receptors or appetite through leptin or leptin receptors
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What are the symptoms of type 2 diabetes?
Common symptoms include persistent thirst, frequent urination, fatigue, slow-healing sores, and blurred vision. These develop slowly as the pancreas fails to produce enough insulin to overcome resistance.
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What is the lipid burden hypothesis and how does it contribute to insulin resistance?
hypothesis relates to obese individuals who become too full + incapable of accommodating more triacylglycerides, leading to an overflow of FAs and an inflammatory state which triggers the further release/production of FAs from adipose sites. This involves the immune system, including macrophages and the production of TNF alpha. It is thought then that when the blood becomes completely saturated with fatty acids, fatty deposits are created which accumulate in muscle cells. These ectopic (accumulated) deposits form a physical barrier between the muscle cell surface and the vesicles containing the GLUT-4 transporters. This means that when insulin signals to muscle cells, the muscle cells are unable to put those GLUT-4 transporters into the muscle cell surface so they can no longer take up glucose and blood glucose levels remain high
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How is glucose metabolism altered in type 2 diabetes?
In normal conditions, glucose in the blood is taken up by adipose tissue and skeletal muscle. The liver regulates blood glucose and can store glucose as glycogen. In type 2 diabetes, the liver increases glucose production from glycogen, glycerol and lactate. This leads to increased glucose released into the bloodstream. Uptake of glucose by adipose tissue and skeletal muscle is impaired. As a result, blood glucose levels remain elevated
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How is lipid metabolism altered in type 2 diabetes?
Type 2 diabetes causes increased levels of lipids in the blood. Mobilisation of triacylglycerol (TAG) increases, leading to increased free fatty acids (FFA) in the serum. Free fatty acids are taken up by other tissues. The amount of fatty acids exceeds the liver’s energy requirements. Excess fatty acids are re-esterified in the liver to form TAG and exported as very-low-density lipoproteins (VLDL). VLDL transports TAG to adipose tissue. Uptake of lipids by adipocytes is often impaired in type 2 diabetes. This results in increased TAG in the blood (hyperlipidaemia)
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What is a key difference between type 1 and type 2 diabetes (lipid storage)?
One of the differences between type 1 and 2 diabetes is that type 2 diabetics may actually have a large store of triacylglycerols and fatty acids that can contribute to exacerbating the situation
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