the triggers for T2DM Flashcards
Triggers
triggers type 2
insulin targets more tissues so you can absorb more glucose in skeletal muscles to bring levels back
more complex and common that type 1
hyperglycaemia
- islet b cells - decreased insulin secretion
- islet alpha cells - glucagon secretion
- skeletal muscles - decreased glucose uptake
- liver - increased production of glucose
- adipocytes - increased lipolysis and decreased glucose uptake
incidence
affects 1 in 11 adults
425 million
1 in 2 undiagnosed
can progress to insulin dependency - drug abuse
risk factors
obesity drug use age family history ethnicity
genetic susceptibility and pre deposition
polygenic disorder
caused by beta cell failure
can be caused by insulin resistance
insulin failure without resistance
spectrum of hyperglycaemia
if tested at the right time will be less problematic
mechanism for disease is not determined
very rare cases
monogenic in newborns and young people
MODY-maturity onset diabetes of young
NDM - neonatal DM
mechanisms have been determined - human genome project allowed us to detect MODY
genetic susceptibility for type 2
over time susceptibility has increased
incidence has increased over the years
due to different backgrounds - african americans have higher case
environmental impact leading to type 2 genetic dysfunction
Islets
only 1% islets, rest of pancreas is exocrine
- beta cells - insulin
- alpha cells - glucagon
- delta cells - somatostatin
- e-cells - ghrelin
- PP-cells - pancreatic polypeptides
glucose-induced insulin secretion
insulin secreting cells are electrically active
beta cells have a resting state of -65mV when no glucose around
in presence of glucose it is transported by GLUT-2 in humans
due to metabolism ATP levels rise
causes K+ channels on membrane to close
cells become depolarised
Ca2+ flows out of cell via calcium channels
insulin released out of cell by exocytosis (1st phase released)
glucose tolerance test
- drink sugary drink to increase plasma glucose levels
- glucose is then taken to pancreas to be converted to insulin
- plasma insulin levels drop as we rest
- insulin levels are kept in secretory granules near the membrane to be released when needed
- glucose metabolism and insulin molecules are coupled to transcription factor (PDX1)
- in humans if enough glucose is consumed you get a secondary rise
- second phase is lost in people who have type 2
- in the Gi tract incretins (GIP and GLP1) are released
- GLP-1 binds to beta cell increasing adenylate cyclase from GPCR and activates cAMP which creates a signalling cascade to increase PKA
- more insulin released from secretory granules at the plasma membrane
well understood beta cell dysfunction
defect in glucokinase
defect in transcription factor PDX1
defects in insulin molecule causing defects in the plasma membrane channels
newborn babies and channels
channel cannot close due to mutations
channels - KCNJ11 and ABBCB
MODY and NDM are good models as they are well understood
poorly understood beta cell dysfunction
CDKAL1 gene
CDKAL1 gene results in reduced beta cell mass
reduced insulin output
predispose to type 2
poorly understood beta cell dysfunction
KCNJ11 gene
KCNJ11 has impaired beta cell function
reduced insulin output
predispose to type 2
insulin hormone
a growth hormone
glucose taken to liver because insulin signalling results in the number of glucose transporters increasing in beta cells
some pathways associated with fat metabolism
insulin signalling can be the problem not the receptor
insulin signalling defects
phosphorylation of serine instead of tyrosine can result in defects
no interaction with PI3 signalling pathway
downstream signalling disrupted
mutations effect sensitivity and efficiency of system
insulin resistance
type 2 gene defects result in resistance to insulin
polymorphisms found in reduced beta cell mass and impaired beta cell function
insulin resistance associations
FTO gene which codes for FTO enzyme
obesity
IRS and PPARG
reduced insulin secretion
resistance pushes the beta cells harder
insulin and obesity
cytokines and inflammation of pancreas
independent genetic impact on beta cell function and insulin production
environment and type 2
more toxic as we get older
collect poo off mice who have type 2 and put it in a mouse that doesnt and they will get type 2
environmental risks
snacking
poor diet
thermogenesis
exercise
treatments
calorie control diet
insulin injections
pregnancy
can lead to very high or very low birth weight
MODY and NDM
mother can acquire type 2 during pregnancy and give it to their babies
cannot control foetal programming
birth weight that is very low can lead to type 1 in future for the child
