15-Glucose Homeostasis

Question 1

Insulin

Answer 1

Proinsulin is the precursor
Linker peptide (23 amino acids): C peptide is cleaved in the granules by proenzyme convertase (PC) 1 / 3; released with insulin
Complexed with zinc
Dimeric, multimeric crystalline forms
Each cell has 9-13,000 granules

Question 2

Insulin actions

Answer 2

anabolic hormone
highly sensitive tissues: liver, skeletal muscle and adipocytes
increase in protein synthesis, decrease in proteolysis
increase in triglyceride synthesis, decreased lipolysis and lipid oxidation
increase in growth and polymerisation

Question 3

Insulin mechanism

Answer 3

Ligand insulin binding to insulin receptor- an intrinsic tyrosine kinase
Binding switches receptor on
Leads to phosphorylation of receptor, causes IRS and SH2 protein activation, and activation of IRS-1
Leads to stimulation of the Pi3 kinase pathway
Activation of the Ras/Ref pathways
Then phosphorylation of a number of downstream proteins - co-ordinated by activation of AKT
AKT (signalling molecule) important for diabetes therapies
Phosphorylation of signalling pathways leads to changes in metabolism, gene expression, and protein transport

Question 4

Glucagon

Answer 4

Mainly produced in alpha cells but can be produced elsewhere
Synthesised by pre-proglucagon gene
Converted to GLP-1 by pro-enzyme convertase 1
Or in the alpha cells via pro -enzyme convertase 2 - converts pre - proglucagon gene into glucagon.
Receptor is a G -protein coupled receptor linked to adenylate cyclase and cAMP
EGP leads to glycogenolysis, lipolysis and gluconeogenesis
Metabolism of adipocytes to increase circulating fatty acids and glycerol (lipolysis)
Liver enzymes convert amino acids and glycerol towards glucose

Question 5

High glucose

Answer 5

Beta cells switched on- release insulin, which leaves islet and enters blood supply
Within the islet (esp. in humans due to more mixing of beta cells than alpha cells), insulin will switch off glucagon secretion- powerful inhibitor of alpha cells
Beta cells release GABA- suppress alpha cell function
Zinc (in secretory granules) will impact neighbouring cell to further inhibit glucagon secretion

Question 6

Low Glucose

Answer 6

No signal for the release of insulin
Beta cells require a threshold for glucose in order to be released- not met at low glucose conc.
Low glucose signals release of glucagon
Glucagon leaves islets and enters circulation
Glucagon stimulates beta cells (priming response to make secretory granules)
Alpha cells switch on beta cells (because alpha cells will, unchecked, raise blood sugar levels inappropriately)
Alpha cells stimulate delta cells
Delta cells have a feedback control over alpha cell function & also inhibit beta cell function
Proximity determines whether or not have beta cells switch on, alpha cells switch on, or whether or not the activities are going to be dampened by the intrinsic activities of delta cells