IMED1003 - Glucose Homeostasis (L22)

THINGS TO KEEP IN MIND FOR THIS LECTURE

- adrenaline = adrenalin

- up arrow (increase) also means activates

- down addow (decrease) also means inhibits

Glucose

- Carbohydrate (monosaccharide)

- energy source (universal fuel)

- Store: glycogen

- 70kg adult < 700g (around 1% wt)

- Liver <120g (around 8% wt)

- Sk muscle <400g (1-2% wt)

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- Catabolised: aerobically (CO2 and H2O) and anaerobically (lactate) --> ATP

- sourced from diet

- anabolised in liver (and kidney) = gluconeogenesis -> blood -> organs (brain)

Glucose Metabolism

- glycogenolysis turns glycogen to glucose

- glycolysis turns glucose to pyruvate

All pathways of Glucose and FA Anabolism and Catabolism

DIAGRAM ON SLIDE 5

Glucose Homeostasis

- Glucose supply = intermittent and body's metabolic demands vary ... glycogen stores mobilised and utilised when required

- Key organs: liver, brain, skeletal muscle, pancreas, adipose, kidney

- How do we regulate metabolic pathways

- Turn on/off specific enzymes

- Allosteric regulation and hormonal regulation are key to glucose homeostasis: some processes are faster than others

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- basically diagram shows the path of glucose from GI tract to body

- some glucose goes to peripheral tissues where it is used to make ATP, the rest goes to the liver where it is stored as glycogen

Glucose Transport Across Membrane

- Various glucose transporters in different tissues: some are insulin-sensitive, others not

- Insulin-sensitive: facilitated transport most tissues e.g skeletal muscle, adipose

- insulin-insensitive: facilitated transport liver (bidirectional), brain, RBC, WBC, eye lens, cornea

- active transport intestinal epithelia, renal tubules

Tissue Glucose Requirements

- Glucose essential fuel for brain (CNS), so blood glucos levels --> tightly controlled around 5mM (mmol/L)

- Can increase glucose use and storage when increaesd blood glucose conc. e.g after eating (postprandial)

- conversely, need to increase glucose conc. when blood glucose conc. is low. e.g after overnight fast

Blood glucose maintained at relatively stable concentration.

Low blood glucose concentration = consequences

- normal range of blood glucose is 3.5-5.5mM if fasting and if well fed normal range is 5.5-7mM

Humans can catabolise triglycerides and proteins (AA) to supply ATP

- The brain consumes around 20% of total body O2 at rest (around 2% body weight)

- metabolism uses around 120g glucose/day

- ATP generated used by Na+/K+ ATPases (ion channels) to maintain membrane potential for nerve impulse conduction

- preferred fuel: glucose

- Can use ketone bodies

- Very low glycogen stores

- Relies on blood glucose

- Extended hypoglycaemia may cause irreversible damage or death

Glucose Regulating Hormones

- Achieved by tissue specific actions of hormones: insulin, glucagon and others and it requires balance

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- insulin produced by beta cells, they decrease blood glucose

How insulin and glucagon affect blood glucose

- insulin acts through a receptor tyrosine kinase

NO LEARNING OUTCOME, BUT U DO NEED TO KNOW BASICS ON HOW THEY ACT, NO DETAIL

Insulin and Glucagon action

- insulin and glucagon signal via different pathways: overall results in phosphorylating/dephosphorylating target proteins

- Insulin signalling via RTK. commonly dephosphorylates target

- glucagon triggers cAMP-mediated phosphorylation in liver ... commonly phosphorylates target

Insulin and Glucagon secretion is responsive to changes in blood glucose concentration

- increased blood glucose after eating

INSULIN: postprandial (after eating) increases, then decreases

- increased blood glucose conc. --> pancreas releases insulin --> signalling

GLUCAGON: postprandial it decreaes, then increaes

- as glucose is taken up and metabolised, blood glucose declines, hence decreased blood glucose conc. --> pancreas releases glucagon -> signalling

Glucose Regulating Hormone Timings of Action

- insulin and glucagon have various timings of actions: fast (<1min), intermediate (10-30min), slower (+1h)

- the "slower" actions can include changes in gene expression

- AND, hormones have varied effects on different tisues... we will concentrate on the liver and a bit on other tissues

- we will look at which enzymes will be impacted for glycogenesis and glycogenolysis

Relationship between Glucose Regulating Hormones and Glycolysis and Gluconeogenesis

- if we want to promote import of glucose into a tissue it makes sense that insulin will promote glucokinase which will phosphorylate it to Glucose-6P, trapping glucose in the cell

- insulin activates phosphofructokinase-1 (key regulatory enzyme) basically it promotes glycolysis, which allows production of pyruvate

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- glucagon has the opposite effect, it inhibits glycolysis

- glucagon promotes gluconeogenesis

- glucagon promotes activity of phosphoenolpyruvate carboxykinase, which promotes gluconeogenesis, insulin inhibits this pathway

Fructose 2, 6-bisphosphate (F2,6BP) in liver

- F2,6BP = allosteric activator of PFK-1 (promotes glycolysis) and inhibitor of fructose 1,6-bisphosphate (inhibits gluconeogenesis)

- F-2,6BP levels are controlled by a homeodimeric bifunctional enzyme that has 2 domains with different activities = phosphofructokinase-2 and fructose 2, 6-bisphosphotase

Glucagon, Insulin and F2,6BP in liver

- when insulin is around, it activates the kinase activity of the enzyme which produces a lot of fructose

Updated Glycolysis vs Gluconeogenesis

DIAGRAM ON SLIDE 19

Insulin Secretion

- secreted when blood glucose is high

NEED TO KNOW THE ONES WITH ASTERISKS AND ARROWS

Glucagon Secretion

secreted when blood glucose is low

Simplistic Overview

- Glucose homeostasis is way more complex - multiple organs and hormones

Insulin lowers blood glucose and stimulates:

- conversion of excess glucose to glycogen

- conversion of excess glucose to fat

- Insulin stimulates glucose uptake in muscle and adipose (glucose -> Glucose 6P, hence trapped)

- in liver, insulin stimulates glycogen synthase and inactivates glycogen phosphorylase: glucose 6P -> glycogen

- Liver glucose transport = high capacity and insensitive to insulin (glycogen synthase activated via dephosphorylation, glycogen phosphorylase inactivated via dephosphorylation)

- In liver, insulin stimulates glycolysis and triglyceride synthesis (glucose 6P -> acetyl CoA -> FA/triglycerides)

- in adipose, insulin stimulates triglycerides synthesis (stores)

Glucagon raises blood glucose

- In liver, activates glycogen phosphorylase and inactivates glycogen synthase -> liver can release glucose

- In liver, reduces [F2,6BP] so inhibits glycolysis and stimulates gluconeogenesis -> liver makes glucose and exports it

- inhibits pyruvate kinase: prevents phosphoenolpyruvate from being converted to pyruvate

- Accumulation of phosphoenolpyruvate favours gluconeogenesis, stimulates PEPCK -> liver makes glucose and exports it

Glucagon affects adipose tissue

- recall stores of triglycerides = glycerol + 3FA

- in adipose tissue, glucagon activates triglyercide hydrolysis (through phosphorylation of perillipin) to expose the lipid droplet to lipases and activates hormone-sensitive lipase to release FA

- results in FA transport to other tissues for their energy production needs, so glucose is spared for the brain