Lecture 23; Hormonal Regulation of Fuel metabolism

Question 1

Describe the two major dietary sugars?

Answer 1

Glucose

Fructose

Galactose is metabolised to glucose

Question 2

What is the set point of blood glucose?

Answer 2

Blood glucose levels need to be maintained at 4-5 mM all the time for the benefit of tissues that have absolute requirement for glucose as an energy source

When blood glucose gets below 2 mM nerves start to malfunction resulting in seizures and even a coma.

Question 3

Why do we need such high level of glucose when proteins and FAs can be metabolised?

Answer 3

Some cells only use glucose as the fuel source i.e

Brain, to generate ATP, drives ion pumps that maintain the ion gradients that are required for the brain to work.

Other cells that rely primarily on glucose include red blood cells and immune cells.

Other tissues (e.g. heart) use some glucose but can also use other energy sources, for example muscle uses large amounts of fatty acids

Question 4

Describe the transport of glucose in the brain;

Answer 4

The plasma membrane of neurons have transport protein called GLUT3 that are permanently in the plasma membrane. These rapidly transports glucose down a concentration gradient by passive transport so as glucose is used more glucose is rapidly transported into the cells.

It is a glucose ‘transporter’ NOT RECEPTOR

Question 5

Where does glucose come from in the diet?

Answer 5

Long chain forms (carbohydrates) such as starches or sucrose.

Question 6

Describe glucose transport in the gut;

Answer 6

Glucose is readily absorbed by the gut using a sodium linked glucose transport protein (SGLT1) to get the glucose into gut cells and then the GLUT2 glucose transporter allows the efflux of glucose into the blood. The problem with this is that we only eat intermittently so this is not a stable supply to allow us to maintain a constant glucose level.

Question 7

Why does the body use a co-transporter? SGLT1?

Answer 7

Co-transport of sodium allows this transporter to transport glucose up a concentration gradient into these cells where glucose concentration is high

GLUT2 is a facilitative transporter as glucose then goes down its concentration gradient

Question 8

How does the liver produce glucose?

Answer 8

Liver produces glucose from things like glycerol and amino acids in a process called gluconeogenesis but if we do this too much then the body will break down fat stores and proteins to such an extent that is unsustainable so this is only used as an emergency mechanism.

Glucose is also stored highly in the liver, as we eat periodically. Glucose is also stored in the skeletal muscle.

Question 9

How is fructose transporter?

Answer 9

GLUT5 then GLUT2

Question 10

Where are the major hormones that regulate glucose made?

Answer 10

IN the SI and Pancreas

SI = lots of neural and hormonal connections

Question 11

How does uptake of glucose from the gut feed forward to regulate hormones that in turn regulate metabolism?

Answer 11

Specialised cells in SI (e.g. L-cells and K-Cells) produce hormones in response to changes in glucose being taken up (hep. port. vein) . Affecting glucose metabolism. i.e glucagon like peptides 1 and 2 (GLP1,2) and Glucose dependent insulinotropic peptide (GIP).

Glucose sensed in the pancreas enroute to the liver in the hepatic portal vein

The islets of langerhans sense glucose; low glucose the α-cells -> Glucagon Insulin secretion from the b-cells is suppressed.

High glucose the α-cells stop releasing glucagon and the b-cells begin to secrete insulin.

Question 12

What is the function of the hepatic portal vein?

Answer 12

Drains all the nutrients from the SI to the liver via the pancreas.

• Allows pancreas to sense glucose
• Also allows GLP1,2 and GIP to be secreted by SI into the HPV and travel to the liver

Question 13

Describe the process of glucose entering the circulation

Answer 13

• Stomach
• SI
• Absorbed directly in HPV
• Enroute to liver it simulates hormone release from SI and Pancreas
• Not all glucose is taken into the liver and some escapes into systemic circulation, reaches the pancreas and increases insulin release.

Question 14

What gut hormones are important regulators of insulin?

Answer 14

GLP

GIP

Question 15

Describe the blood glucose of someone who has just eaten;

Answer 15

Rises one or two mM, but then is restored to homeostatic levels as glucose is stored.

Takes 90-120mins

Question 16

Describe the source of GLP1;

Answer 16

• derived from the transcription product of the proglucagon gene.
• SI L-cells, secreted in response to nutrients
• GLP-1(7-36) binds to GLP-1 receptor which is GPCR coupled to Ga(s) = cAMP prod.
• T(half )2 minutes, due to rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-IV)

Question 17

What are the effects of GLP1?

Answer 17

• promote b-cell survival so preserve b-cell mass
• regulating appetite (brain)
• potentiates (b) insulin secretion and inhibits glucagon (a)

Question 18

Write notes on GIP;

Answer 18

• Formerly known as Gastric Inhibitory Peptide
• also potentiates insulin release
• secreted from K-cells in intestine in response to high glucose and binds to a specific GPCR in target tissues

Question 19

What does the entire proglucagon gene encode for?

Answer 19

Glucagon

GLP1

GLP2

Question 20

What are the cell types in the pancreas and what hormones do they produce?

Answer 20

95% exocrine pancreas

5% endocrine;

• a = glucagon
• b = Insulin
• d = Somatostatin
• PP = Pancreatic polypeptide

Question 21

What is seen when we look at glucagon and insulin?

Answer 21

There is a continued yo-yo effect i.e their levels are inversely related

Question 22

Describe how glucose stimulates insulin secretion;

Answer 22

• B cell takes up glucose via GLUT 2
• Glucokinase converts it to G-6-P
• Enters the glycolysis cycle and forms pyruvate
• Pyruvate enters the TCA cycle and ATP is produced
• ATP shuts K channel. RMP rises
• Voltage Sensitive Ca channels open, Ca influxes and Stimulates exocytosis of insulin storage granules.

Question 23

Describe how GLP1 stimulates insulin release;

Answer 23

GLP1 binds GLP1 receptor this generates cAMP which potentiates the exocytosis of insulin storage granules.

Question 24

Describe how glucose concentration affects the rate of insulin release;

Answer 24

The kinetics of the various transporters and glucokinase increase for increasing glucose concentration within the physiological range of concentrations.

Therefore there will be an increase in G6P production and thus insulin because of the increased rate of transport (GLUT2) and rate of production (glucokinase)

GLUT 4 (muscle specific) wont change its rate of transport because it is Vmax at physiological range.

Question 25

Describe insulin secretion;

Answer 25

It has two phases

Phase 1; ~5mins, very high secretion

Phase 2; long term increases in conc. at a slower rate

Question 26

How else does insulin and glucose affect the B cells?

Answer 26

It regulates gene transcription to replace itself.

Question 27

What is essential for insulin formation?

Answer 27

Zinc

Question 28

What is essential for insulin formation?

Answer 28

Zinc

Question 29

How does insulin and GLP1 affect glucose metbolism?

Answer 29

1) Direct effects of insulin on glucose metabolism main metabolic target tissues (i.e in liver, muscle and fat)
2) Indirect effects (mainly on liver and pancreas) via efferent nerves (mostly the vagus nerve) which are regulated in part by hormones including insulin, leptin and GLP-1 binding to certain neurons in the brain.

Question 30

Describe insulin signalling;

Answer 30

Major Insulin effects / receptors are in Liver, muscle and Adipose

There are also high levels of insulin receptors on some specific neurons and this seems important in overall metabolic regulation

Insulin receptor is a α2β2 heterotetrameric receptor tyrosine kinase highly homologous to the IGF-1 receptor.

Insulin binds to extracellular surface of α subunit activating tyrosine kinase activity in intracellular β subunit (see previous notes).

Insulin phosphorylates IRS-1 on multiple tyrosines, many in motifs capable of binding SH2 domain.

One of most important molecules seems to be the class-1 PI 3-kinase. Blocking activation of this molecule blocks almost all of insulins effects on cells.

Should know this already

Question 31

Describe insulin action;

Answer 31

Insulin’s ability to control BG levels depends on both its effects on hepatic glucose metabolism (i.e switching from net production to net uptake) and its stimulation of glucose uptake into muscle and fat

In the liver insulin counters the actions of glucagon resulting in shutdown of the glycogenolysis and gluconeogenesis.

Once glucose gets past the liver then 80-90% of insulin mediated glucose disposal in the rest of the body is into muscle and this is because they have the GLUT4 glucose transporter which responds to insulin

Lipolysis is also suppressed by insulin

Insulin also acts to temporarily suppress VLDL secretion from the liver.

Question 32

Does glucagon affect muscles and fat?

Answer 32

Glucagon doesn’t affect muscle and fat due to low levels of glucagon reaching the periphery and low levels of receptors on muscle and fat. In these tissues insulin stimulates both increased uptake and storage of glucose. An important additional action of insulin in fat is to shut down lipolysis. This allows storage of energy as triglycerides and also regulates circulating FFA levels

Question 33

Describe the livers role in glucose storage;

Answer 33

Liver acts an important place for storing excess glucose when levels are high and it is also the main source of glucose in absence of intake from the gut. This is referred to as hepatic glucose output

Question 34

How does the liver produce glucose?

Answer 34

Liver has 2 mechanisms for producing glucose
- Release of glucose from glycogen in the liver (glycogenolysis). (large stores)

• De novo production of glucose via gluconeogenesis due to unique presence in liver of 2 enzymes that can reverse glycolysis. These are Phosphoenolpyruvate-carboxy-kinase (PEPCK) and Glucose-6-phosphatase(G6Pase)

Question 35

What is an acute regulator of glucose production in the liver?

Answer 35

Glucagon

Question 36

Describe whats necessary for glycogen release?

Answer 36

Glycogenolysis allows breakdown of glycogen stores between meals to produce glucose-6-phosphate but this can’t be released into the blood unless it is dephosphorylated and only liver produces the enzyme required to do this (Glucose-6-phosphatase)

Concentration gradient allows glucose to leave the cell via GLUT 2

Question 37

Describe gluconeogenesis;

Answer 37

Gluconeogenesis allows liver (but not other organs) to produce glucose in starved state by reversing glycolysis due to presence of a special enzyme called PEPCK which is found only in the liver

Pyruvate (from alanine or lactate) is converted by PEPCK to phosphoenolpyruvate, glycerol is added forming G6P. glucose-6-phosphotASE converts this to glucose.

Controlled by glucagon

Question 38

What stimulates glycogen storage?

Answer 38

Insulin stimulates glycogen synthase and so diverts glucose to glycogen
(plus it reduces levels of PEPCK and G6Pase so preventing efflux)

Question 39

How is fructose different?

Answer 39

• Transported via GLUT2
• Converted by Fructokinase to F1P (uric acid is produced as bi-product, depleting ATP)
• F1P is converted to disproportionate lipid synthesis

Question 40

Describe the effects of glucose fluxes in fed states and effects of insulin and incretins;

Answer 40

Very high levels of insulin (> 1nM) arrive at liver shutting down hepatic glucose production stimulating hepatic glucose storage

Lower levels of insulin (approx 100-200 pM) escape the liver and arrive in peripheral circulation where it is enough to stimulate uptake of glucose into muscle and adipocytes

Question 41

Whats the role of muscle in glucose regulation?

Answer 41

Muscle tissue can use both fats and glucose as an energy source but after either insulin stimulation or exercise it greatly increases the amount of glucose it takes up.

Some glucose is stored as glycogen and some is used to produce ATP later in the muscle.

Because we have lots of muscle in our body it means that even a small increase in uptake of glucose into each muscle cell can make quite a big difference to the amount of glucose in our blood. This is one reason why exercise is quite a good way of lowering our blood glucose levels.

Question 42

What does insulin do to glucose uptake into the muscle?

Answer 42

Insulin stimulates glucose uptake into muscle and it can be stored as glycogen but there is no glucose-6-phosphatase so when glycogen is broken down it can only be used in the muscle to produce ATP rather than being released like liver

Question 43

What does insulin do to adipose tissue?

Answer 43

Insulin stimulated uptake of glucose in adipocytes promotes synthesis of triglycerides and release of leptin

Insulin also helps keep triglycerides high by blocking lipolysis (i.e the breakdown of triglycerides)

Question 44

What does leptin do?

Answer 44

Leptin produced in response to nutrient inflow into fat cells and goes to hypothalamus to regulate food intake

Question 45

What can promote the release of stores from adipose?

Answer 45

These stores of energy can be released later by agents that signal through cAMP and have receptors on adipocytes (e.g. adrenaline) promote breakdown of triglycerides (i.e. lipolysis)

Question 46

How exactly does glucose act on muscle and adipose?

Answer 46

Insulin stimulates glucose transport into muscle and fat by stimulating the movement of GLUT4 glucose transporters to the plasma membrane from a pool that is normally sequestered inside the cell

Question 47

Where does most glucose go to when consumed?

Answer 47

Muscle and liver are where most of the glucose goes after insulin stimulation showing how important these are for lowering blood glucose

But only liver can release glucose back into the blood stream later

Question 48

How does the brain play a role in BG?

Answer 48

Insulin and GLP-1 can also regulate glucose metabolism by acting centrally (i.e on neurons in brain) to regulate efferent nerves that regulate glucose metabolism in liver and hormone secretion in pancreas

Question 49

What happens if we have no insulin?

Answer 49

We have no stores of glucose in the liver so between meals the liver has to resort to gluconeogenesis to provide a supply of glucose for the brain so body goes in to a catabolic state.

Fat cells don’t store fat but instead they release it so free fatty acids in the blood get to high levels resulting ultimately in high levels of ketone bodies which can acidify blood to dangerous levels.

Question 50

How does exercise stimulate glucose uptake independently of insulin?

Answer 50

Muscle contraction acutely stimulates glucose uptake by stimulating GLUT4 translocation in muscle. (even in paraplegics and diabetics)

This process uses a different mechanism to insulin and is mediated by a build up of AMP as ATP levels falls. This results in activation of AMP activated protein kinase (AMP Kinase- see previous lectures).

Chronic exercise also has an effect to increase levels of GLUT4 in muscle which has beneficial effects on glucose metabolism

Question 51

How is the insulin signal shut off?

Answer 51

Insulin in broken down after stimulation but insulin receptors are recycled to plasma membrane ready for another round of signalling

Question 52

How does the kidney regulate blood glucose?

Answer 52

In addition to insulin mediated glucose disposal pathways the kidney is another important point at which blood glucose levels are controlled as there is a constant balance between excretion and reuptake of glucose in the kidney

This is a mechanism to conserve blood glucose (SGLT2 in the kidney)

This is solely dependent on the total levels of glucose in the blood

Glucose will spill over into the urine at higher blood glucose concentrations

Question 53

What glucose transporter is active in the kidney?

Answer 53

The kidneys filtration system allows glucose to move into urine but this is wasteful so kidneys have a special glucose transporter called SGLT2 which reabsorbs glucose against a concentration gradient by co-transporting sodium.

Question 54

What are important modifiers of glucose homeostasis?

Answer 54

Stress hormones are very important modifiers of glucose homeostasis

i.e Adrenaline rapidly mobilises glucose by stimulating glycogen breakdown in liver

Question 55

What are the effects of glucocorticoids on blood glucose?

Answer 55

Glucorticoids are key stress hormones regulating glucose metabolism (e.g. corticosterone and cortisol)

They are so named as they are produced in cortex of kidney and they regulate glucose levels

Glucocorticoid production in the kidney cortex is cyclical with overall levels being regulated in a diurnal manner

Question 56

What do glucocorticoids signal via?

Answer 56

Glucocorticoids signal via a nuclear receptor to directly regulate a wide range of genes

Question 57

What do glucocorticoids alter in the brain?

Answer 57

Glucocorticoids change the set point to favour glucose production for use by the brain.

Question 58

How do glucocorticoids alter the set point of blood glucose?

Answer 58

Cortisol regulates genes to switch the set point in glucose homeostasis towards production of glucose and sparing glucose for use by key tissues such as nerves, heart and red blood cells.

It does so by;
1. Increasing gluconeogenesis in the liver by increasing expression of key genes.

2. The new glucose produced is directed towards nerves, blood etc by inhibiting the uptake of glucose into muscle and fat.
3. A normal levels they promote lipolysis in fat tissue to supply material for gluconeogenesis(Paradoxically it can also store lipids in some fat depots when glucocorticoid levels are really high)
4. In physiological levels they can have a catabolic effect in muscle to supply amino acids for gluconeogenesis.