Pancreas Intro + insulin Flashcards
Cells secreting Pancreatic polypeptide
F cells
Cells secreting Glucagon
A cells
Cells secreting somatostatin
D cells
Cells secreting insulin
B cells
Chemistry of Insulin
Polypeptide enzyme with 2 chains of amino acids linked by disulfide bridges
Halflife of insulin
5 minutes
Normal level of insulin in urine
Little to none
Describe the transport & Breakdown of insulin
- Insulin circulates in the plasma in free form only
- When it binds to receptor of cells, it is internalized by Receptor mediated endocytosis
- It is then destroyed in the cell by Insulinaze enzyme
Explain why IGF-1 & IGF-2 do not fix DM after pancreatectomy
even though the act on same receptor as insulin, and are not supressed by specific anti-insulin antibodies, their effect is very weak compared to insulin
Describe structure of Insulin receptor
Tetramer (4 subunits):
* 2 alpha: outside cell membrane
* 2 Beta: intracytoplasmic
Mechanism of action of Insulin
- the 2 intracytoplasmic Beta subunits possess tyrosine kinase activity
- it causes autophosphorylation when insulin binds (activation)
- active tyrosine kinase then phosphorylate Insulin receptors Substrates (IRS 1,2,3,4)
When does number of Insulin rececptors decrease
obesity & Acromegaly –> High insulin level (as down regulation)
When does number of Insulin rececptors Increase
In starvation —> prolonged low insulin levels (up regulation)
When does affinity of Insulin rececptors decrease
excess Glucocorticoids (cortisol decreases Peripheral glucose utilisation)
When does Affinity of Insulin rececptors Increase
- Adrenal insufficiency
- Starvation
Describe the cellular activity of insulin depending on time & site of binding
Rapid effect (seconds): increases permiability of the cell to:
* glucose
* Amino Acids
* Potassium
* Phosphate
Intermidiate effect (minutes):
* Phosphorylation & dephosphrylation of metabolic enzymes in the cell
Delayed effect (hours):
* Change in rate of transcription & Translation
* Change rate of DNA synthesis
Action of Insulin on Carbohydrate metabolism
reduces blood glucose to maintain it:
On Muscles:
* Translocation of endosomes containing GLUT4 to cell membrane
* Decreases utilisation of fat as source of energy
On Liver:
* Increases Phosphorylation of glucose into G6P, thus maintaining a concentration gradient & increasing uptake of glucose by liver
* Stimulates glycogenesis
* Inhibits glycogenolysis
* Inhibits gluconeogenesis
On Adipose tissue:
* Increases Number of GLUT4 –> increases Uptake of adipose tissue for glucose –> glycerol
Explain how Exercise can help in DM
- Exercise acitvates 5’ AMP Kinase
- It stimulates translocation of GLUT4 Endosomes to cell membrane (like insulin)
True or false, insulin increases GLUT 2 on cell membrane
False, GLUT 2 (in liver) is insulin insensitive
True or false, insulin increases GLUT 4 on cell membrane
True, in Muscles and adipose tissue
Sites where insulin doesnt increase glucose uptake
- RBCs
- Brain neurones
- Renal tubules
- Intestinal mucosa
Action of Insulin on Fat metabolism
- Fat sparing: decreases utilisation of fat as energy source
- Lipogenic (excess glucose –> FFA)
- Inhibits lipolysis
- stimulates use of Ketoacids by peripheral tissue (Antiketogenic)
Action of Insulin on Protein metabolism
Anabolic:
* Increases uptake of AA
* increases Transcription & translation
* Inhibits protein catabolism (& gluconeogenisis)
Action of Insulin on Growth
- Direct: synthesis of macromolecules for cartilage & bones
- Indirect: increases transcription of IGF-1, & inhibits transcription of IGF-1 binding protein so it stays in free active form
Relation between Potassium & Insulin
- Insulin can be clincally used in renal failure associated with Hyperkalemia: It increases Na+K+ pump, therefore increasing intracellular potassium and decreasing plasma potassium
- Hypokalemia decreases insulin secretion: such as in primary hyperaldosteronism
Explain why thiazide diuretics is not advised in DM
It increases Potassium excretion —> Hypokalemia
* Hypokalemia affects insulin secretion –> worsens DM
Explain how food glucose causes secretion of Insulin
- After meal, glucose enters pancreatic B cells through GLUT2
- Glucose is oxidised to give ATP
- ATP closes ATP sensitive K+ Channels
- This decreases K+ efflux
- K+ accumulates intracellular & causes depolarization
- Depolarization opens Voltage gated Ca2+ channels
- Ca2+ influx
- Causes exocytosis of Insulin
Factors increasing/stimulating insulin secretion
food:
* Glucose
* Amino acids (especially Arginine & Lysine)
Hormones:
* GIP
* Gastrin
* Secretin
* CCK
* Glucagon
others:
* Parasympathetic innervation
* Beta adrenergic activation
* cAMP
Factors inhibiting Insulin secretion
- Somatostatin
- Insulin itself (negative feedback)
- Leptin
- (Alpha2) sympathetic innervation
Describe how other non GIT & pancreatic hormone influence Insulin secretion
- May cause hyperplasia of B cells–> More insulin
- may decrease insulin action on peripheral tissue (cortisol)
- May exhaust B cells
