Insulin Flashcards
what is it called if the concentration of glucose in the blood is too low
hypoglycaemia
what is it called if the concentration of glucose in the blood is too high
hyperglycaemia
what is the normal range of glucose
- The normal range is between 3.5-5.5 mmol/L
where can glucose be stored
- liver
- skeletal muscle
- adipose tissue
what is the role of insulin
- released when glucose is too high, it is to make sure that glucose is stored in the cells
what form is glucose stored in
glycogen
what forms the endocrine part of the pancreas
islet of langhernas
what cells are the inslet of langerhans produced from and what do they produce
- Alpha cells producing glucagon
- Beta cells producing insulin
- Delta cells producing somatostatin
- PP cells producing pancreatic
- polypeptide
- Epsilon cells producing ghrelin
These cells help control each other and communicate with each other
name two jobs of the pancreas
- Regulation of insulin secretion to promote glucose storage after meals
- Regulation of glucose output from the liver during fasting
describe the structure of insulin
- polypeptide
- two polypeptide chains linked by three disulphide linkages
- the alpha chain is made out of 21 amino acids and the beta chain is made out of 30 amino acids
- monomers tend to form dimers when insulin concentration increase s
- in the presence of zinc ion and at specific pH dimers form hexamers
what is the storage for of insulin
- In the presence of Zn2+ and at specific pH dimers form hexamers (storage form of insulin)
how is insulin synthesis regulated
- Transcription from the insulin gene
- mRNA stability
- mRNA translation
- post translation modifications
- secretion
insulin synthesis and secretion are….
- insulin synthesis and insulin secretion are largely independent
describe the synthesis of inulin
- insulin is initially synthesized as preproinsulin in pancreatic B cells
- About 5–10 min after its assembly in the endoplasmic reticulum, preproinsulin is processed into proinsulin
- Proinsulin undergoes maturation into active insulin through the action of cellular endopeptidases within the Golgi apparatus
- Endopeptidases cleave off C peptide from insulin by breaking the bonds between lysine 64 and arginine 65, and between arginine 31 and 32, when the proinsulin is cleaved the chains are called chain A and chain B
- Insulin and C-peptide are then stored
- awaiting secretion
for each molecule of insulin you produce you also produce …
a molecular of C peptide
describe the mechanism of insulin secretion
- Glucose enters the β-cells through the glucose transporter
- Glucokinase converts glucose into glucose 6-phosphate (this means that there is an increase in ATP in the cell) acts as the glucose sensor for insulin secretion
- the ATP is generated via the pyruvate through the Krebs cycle and with the electron transport chain, this generates ATP which leads to a rise in the ATP:ADP ratio within the cell
- a rise in ATP causes the ATP sensitive potassium channel to close
- this creates a depolarisation of the membrane
- because of this depolarisation the voltage gated calcium channel ion opens
- this increases the intracellular concentration of calcium
- calcium causes granules containing insulin to move to the membrane
- this then causes the release of insulin by exocytosis
when is insulin secretion only activated
- when glucose is higher in the blood that normal
- The Km of the glucose carrier and of glucokinase ensures that initiation of insulin secretion by glucose occurs only when glucose levels exceed ~5 mM
describe the phases of insulin secretion
- The first phase release is rapidly triggered in response to increase blood glucose level
- The second phase is sustained slow release of newly formed vesicles
name some other factors that can cause insulin release
- Amino acid mainly leucine and arginine – they produce ATP which can cause release of insulin – can cause the depolarisation of the membrane itself
- Intracellular catabolism of amino acids increases the intracellular ATP/ADP ratio
- Leucine acts through allosteric activation of glutamate dehydrogenase (GDH) and it can also be transaminated to α-ketoisocaproate (KIC) that is converted into acetyl-CoA
- Amino acids such as arginine can directly depolarise the plasma membrane
- Gastrointestinally-derived incretins glucagon-like peptide-1 (GLP-1)
- Glucose-dependent insulinotropic peptide (GIP)
- Fatty acids
- Parasympathetic release of acetylcholine (via phospholipase C)
- Cholecystokinin (CCK, via phospholipase C)
- Most of them require glucose (they can only potentiate the glucose induced secretion
what do insulin responsive cells have
- they express a specific tyrosine kinase receptor at the plasma membrane
- either IGF-1 or IGF-II
what type of receptors are insulin receptors
tyrosine kinase receptors
describe how the insulin receptor is activated
- In condition where the concentration of glucose is normal range so there is no insulin around
- So there are molecules such as IRS (insulin receptor substrate which si an adaptor protein), PI3K lipid kinase, AKT- protein kinase, these prevent the glucose from going into the cell
- Glucose is hydrophobic so needs a transporter to go into the membrane, in the absence of insulin this glucose transporter is closed
- When insulin binds to the tyrosine kinase receptor, the receptor becomes activated and the receptor becomes phosphorylated
- Because of this phosphorylation IRS binds to the receptor, IRS cannot bind to the receptor if the receptor is not phosphorylated
- Once at the membrane IRS itself gets phosphorylated by the tyrosine kinase activated phosphorylated receptor
- Because IRS is phosphorylated P13K (lipid kinase) can go to the membrane
- Coverts P2 TO P3
- Then AkT(Protein kinase) can now bind to the membrane once P3 has 3 phosphate
- AkT can allow the transport of the transporter for glucose from into the cell to the membrane
- Glucose can then enter the cell
- Glucose can then be converted into glycogen
how is glucose uptakes into cells in the muscle and adipocytes
- Glucose cannot cross the plasma membrane: its uptake requires specific glucose transporters
- The glucose transporter GLUT4 is contained in intracellular vesicles in the absence of insulin
- Insulin-induced Akt activation stimulates GLUT4 translocation to (and insertion into) the plasma membrane and ultimately glucose uptake
Name the type of glucose transporters
Glut 1 - found in all cells, has a low kM
Glut 2 - liver/pancreas uptake (high Km)can act as a glucose sensor in the liver and pancreas
Glut 4 - glucose uptake in muscle and adipose (low Km) cellular location is controlled by insulin
what type of glucose transporter is in the muscle and adipocytes
GLUT 4
describe the process of glycogen synthesis and how it is broken down
- Start with glucose – 6 phosphate
- Move the phosphate from carbon 6 to carbon 1 producing glucose-1-phosphate this is a reversible reaction
- Energy is put in to the system via UTP (same type of thing as putting ATP in the system) this produces UDP attached to glucose and 2 phosphate groups joined together called PPi
- UDP-glucose has the enzyme glycogen synthase acts on it which takes the glucose of off UDP and adds it onto the glycogen chain this produces glycogen +1 and UDP
- Break down occurs through the enzyme of glycogen phosphorylase which produces glucose-1-phosphate and produces a glycogen chain which is 1 glucose less as it removes a glucose from glycogen
what does insulin stimulate and inhibit
- stimulates glycogen synthesis in the muscles
- stimulates lipogenesis in the adipocytes
- inhibits lipolysis
what is the difference between hexokinase and gluokinase
- The difference between hexokinase and glucokinase is that glucokinase has an higher Km as it is found in the liver and pancreas
How does insulin stimulate glycogen synthesis in the muscles
Insulin stimulates glycogen synthesis in muscles
Glucose is converted to glucose-6-phosphate which is converted to glucose-1-phospahte which is converted to UDP-glucose which is converted to glycogen, this is glycogenesis
- Akt phosphorylates and inactivates glycogen synthase kinase this allows activation of glycogen synthase
what does insulin stimulate and inhibit
- stimulates glycogen synthesis in the muscles - it does this by dephosphorylaing glycogen synthesis
- stimulates lipogenesis in the adipocytes
- inhibits lipolysis
- inhibits gluconeogensis
How does insulin inhibit lipolysis
- Insulin inhibits hormone sensitive lipase
- Inhibition of hydrolysis of triglycerides and release of the FFAs into the circulating blood
- Malonyl-CoA inhibits the transport of FFAs into mitochondria via CPT-1 therefore inhibiting beta oxidation
what is the role of insulin and the liver
- It controls the activiate of the glucokinase
It enhances glucose uptake
It increases glycogen synthesis – glycogen can increase up to 5-6% of the liver mass
Insulin increases lipogenesis – lipids are exported as lipoproteins
Insulin inhibits gluconeogenesis
what is the role of insulin in other places
Insulin promotes protein synthesis and storage
It stimulates transport of amino acids
into the cells
- Valine, leucine, isoleucine, tyrosine, phenylalanine
It increases translation of mRNAs
- Synthesis of new proteins
It inhibits catabolism of proteins
- It decreases aminoacids release from cells (muscle)
insulin promotes K+ intracellular uptake
what is glucose converted to in the adipose tissue
In the adipose tissue glucose is converted to fatty acids and glycerol and then triglycerides
what happens when glucose is reduced
Insulin decreases so ..
- glycogen broken back down into glucose then into ATP
- in the adipose tissue hormone sensitive lipase is no longer inhibited so triglycerides are now broken down into glycerol and fatty acids to produce ATP, these then are transported into the mitochondria and can go through beta oxidation as malongyl CoA is no longer inhibited
- gluconeogensis can take place
glycogen in the muscle is used
in the muscle only
where can fatty acids be used
- Fatty acids can be used by most tissues to generate acetyl CoA and therefore ATP but not by the brain
what is gluconeogensis
this is the formation of glucose from substances that have carbon in it
what can be the sources of gluconeogensis
- Uses amino acids such as alanine and glutamine, can be converted into a form of glucose
- Pyruvate – converts to lactate, lactate goes into Cori cycle and converted into glucose
- Triglycerides converted into free fatty acids and glycerol
- Glycerol is converted into glucose
why does eventually a accumulation of acetyl CoA occur during gluconeogensis
- Oxaloacetate used for gluconeogenesis at some point, the more the gluconeogesis keeps going the more the imbalance between how much acetyl-CoA you have and the TCA cycle working
- Eventually there is an accumulation of acetyl-CoA that cannot enter the TCA cycle as there is a lack of oxlaoacetate and is converted into ketone bodies – these can be used in the brain
what are the mechanism that switch of insulin signalling when the glucose goes back to normal
- Endocytosis and degradation of the receptor bound to insulin
- Dephosphorylation of the tyrosine residues by tyrosine residues by tyrosine phosphatases
- Decrease in the number of receptors also leads to reduced insulin signalling
- Serine/threonine kinases – reduce the activity of the insulin receptor
describe one example that can lead to insulin resistance
- Reduced response to insulin in target tissues
- Tyrosine is not phosphorylated anymore
- Leads to hyperglycaemia and dyslipidaemia
what does insulin do in the liver
- increase glycogen synthesis
- increase lipogenesis
- decrease gluconeogensis
what does insulin do in the muscle
- increase glucose uptake (GLUT 4 translocation)
- increase glycogen synthesis
- decrease protein catabolism
what does insulin do in the adipocytes
- increase glucose uptake (GLUT 4 translocation)
- increase lipogenesis
- decrease lipolysis
what happens if you have reduced response to inulin in the liver, muscle and adipocytes
Liver Reduced glycogen synthesis Impaired lipogenesis Increased gluconeogenesis Increased glycogenolysis
Muscle
Reduced glucose uptake
Reduced glycogen synthesis
Increased protein catabolism
Adipocytes
Reduced glucose uptake
Reduced lipogenesis
Increased lipolysis
why is glycogen a good store of glucose
- Easily to store and access therefore it is quick and easy to make and breakdown
- Stores glycogen
- Less osmotically active therefore doesn’t effect the water balance of the cells, it causes less water to come into the cell and this prevents bursting
- Acts as a glucose buffer
- The only tissue that can export glucose back to the blood is the liver
- Muscle glycogen can only go into glycolysis therefore it can only be used in the cell where that glycogen is
