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GM&H III (24/10) (Ins Maturation (24 AA-long signal seq targets ProInsβ¦
GM&H III (24/10)
Ins Maturation
- 24 AA-long signal seq targets ProIns to the ER,
where ; storage vesicles
- Must be proteolytically cleaved to release mature peptide
- Ca2+ activates Proteases that cleave the C-peptide
from ProIns in storage vesicle :red_flag:
~ ; C-peptide & ProIns
~ to ; active Ins
- Tests of Ins levels measure C-peptide
~ if express C-peptide in blood, ;ing Ins
- Once released, v short half-life
-
Structure - A :pencil2:
- A, B chains joined by Disulfide bridges
- PreProIns: 1st form of Ins
- :red_flag: then ProIns β Golgi (in granules)
~ cleave more so ; π, π chains - active form of Ins
~ AND C-peptide
- π, π packed into secretory granules
~ exit π-cell via signal of high blood glu
Structure - B :pencil2:
- Ins gene transcribed to Ins mRNA
β cytosol, translated using ribosomes
~ ; Ins pro
- signal seq direct into rER
~ as pro elongate, cleave signal seq
- ; ProIns β Golgi :red_flag:
Pancreas
Islets of Langerhans
- aka Pancreatic Islets
- form Endocrine portion of pancreas
~ π ; Glucagon
~ π ; Ins
~ π
; Somatostatin
π-cells ; Ins when High blood glu
- Glu enter π-cells via GLUT2 - transporter
~ enter Glycolysis, β [ATP]
- ATP binds to ATP-gated K+ chs
~ K+ chs close, depolarise p. memb
- Trigger opening of voltage-gated Ca2+ chs
~ β Ca2+ in cytosol - of π-cells
~ trigger release of Ins by exocytosis...
~ ...of Granules
- secreted via π-cells β b. stream
-
Ins Receptor
- a Tyr Kinase - enz coupled rec
~ transmembrane,
~ made of dimer: π, π
~ π: cytosol, phosphorylation
- bind w Ins = autophosphorylation
- Activated rec phosphorylates intracell pros
- the Best characterised substrate:
~ Ins Rec Substrate 1 or IRS-1
INS + Body Processes:
- Glu Transport
- GLUT4 Translocation
- Synth: Gly, FA, Pro
- Gene: Expression, Transcription
:pencil2: this type of rec can:
- amplify signal - by activate multiple molcs
- diverge when ; effect in target cells
- Phosphorylate intracell molcs ; cascade
~ then ; response in cell
- characterise broadly
Passive Glu Transporters
-
:pencil2: numbers - based on where expressed
- 2: cell surface on liver
- 4: x alw on cell surface - regulated by Ins
~ stimulate recs to come up to surface
~ to allow transport of Glu into Ts when high Glu
Ins Effects on GLUT-4
- Stimulate Glu uptake, use, storage
- Major transporter 4 Glu uptake - GLUT4
~ Translocated to p. memb thru Ins action
~ from intracell
- Stimulate fusion of GLUT4 vesicles w p. memb
- When β blood levels of Ins, GLUT4
Transporters recycled back into cytoplasm
~ as vesicles
- this mechanism - MUSC & FAT je
~ liver - alw on surface
Glucagon
Effects
- Stimulate liver cells to GNG
~ hydrolyse Gly β Glu
- Stimulate Lipolysis & FA use 4 Γ© supply
~ 4 other Ts, so Glu β br
- Increase AA uptake by liver
~ (trans)deaminate AAs, convert to carbs
- Decrease AA uptake in musc
~ oΓΉ it would've been converted to pro
Main
- Pancreatic π-cells ; Glucagon,
~ a peptide hm
~ when low blood Glu (fast, starve, disease)
- Promotes liver Glu production & release
:pencil2: Act through cAMP - & act thru recs
- GPCR work thru 2nd messenger molcs
- Glu + rec activate AC ; cAMP
~ stimulate enzs 4 Gly bd
~ inhibit Pyruvate production from G-6-P
Summary
FED state:
- β blood Glu, Ins
- β Glucagon
- Blood Glu enter Ts, so β blood Glu
- Glu β Gly = Glycogenesis
FASTED state:
- β blood Glu, Ins
- β Glucagon, blood Glu
~ so β Glu levels
- Liver Gly β Glu = Glycogenolysis
-
Hormonal Regulation of Metm
- how Ins, Glucagon work thru recs,
cell signalling pathways
- hypoglycemia: low blood Glu