LECTURE 6 (Insulin, Glucagon & DM) Flashcards
What is the Pancreas composed of?
- Acini = secrete digestive juices into the duodenum
- Islets of Langerhans = secrete insulin and glucagon directly into the blood
Describe the Islets of Langerhans
- Islets organised around small capillaries into which cells secrete their hormones
- Consist of alpha, beta and delta cells
- Beta cells (60%) = secrete insulin and amylin
- Alpha cells (25%) = glucagon
- Delta cells (10%) = somatostatin
- PP cell (present in small numbers) = pancreatic polypeptide
Explanation: Close proximity allow for direct control of hormones by other hormones -> insulin inhibits glucagon secretion, amylin inhibits insulin secretion and somatostatin inhibits the secretion of both insulin and glucagon
What is the function of Insulin?
- Causes excess carbohydrates to be stored as glycogen mainly in the liver and muscles
- Excess carbs that aren’t stored as glycogen as converted into fats and stored in adipose tissue
- Promotes amino acid uptake by cells and conversion into proteins
- Inhibits breakdown of proteins that are already in cells
Describe the synthesis of insulin
1) Insulin consists of A, B and C peptide chains. It is synthesised in the beta cells and is first formed as PREPROINSULIN by ribosomes, then cleaved into PROINSULIN by the endoplasmic reticulum then into INSULIN by the Golgi apparatus
2) Insulin and C-peptide are packaged into secretory granules and secreted in equimolar amounts. A small amount of PROINSULIN is also secreted.
[Proinsulin and C peptide have no insulin activity]
3) C protein binds to a G-protein coupled membrane receptor and activates the SODIUM-POTASSIUM ATPase and ENDOTHELIAL NITRIC OXIDE SYNTHASE + measurement of C peptide levels by radioimmunoassay can be used to determine natural insulin patients are producing
Describe the removal of insulin
Insulin circulates in the blood in an unbound form + has a quick half-life (lasts for only 10-15 mins) -> Insulin not combined with target cells are degraded by INSULINASE (mainly in liver, lesser extent in kidneys + muscles, slightly in most tissues) -> Rapid removal is important for control functions of insulin
Describe what happens when Insulin binds to target cell receptors
1) Insulin receptor has two alpha subunits that lie entirely outside the cell membrane + two beta subunits that penetrate through the membrane, protruding into the cell cytoplasm. When insulin binds to the alpha cells, the beta cells become autophosphorylated
2) Autophosphorylation activates a local tyrosine kinase -> causes phosphorylation of other intracellular enzymes including insulin-receptor substrates (IRS)
3) Insulin directs intracellular metabolic machinery to produce desired effects on carbohydrate, fat and protein metabolism
What are the effects of insulin stimulation?
- The body’s cells increase their uptake of glucose (especially muscle + adipose cells but not neurons)
- Cell membrane becomes more permeable to amino acids, K+, phosphate ions -> causes increased transport into cell
- Activity levels of intracellular metabolic enzymes change
- Changed rates of translation of into new proteins + transcription of DNA in the nucleus
During much of the day, why does muscle tissue depend on fatty acids not glucose?
The normal resting muscle membrane is only slightly permeable to glucose, except during insulin stimulation
Under which two conditions do muscles use large amounts of glucose?
- During moderate/heavy exercise
[exercising muscle fibers become more permeable to glucose due to the contraction process] - During the few hours after a meal
[pancreas secretes large amounts of insulin which causes rapid transport of glucose into muscle cells]
Describe how insulin promotes increased glycogen in the liver
1) Insulin inactivates LIVER PHOSPHORYLASE (enzyme that causes liver glycogen to split into glucose) which prevents breakdown of glycogen stored in liver cells
2) Insulin causes enhanced uptake of glucose from blood by increasing activity of GLUCOKINASE (phosphorylates glucose after it diffuses into liver cells) -> once phosphorylated, glucose is “temporarily trapped” since it cannot diffuse back across cell membrane
3) Insulin promotes glycogen synthesis by increasing activity of GLYCOGEN SYNTHASE
What happens when the blood glucose level begins to fall?
1) Decreasing blood glucose causes pancreas to decrease its insulin secretion + lack of insulin stops further synthesis of glycogen and uptake of glucose by liver from blood
2) Lack of insulin activates PHOSPHORYLASE which splits glycogen into GLUCOSE PHOSPHATE
3) Lack of insulin activates GLUCOSE PHOSPHATASE which causes the phosphate radical to split from the glucose, allowing free glucose to diffuse back into the blood
What does Insulin do to excess glucose?
It converts excess glucose into fatty acids
Explanation: Fatty acids are packaged as triglycerides in VLDL and transported in the blood in his form to adipose tissue and deposited as fat
How does Insulin inhibit gluconeogenesis?
By decreasing the quantities and activities of the liver enzymes required for gluconeogenesis
How is the brain different to other cells of the body?
- Insulin has little effect on uptake or use of glucose since brain cells are permeable to glucose and can use it without the intermediation of insulin
- Normally only use glucose for energy
[SO IMPORTANT to keep glucose above a critical level otherwise symptoms of hypoglycaemic shock, fainting, seizures and coma]
What effects does insulin have on fat?
- Increases utilisation of glucose by body’s tissues -> decreases utilisation of fat -> acts as a fat sparer
- Promotes fatty acid synthesis which are transported from liver to adipose tissue
[via blood lipoproteins]
What factors lead to increased fatty acid synthesis in the liver?
- Insulin increases the transport of glucose into the liver cells -> excess glucose not made into glycogen become available to form fat
[glucose -> pyruvate -> acetyl CoA (substrate from which fatty acids are synthesised)] - Excess of citrate and isocitrate ions is formed by citric acid cycle when excess amounts of glucose is used -> ions activate ACETYL-COA CARBOXYLASE which converts acetyl-CoA into Malonyl-CoA (first stage of fatty acid synthesis)
- Fatty acids synthesised in liver and used to form triglycerides -> travels in blood as lipoproteins -> Insulin activates lipoprotein lipase in capillary walls of adipose tissue to convert triglycerides into fatty acids so they can be absorbed by adipose cells
What are the effects of insulin on fat storage in adipose cells?
- Insulin inhibits the action of hormone-sensitive lipase
(enzyme causes hydrolysis of triglycerides in fat cells -> blocks release of fatty acids from adipose tissue into circulating blood) - Insulin promotes glucose transport through the cell membrane into the fat cells
[used to form ALPHA-GLYCEROL PHOSPHATE which combines with fatty acids to form triglycerides that are the storage form of fat in adipose cells]
What happens in Insulin deficiency?
- Hormone-sensitive lipase is strongly activated -> hydrolysis of stored triglycerides + a lot of fatty acids and glycerol in circulating blood
- Excess fatty acids promotes liver conversion into phospholipids and cholesterol -> promotes development of atherosclerosis
- Increase in fatty acids increases carnitine transport of fatty acids into mitochondria, increasing beta oxidation, increasing Acetyl-CoA -> a lot of Acetyl-CoA is converted into Acetoacetic acid which is converted to B-hydroxybutyric acid and acetone [KETONE BODIES] -> “ketosis” (large amounts of ketone bodies) can leas to acidosis, coma and death
How does Insulin promote protein synthesis and storage?
- Insulin stimulates transport of many of the amino acids into the cells
- Insulin increases the translation of mRNA and rate of transcription of DNA sequences
- Insulin inhibits the catabolism of proteins
- In the liver, insulin depresses the rate of gluconeogenesis
TO SUMMARISE: Insulin promotes protein formation and prevents degradation of proteins
What happens to proteins in Insulin deficiency?
Catabolism of proteins increases, protein synthesis stops and large quantities of amino acids are dumped into the plasma [plasma amino acids used as energy or substrates for gluconeogenesis] -> Increased urea excretion in urine -> Protein wasting leading to extreme weakness and many deranged functions of organs
