Scott: Mechanism and Genetics of Diabetes Flashcards
What is maturity onset diabetes of the young?
Rare, autosomal dominant , monogenetic disorders
Caused by mutations in single genes that disrupt pancreatic β cell function.
Give clues to important functions in β cells.
What is the etiology of T1D?
Insulin is not made because pancreatic beta cells are
destroyed by an autoimmune process.
What is hte autoimmune process that leads to the destruction of beta cells?
Genetic defect> TCR that recognize self NOT weeded out> Viral infection> viral epitope mimics B cell protein> TCR (that wasn't weeded out) that recognize B cells are amplified> IR against cells> 80% destroyed> individuals become assymptomatic
How do viral infections lead to an inflammatory response?
Epitopes of some viruses mimic beta cell proteins
viruses promote inflammatory cytokine production
What are the major genetic variants associated with T1D?
polymorphisms in MHCII genes
How are T cells that can initiate an autoimmune response usually eliminated?
USUALLY during T cell development, MHCII proteins present “self” peptides. T cells expressing TCR that STRONGLY binds MHCII + self are targeted for apoptosis.
What is tolerance and how does it relate to MHCII?
Tolerance requires that individual’s MHCII proteins can bind self antigens.
What influences an individual’s immune response and tolerance?
Different MHCII alleles encode MHCII proteins w/ different peptide binding capabilities
What MHCII polymorphisms are strongly associated w/ T1D?
DR3/DQ1*0201
DR4/DQ1*0302
Why are DQB1 alleles associated with diabetes?
altered AA site binding site>
weaker interaction with peptides
*Most high risk variants of MHCII can’t bind pancreatic B cell peptides strongly so T cells carrying TCR for these peptides aren’t weeded out during development
Can T1D be prevented?
Current research aims to identify individuals at an earlier stage of the AI process and BLOCK it to prevent B cell destruction
*Current clinical trials aim at prevetening diabetes in close relatives w/ T1D autoantibodies
(Teplizumab)
What is the MCC of T2D in individuals of european descent?
Obesity
Does genetics play a role in T2D?
Twin concordance 70-90%
One parent Increases chances
Two parents 40%
What is the precursor to T2D?
insulin resistance–decreased ability to respond to insulin
How does insulin resistance develop?
Insulin resistance develops through processes like inflammation and dysregulation of lipid metabolism in:
adipose
skeletal muscle
liver
When does T2D occur?
ONLY if beta cell fxn is lost
What are the several stages of chronic inflammation in adipose tissue that leads to insulin resistance?
- initial increase in size of adipocytes> increased uptake of glucose and TG storage
- Pro-inflammatory secretion of MONOCYTE CHEMOTRACTANT protein
- Inflammatory recruitment of MPHAGES
How does the secretion of TNFa lead to insulin resistance in adipocytes?
TNFa binds to TNFR on adipocyte cell>
activates serine threonine kinase (JNK)>
JNK phosphorylates and inactivates IRS>
inactivation of IRS makes insulin signaling ineffective (INSULIN RESISTANCE)
What happens to insulin in adipose tissue that is “insulin resistance”?
insulin still BINDS to receptor but can’t stimulate translocation of Glut4 and uptake of glucose
How does TNFa promote SYSTEMIC insulin resistance?
Increases the release of FFA>
promotes IR in skeletal and peripheral tissue
What happens in adipose tissue under conditions of excess nutrition and inflammation?
Favors free FA release over TG formation>
Decreased glucose uptake
Activation of HSL
TNFa inhibits PPARy activity
What plays a major role in skeletal muscle insulin resistance?
elevated FFA
What happens in skeletal muscle in the presence of excess FFA?
FFA complex w/ FetuinA> bind TLR4> signals and activates JNK> activated JNK phosphorylates IRS> inhibits insulin signaling> GLUT4 is not translocated> glucose is not taken up> leads to more glucose free in circulation
What is the source of most of the excess glucose that contributes to T2D?
hepatocytes
How do hepatocytes take up glucose? Is this regulated by insulin?
GLUT 2
NOT regulated by insulin
What is the mechanism by which FFA in the hepatocytes lead to insulin resistance?
FFA bind TLR4>
IRS phosphorylation
FFA taken up by the cell are metabolized to form DAG> PKC> IRS
FFA taken up by the cell are metabolized to form ceramide which inactivates Akt
What are the two mechanisms by which insulin resistance leads to decreased storage and increased production of glucose in the liver?
- inhibition of glycogen synthesis (decreased phosphorylation of GSK3, decreased activity of GS)
- Increased gluconeogenesis (translocation of FOXO1 to nucleus and trxn of gluconeogenesis enzymes)
What is the main cause of elevated blood glucose in a pt w/ T2D?
unregulated liver gluconeogenesis
Why is Metformin the front line drug for tx of T2D? What is the MOA of Metformin?
limits excess gluconeogenesis
Inhibits complex 1 of mitochondrial ETC> decreased energy change> increased AMP/ATP:
- Activation of AMPK> increased FA oxidation and decreased lipogenesis
- Inhibition of gluconeogenesis at SEVERAL steps
How do the interactions among insulin resistance tissues affect insulin resistance?
amplifies hyperglycemia
What is the pancreatic beta cell response to initial hyperglycemia?
- increase insulin output to overcome affects of decreased signaling
- relative insufficiency d/t insulin resistance
- in T2D destruction of beta cells d/t inflammatory process
When does T2D develop?
When insulin secretion can’t keep up d/t:
- genetic susceptibility (SLC30A8)
- Apoptosis as a result of excess nutrients
What mechanisms contribute to apoptosis of beta cells?
hyperglycemia and FFA>
oxidative and ER stress>
activates apoptotic pathways
How does oxidative stress lead to beta cell dysfunction?
excess nutrients> overloads ETC> excess H gradient> transfer of e to copmlex III is inhibited> electrons are transfered to O instead> generates ROS> increased ROS > oxidative stess
Why are beta cells highly susceptible to damage by ROS?
low levels of anti-oxidant enzymes
How do excess nutrients cause ER stress?
ER site of protein folding for insulin> ER stress> signaling pathways called UPR> unfolded protein response> initiates apoptosis
What is the connection between ER stress and apoptosis?
Oxidative stress and ER stress activate the inflammasome complex
What is hte inflammasome complex?
activates pro apoptotic cytokine IL1b>
IL1B binds to pancreatic B cell>
apoptosis
What is responsible for many of the consequences of T2D?
ER/oxidative stess and advanced glycosylation end products (AGE)> leading to vascular damage
What are three of the main end consequences of T2D?
- foam cells in arteries> plaques> CVS risk
- GC disruption of filtration barrier> end stage kidney disease
- Retinal capillary> increased permeability> angiogenesis> adult onset blindness
What is AGE?
Advanced glycation end produc
What is the mechanism of age?
Non-enzymatic modificiation of proteins by sugars and lipids that are formed in hyperglycemic environments>
accumulates in vessel walls>
vascular disease
How do AGEs cause vascular disease?
- disrupt fxn by adding bulky non-functional modification by promoting crosslinking
- Soluble form binds to receptors> promotes formation of ROS> promotes release of inflammatory cytokines
