27. Insulin Secretion and Action Flashcards
What is the physiological range for normal fasting blood glucose?
Why is the brain dependant on extracellular glucose concentration?
Where is insulin synthesised?
3.5 - 5.5 mmol/L (if more = insulin secreted; if less = glucagon secreted)
The brain can’t: synthesise glucose, store much glucose, metabolise substrates other than glucose (and ketones), extract enough glucose from ECF at low conc
Beta cells of islets of langerhans in pancreas. IoL = endocrine part of pancreas (which is mainly an exocrine gland)
What are the main cell types (and hormones they produce) in the islets of Langerhans?
Describe the structure of insulin.
How is insulin synthesised, and why in this fashion?
Alpha cells (glucagon), beta cells (insulin), delta cells (somatostatin), PP cells (pancreatic polypeptide), epsilon cells (ghrelin). All work together and control each other.
Made of 2 chains linked by disulphide bonds
As preproinsulin (110 AA) in pancreatic beta cells -> 5-10mins after assembley in endoplasmic reticulum, its processed into proinsulin (86) (signal sequence cleaved off). Matures into active insulin (51) via action of cellular endopeptidases in golgi (cleave off C peptide (35)). Insulin and C-peptide stored awaiting secretion. Posttranslational modification! Steps = can be regulated and produced when needed.
Is insulin synthesis and secretion one process?
Describe the mechanism of insulin secretion.
What are the 2 phases that beta cells can release insulin in?
No - largely independant.
Glucose enters beta cells via GLUT1 (regulated by glucokinase - Km of carrier and GK ensure that initiation of insulin secretion only when BG >5mM) -> glucose-6-phosphate -> pyruvate (glycolysis) -> TCA and ETC = lots of ATP -> rise in ATP:ADP in cell -> KATP channels close -> depolarised membrane -> VG Ca2+ channels open -> vesicles fuse with membrane and release contents = insulin secretion
1) release rapidly triggered in response to increased BG
2) sustained, slow release of newly formed vesicles
* NB: glucose stimulates insulin secretion AND biosynthesis*
What mechanisms can amplify insulin secretion?
1) intracellular catabolism of AA increases intracellular ATP:ADP - leucine acts via allosteric activation of glutamate dehydrogenase and it can be transaminated and then converted to ACoA -> fed into TCA -> increase prod of ATP
2) AA like arginine directly depolarise plasma membrane
3) Fatty acids and ACh = release intracellular Ca2+ store
END RESULT = increase intracellular Ca2+ via closure of KATP pump and opening of VGCC
4) GLP-1 -> insulin secretion
What does inslin act most on?
Describe the structure of the insulin receptor and what happens once insulin binds.
Muscle cells, hepatocytes and adipocytes, AND can act on beta cells itself
Dimeric transmembrane receptor. Insulin binds to extracellular portion of alpha subunit -> conformational change activates kinase domain on intracellular portion of beta subunit, which autophosphorylates tyrosine residues on the C-terminus of receptor and within the adaptor protein IRS -> lipid kinase can then bind to IRS - convert lipid PIP2 to PIP3 -> protein kinase (Akt) activated -> phosphorylation of downstream effectors
What does insulin stimulate in muscles?
What does insulin stimulate in adipocytes? And inhibit?
How are specific glucose transporters in muscle and adipose tissue affected by insulin?
In muscles: 1) Glucose uptake in muscles (mediated by specific glucose transporters)
2) Glycogen synthesis in muscles (Akt (protein kinase) also stimulates this) by inactivating glycogen synthase kinase (GSK) which usually inhibits glycogen synthase
In adipocytes: glucose uptake (GLUT4) and lipogenesis (glucose used to synthesise glycerol -> + FA = TGL - store energy), and inhibits lypolysis (inhibits hormone sensitive lipase (HSL) that hydrolyses TGL, and also blocks transporter that lipids use to enter mitochondria for lipolysis).
Once Akt activated = activates translocation of GLUT4 to plasma membrane
What does insulin stimulate in the liver? And inhibit?
List some other functions of the liver.
Enhances glucose uptake (NOT via transporter- instead via glucokinase activity), increases glycogen synthesis (100g store), increases lipogenesis (lipids exported as lipoproteins), INHIBITS GNG.
Promotes protein synthesis and storage, stimulates transport of AA into cells, increases mRNA translation, inhibits protein catabolism, promotes K+ intracellular uptake
What happens after eating? (Glucose excess)
What happens during fasting? (Between meals)
As length of fast increases?
Beta cells of IoL produce and release insulin. Increase uptake of excess glucose to: muscle (and conversion to glycogen), adipose (conversion to TGL), liver (stops GNG, stored as glycogen/TGL). BG falls
Glucose level normal range - insulin secretion stops (GLUT4 not at muscle/adipose membrane anymore, glucokinase less active in liver). Glycogenolysis first (liver has 100g to use) then GNG starts (not inhibited anymore)
Liver = main organ to keep glucose balance via GNG to release glucose -> blood, mainly for brain. Uses AAs and glycerol for producing glucose (FA used most unless really starved). Other tissues can adapt and use FA to produce ATP via beta oxidation = break down lipids and get Acetyl CoA -> TCA -> make ATP.
Eventually ACoA accumulation (oxaloacetate needs glucose precursors so imbalance) which induces formation of ketone bodies -> can be sent to brain which can be beta oxidised -> A CoA. Muscle wasting.
What 4 thing switch off insulin signalling?
Endocytosis and degradation of receptor bound to insulin, dephosphorylation of tyrosine residues by tyrosine phosphatases, decrease in number of receptors leads to reduced insulin signalling. SERINE/THREONINE KINASES reduce insulin activity.
