insulin secretion and action Flashcards
why is the brain dependent on glucose?
can’t store glucose
cant metabolise substrates
what is hyperglycaemia?
glucose concentrations are too high
what is hypoglycaemia?
concentration of glucose is too low
what is the normal fasting range of glucose?
3.5-5.5mmol/L
what is the range of glucose 2 hours after meals?
less than 8mmol/L
what organs can store glucose?
skeletal muscle, liver, adipose tissue
what molecules can glucose be converted into to be stored?
triglycerides and glycogen
when is insulin released?
when glucose levels are too high
how is the pancreas involved in glucose homeostasis?
o Regulates insulin secretion to promote glucose storage after meals
o Regulates glucose output from the liver during fasting
is the pancreas an exocrine or endocrine organ?
o Exocrine – can release digestion hormones
o Endocrine function – made up of islets of Langerhans (2% of the total mass of the pancreas)
what cells make up the islets of langerhans and what do they secrete?
alpha beta delta PP cells epsilon cells
what do alpha cells release?
glucagon
what do beta cells release?
insulin
what do delta cells release?
somatostatin
what do PP cells release?
pancreatic polypeptide
what do epsilon cells release?
ghrelin
what is insulin?
Polypeptide – 2 chains linked by 3 disulfide linkages
what chains make up insulin?
o A chain – 21 amino acids
o B chain – 30 amino acids
when do the insulin polypeptides form dimers?
when insulin concentrations increase
when do the insulin dimers form hexamers?
in Zn2+ and at specific pHs
what is the storage form of insulin?
hexamers
what is the active form of insulin?
monomers
what happens to insulin hexamers when they’re secreted?
dissociates into monomers
how is the endogenous production of insulin regulated?
o Transcription from the insulin gene o mRNA stability o mRNA translation o Post-translational modifications o Secretion
explain the process of insulin synthesis
• Initially synthesised as preproinsulin in pancreatic B-cells
• 5-10mins after assembly in the ER, preproinsulin is processed into proinsulin
• Proinsulin matures into active insulin via action of cellular endopeptidases within the Golgi apparatus
• Endopeptidases cleave off C peptide from insulin
o Break bonds between lysine 64 and arginine 65 and arginine 31 and 32
• Insulin and C-peptide are then stored awaiting for secretion
how does glucose enter b cells?
through the GLUT1 transporter
what does glucokinase do?
converts glucose into glucose-6-phosphate
what is the mechanism of insulin secretion?
Glucose enters B cells through GLUT1 transporter
• Glucose is converted to G6P and to pyruvate through glycolysis
• Pyruvate generates ATP through the Krebs cycle and the ETC
• Causes a rise in ATP:ADP ratio within the cell
• At sub-stimulatory glucose concentrations, K-ATP channels are open – resting membrane potential is maintained at hyperpolarised level (-70mV)
• Increased ATP:ADP ration causes closure of K-APT channels and membrane depolarisation
• Voltage gate calcium channels open intracellular concentration of calcium increases insulin secreted
how do B cells release insulin?
o 1st phase – release is rapidly triggered in response to blood glucose levels
o 2nd phase – sustained, slow release of newly formed vesicles
what other signals can stimulate insulin release?
- Intracellular catabolism of amino acids increases the intracellular ATP/ADP ratio
- Leucine acts through allosteric activation of glutamate dehydrogenase (GDH) – can be transaminated to a-ketoisocaproate (KIC) – converted to acetyl-CoA
- Amino acids e.g. 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)
what is the insulin receptor?
Insulin receptor - transmembrane receptor activated by insulin, IGF-I, IGF-II - belongs to class of tyrosine kinase receptors
how is the insulin receptor activated?
- Insulin binds to the extracellular portion of the alpha subunits
- Causes conformational change that activates the tyrosine kinase domain on the intracellular portion of the beta subunits
- Activated kinase domain autophosphorylates tyrosine residues on the C-terminus of the receptor + tyrosine residues within the adptor protein IRS
how does insulin signalling occur?
- Receptor becomes phosphorylated when the insulin binds
- IRS from the cytoplasm can now bind to the receptor
- IRS becomes phosphorylated by the receptor
- Bc IRS is phosphorylated, P13K can bind to IRS at the membrane
- Lipid gets phosphorylated
- Akt can now bind to the lipid and trigger reactions e.g. translocation of the transporter of glucose into the membrane
- ATP needed to move the receptor
- ATP is only activated when the insulin binds
what happens to IRS, P13K and Akt when there’s no insulin? what further implications does this have?
they’re inactive
glucose can’t enter the cell
glucose cant be converted into glycogen
why cant glucose cross the plasma membrane?
needs specific glucose transporters
where is GLUT4 found?
contained in intracellular vesicles in the absence of insulin
what does insulin-induced Akt activation lead to?
stimulates GLUT4 translocation to (and insertion into) the plasma membrane and ultimately glucose uptake
how does insulin stimulate glycogen synthesis in muscles?
Akt phosphorylates and inactivates glycogen synthase kinase (GSK): this allows activation of glycogen synthase (GS)
what effect does insulin have on lipogenesis and lipolysis?
Insulin stimulates lipogenesis in adipocytes and inhibits lipolysis
how does insulin stimulate lipogensis and inhibit lipolysis?
- Insulin inhibits hormone sensitive lipase
- Inhibits hydrolysis of triglycerides and release of FFAs into the circulating blood
- Malonyl-CoA inhibits transport of FFAs into mitochondria via CPT-1 therefore inhibiting beta oxidation
what is the effect on;
- glucose uptake
- glycogen synthesis
- lipogenesis
- gluconeogenesis
enhances glucose uptake
increases glycogen synthesis
increases lipogenesis
inhibits gluconeogenesis
what effect does insulin have on protein synthesis and storage and how?
• It stimulates transport of amino acids into the cells
o 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)
what effect does insulin have on K+ intracellular uptake?
promotes K+ intracellular uptake
describe post-prandial metabolism
- High glucose will stimulate insulin release from the pancreas
- Acts on the liver to convert glucose to glycogen
- Glucose is also converted to triglycerides in the liver
- Gluconeogensis in the liver is inhibited
- Breaking down of glycogen and triglycerides is inhibited
why does beta oxidation happen when there are reduced glucose levels?
When there are reduced glucose levels, no insulin is secreted HSL no longer inhibited triglycerides are broken down into glycerol and fatty acids beta oxidation
what organs can use fatty acids and what is it used for?
• Fatty acids can be used by most tissues to generate acetyl-CoA and therefore ATP but not by the brain
what is glycogenolysis?
breaking down of glycogen
what is gluconeogenesis?
synthesis of new glucose – once it’s broken down all the glycogen
what can be used as precursors for gluconeogenesis?
Carbon based molecules can be used as precursors for gluconeogenesis
what happens to accumulation of acetyl-coA that cant enter the TCA cycle?
converted into ketone bodies
what are mechanisms that can switch the insulin signalling off?
- Endocytosis and degradation of the receptor bound to insulin
- Dephosphorylation of the tyrosine residues by tyrosine phosphatases
- Decrease in the number of receptors also leads to reduced insulin signalling
- Serine/Threonine kinases reduce the activity of insulin receptor
