Genetics of DM [Pat Scott] Flashcards
Which has a stronger genetic link, DM1 or DM2?
According to Pathoma: DM2 actually has a stronger genetic link than DM1 [although it also has one]
Which DM type is the most prevalent?
T2D [90%!!!]
increasing in young ppl too
What type of inheritance is MODY?
what gene mutations are involved for each type?
Maturity Onset Diabetes of the Young
- rare, autoD, monogenetic DO
- monogenetic= mutations in single genes disrupt pancreatic B-cell fxn
- MODY1: defect in hepatocyte nuclear transcription factor [HNF]-4a?
- 2: glucokinase defect [skildum said type 1 was this..]
- 3 HNF-1a & 5: HNF-1B
- 4 insulin promoter factor-1
- 6 NeuroD1
What are 3 proposed causes of T1D?
- T cell R recognizing self Ag’s of pancreatic B cells are not weeded out because of genetic defects in the immune sys.
- viral infxns lead to inflam. response
- autoimmune
- mounts further TCR immune response
What are the major genetic variants associated with T1D?
polymorphisms in MHCII genes:
-
HLA- DR3/4 is highest
- DQ1 is a subset? of DR3 & DR4–> has an altered AA binding site = less stable
When does insulin deficiency become apparent?
when 80% of B cells are destroyed/non-fxnl
too late to reverse
pre-clinical phase may be identifiable by immune changes, still working on it tho
What is the etiology of T2D?
- excess nutrients–> hyperglycemia & fFA’s –>
- inflammation, dysregul8d lipid metabolism, & cell stress–>
-
insulin resistance–>
- [some ppl compensate at this pt]
- relative insulin insufficiency–> B cell destrxn
- can progress to absolute insufficiency
What is the genetic component of T2D?
UNKNOWN but strong:
- twin studies: 70-90% concordance
- 1 parent: ^^ risk
- 2 parents: 40% risk
***environment is also important
What tissues does insulin resistance occur in? [T2D]
adipose
Sk.muscle
liver
What contributes the most to insulin resistance in adipose?
chronic INFLAMMATION
- non-pathogenic: intial^^ in size due to ^^uptake of glu & storage of TG’s
- pro-inflammatory: secretion of monocyte chemotractant protein-1 {MCP-1]
- inflammatory: recruitment of mac’s which secrete TNFa
How does TNFa contribute to adipose insulin resistance?
- TNFa binds TNFR on adipocyte cell surface
- activates serine threonine kinase [JNK]
- JNK phosphorylates & inactivates IRS1
- inactive IRS makes insulin signaling ineffective
- insulin can still bind its R but can’t stimulate translocation of GLUT4 to surface & glu uptake
Insulin resistance + TNFa actions lead to what?
great ^^^^ in free FA release!!!
- which recruits mac’s –> enlarging adipocyte–> secrete TNFa
- TNFa increases insulin resistance = VICIOUS CYCLE
What else does increased FFA’s influence?
Skeletal Muscle insulin resistance
- fFA’s complex w/ TLR4
- activates JNK again
- phosphorylates IRS–I insulin secretion
- GLUT4 not translocated–> glu not taken up!
How do heaptocytes develop insulin resistance?
^^lipids in circulation–> inhibit insulin R signaling in Liver
- fFA binds TLR4 –> IRS phosphorylation
- fFAs taken up into cell–>
- met into DAG–> activates PKC –> phosphorylates IRS again
- OR met into ceramide–> inactivates Akt
- means FOXO1 can go into nucleus & ^^GNeo!
- and inhibits glycogen synthase
What is the main cause of elevated blood glu?
unregulated liver GNeo!!!
hence, we use metformin!!
