BOD L3+4 T2 Diabetes genes and mechanisms Flashcards
Aim: To link understanding of pancreatic function with type 2 diabetes pathology and treatment rationales. LO: -Detail the main cellular pathways of insulin secretion and islet immunomodulation. -Provide detail of the molecular events leading to pancreatic dysfunction in type 2 diabetes, an ddetiail how diet and extracellular environment impact upon this. -Provide detail of specific genes linked to diabetes predisposition.
How does the immune systems role differ between T1 and T2 diabetes?
T1 is antibody driven where as T2 is innate immune driven (by cytokines and inflammation). Inflammationg driven by high sugar, high fat, sedentary lifestyle. Lipo-/gluco- toxicity damage on beta cells.
The lipo-/gluco- toxicity seen in beta cells in T2D causes epigenetic mutations. Why are these pancreatic beta cells exquisitely sensitive to their extracellular environment?
As they monitor blood sugar/fat levels in real time they are constantly screening blood with no off switch, so toxicity from high levels builds up within these cells.
What are the two ways beta cells dysfunction in diabetogenesis?
Abnormal insulin secretion,
Reduced beta cell mass
Briefly with the aid of this diagram, how does high blood glucose lead to insulin secretion?
Glucose enters cell via Glu2 transporter. Rise in glycolysis and ATP production.
High ATP levels act on potassium ion channel to close. Causes membrane depolarisation.
This causes calcium ion channels to open, Calcium ions flood into cell, which act on insulin vesicles, causing fusion between insulin granule and membrane. Insulin secreted from cell.
Insulin secretion is a multistep process and is released in different phases. Why is this?
Insulin and the granule exists within the cell at different stages of development to cause this.
Insulin is trafficked arround the cell from the ER to the Golgi to the plasma membrane. Which three molecules identify each of these section of the cell?
The ER is coated in COPII.
The early Golgi apparatus is coated in COPI.
The late golgi and plasma membrane are coated in clathrin.
Briefly outly how insulin moves from pro-insulin to mature insulin being secreted.
Pro-insulin formed in the ER moves to the golgi, it is packaged into secretory granules. As it moves away to cell membrane, it matures due to influx of protons (acidification) which activates enzymes inside, cleaving C-peptide on insulin, making mature protein. This mature insulin solidifies to crystal. It resolutes when secreted in extracellular fluid (blood).
Explain the large inital release of insulin.
This is the release of the immediately releasable granules which are mature and already found at cell membrane.
Where can the second phase of insulin be found in the cell?
Where can the third reserve pool be found?
Granule is docked and protein mature, but not ready to be activated.
The third pool isn’t tethered to cell membrane so needs translocating, and also protein needs activating.
How does beta cell dysfunction in diabetogenesis alter insulin secretion?
Abnormal insulin secretion:
- Absent first phase response to intravenius glucose
- Delayed and blunted response to a mixed meal
- Abnormal insulin secretory oscillations
- Increased levels of proinsulin and proinsulin breakdown intermediates.
SNARE proteins are necessary for membrane fusion. Which two snares are involved in this?
What enters cells to cause the two SNARE proteins to bind, membranes to fuse and therefore release insulin?
v-SNARE (vesicular) is found on secretory granule surface.
t-SNARE is found on inner cell membrane.
Calcium ions entering cell causes this.
What do calcium ions act upon during insulin secretion to initate membrane fusion?
Calcium ions activate Calpane, an enzyme, which when activated clips SNAP-25, which brings SNARE proteins together.
(activated) SNAP-25, Syntaxin 1 and VAMP-2 bring SNARE proteins together.
What is microarray?
Method used to detect expression of tens of thousands of genes simultaneiously, global gene expression, SNP, methylation, amplification etc
Light-directed chemical synthesis that enables synthesis of hundreds of thousands of compounds in precise locations.
What is the affect that T2D has on the expression of the secretory machinery?
There is a decrease. Not enough SNARE expressed.
How are the membrane fusion proteins found on the membrane?
Found anchored and localised on lipid rafts. Allows them to collect together in high numbers locally. t-SNARE and associated proteins (including calcium channel) found on this raft.
What effect does hyperglycaemia have on islet inflammasomes?
Activates. Due to high levels of ROS generated from glucose metabolism, inflammasome activates caspase 1 which activates IL-1beta.
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