Insulin Synthesis Steps
DNA (chromosome 11) in β cells -> mRNA -> Preproinsulin -> proinsulin (signal peptide, A chain, B chain, and peptide C) -> insulin
Glucagon Synthesis Steps
DNA from alpha cell-> mRNA -> preproglucagon-> proglucagon -> glucagon
Proinsulin
Composed of the B and A subunits of insulin joined by the C-peptide region.
Major inhibitors of Insulin
Somatostatin and epinephrine
Functions of Somatostatin
- Inhibits release of gastrin, CCK and GIP. Decreases gastric acid and pancreatic secretions.
- It decreases gut motility and secretion.
It is also released due to same stimuli as insulin
What are the two types of glucose transporters
- Facilitative glucose transporters (GLUT): Energy and sodium independent (no energy is needed)
- Sodium-coupled glucose transporters (SGLT): Require a co-transporter which is Na2 and it require ATP
What is the signalling pathway for Insulin
- Insulin binds to it receptor causing a conformational change 2. Causes the phosphorylation of docking proteins such as IRS-1,2,3,4, which in turn activate the signalling pathways PI3K, PKB, MAPK, p70S6.
3.Results in glucose transport, glycogen synthesis, lipogenesis, protein synthesis, gene expression, cellular growth.
What is the function of Metformin
- Suppresses hepatic glucose production, increases muscle glucose uptake and inhibits complex 1 of respiratory chain. It shares it metabolic effect with AICAR.
- Increase AMPK activity and can increase glucose transport/metabolism in skeletal muscle
Functions of GSK3 and FOXO
- GSK3 regulates hepatic glycogen synthesis
- FOXO regulates hepatic gluconeogenesis
Function of Akt
- Akt mediates many of the pleiotropic responses to insulin by regulation of many targets.
- Once active, Akt enters the cytoplasm, where it leads to the phosphorylation and inactivation of glycogen breakdown kinase 3 (GSK3), which activates glycogen synthase and it also inhibits phosphorylation FOXO which leads to no gluconeogenesis
What is a PYG
PYG a is an enzyme responsible for the release of glucose-1-phosphate from glycogen polymers.
How do Thiazolidinediones work
- Increasing the body’s sensitivity to insulin.
- It increases glucose uptake into skeletal muscle cells, decreases glucose release from liver.
3.Does not increase insulin release and does not require -cells
How do Sulfonylureas and meglitinides work
- These kick-start the pancreas’ release of more insulin. block ATP-sensitive K+ channel just like ATP.
- Sulfonylureas bind to and close ATP-sensitive K+ (KATP) channels on the cell membrane of
pancreatic beta cells, which depolarizes the cell by preventing potassium from exiting. This
depolarization opens voltage gated Ca2+ channels. The rise in intracellular calcium leads to
increased fusion of insulin granulae with the cell membrane, and therefore increased
secretion of mature insulin.
How do DPP-4 inhibitors and SGLT-2 inhibitors work
- DPP-4 inhibitors. These drugs increase insulin production in the pancreas and decrease glycogen (glucose stored in the liver). Rapidly causes inactivation to GLP-1 and GIP when the oral intake of glucose results in an increase in GLP-1 and GIP.
- SGLT-2 inhibitors. This class blocks glucose from being absorbed into the kidneys and causes it to be eliminated through the urine instead. Works by inhibiting SGLT2 in the PCT, to prevent reabsorption of glucose.
What is the function of Ghrelin
- Octanoylated peptide, produced and secreted by oxyntic cells in stomach (hunger signal).
- Stimulates appetite.
List some inhibitors of appetite
- Glucagon-like peptide-1,
- Oxyntomodulin,
- peptide YY
- Cholecystokinin
- Pancreatic polypeptide
Alpha- MSH
- Melanocortins (alpha-MSH) : Anorexigenic
- Formed by sequential cleavages of the proopiomelanocortin (POMC) precursor polypeptide.
- When alphaMSH levels are high in the hypothalamus this peptide inhibits food intake.
What are the two melanocortin receptor subtypes
- M3: Enhances food intake
- M4: Suppresses food uptake via binding to alpha-MSH
Name two orexigenic peptides
- NPY: 36 aa peptide and the most abundant neuropeptide in the brain.
- AGOUTI: Co-expressed with NPY in ARC (arcuate nucleus) neurons. Antagonists to MC3 and MC4 receptors.
Name the two most important Anorexigenic Peptides
- Insulin which is made and released from pancreatic (beta cells
- Leptin is made and released
from fat cells. Inhibits food intake and energy expenditure
These are the 2 hormones that inform the brain about the fat status.
Where are Adiposity and Satiety signals released from.
- Satiety: GI tract
- Adiposity: Released from adipose tissue
Both regulate food intake
What are the signalling pathway which leads to vascular contraction.
- ET-1 is synthesised in the endothelium as a preproET-1, then is converted as proET-1 and then as active form ET-1. Which then can leave the cell, to interacts with smooth muscles cells causing contraction.
- Ang-II is produced by the kidney and it has multiple target tissue. When it transported to the smooth muscle it increases calcium dependent vascular contraction. High levels of Ang-II promote high blood pressure and vascular inflammation.
What are examples of some vasodilators.
- Nitric oxide (NO)
- Endothelial derived hyperpolarising factor (EDHF)
What is Metabolic Syndrome
A Constellation of interconnected physiological, biochemical, clinical, and metabolic factors that directly increases the risk of cardiovascular disease, type 2 diabetes mellitus, and all-cause mortality.
