the triggers for T2DM

Question 1

Triggers

Answer 1

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

Question 2

hyperglycaemia

Answer 2

1. islet b cells - decreased insulin secretion
2. islet alpha cells - glucagon secretion
3. skeletal muscles - decreased glucose uptake
4. liver - increased production of glucose
5. adipocytes - increased lipolysis and decreased glucose uptake

Question 3

incidence

Answer 3

affects 1 in 11 adults
425 million
1 in 2 undiagnosed
can progress to insulin dependency - drug abuse

Question 4

risk factors

Answer 4

obesity
drug use
age
family history
ethnicity

Question 5

genetic susceptibility and pre deposition

Answer 5

polygenic disorder
caused by beta cell failure
can be caused by insulin resistance
insulin failure without resistance

Question 6

spectrum of hyperglycaemia

Answer 6

if tested at the right time will be less problematic

mechanism for disease is not determined

Question 7

very rare cases

Answer 7

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

Question 8

genetic susceptibility for type 2

Answer 8

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

Question 9

Islets

Answer 9

only 1% islets, rest of pancreas is exocrine

1. beta cells - insulin
2. alpha cells - glucagon
3. delta cells - somatostatin
4. e-cells - ghrelin
5. PP-cells - pancreatic polypeptides

Question 10

glucose-induced insulin secretion

Answer 10

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)

Question 11

glucose tolerance test

Answer 11

1. drink sugary drink to increase plasma glucose levels
2. glucose is then taken to pancreas to be converted to insulin
3. plasma insulin levels drop as we rest
4. insulin levels are kept in secretory granules near the membrane to be released when needed
5. glucose metabolism and insulin molecules are coupled to transcription factor (PDX1)
6. in humans if enough glucose is consumed you get a secondary rise
7. second phase is lost in people who have type 2
8. in the Gi tract incretins (GIP and GLP1) are released
9. GLP-1 binds to beta cell increasing adenylate cyclase from GPCR and activates cAMP which creates a signalling cascade to increase PKA
10. more insulin released from secretory granules at the plasma membrane

Question 12

well understood beta cell dysfunction

Answer 12

defect in glucokinase
defect in transcription factor PDX1
defects in insulin molecule causing defects in the plasma membrane channels

Question 13

newborn babies and channels

Answer 13

channel cannot close due to mutations
channels - KCNJ11 and ABBCB
MODY and NDM are good models as they are well understood

Question 14

poorly understood beta cell dysfunction

CDKAL1 gene

Answer 14

CDKAL1 gene results in reduced beta cell mass
reduced insulin output
predispose to type 2

Question 15

poorly understood beta cell dysfunction

KCNJ11 gene

Answer 15

KCNJ11 has impaired beta cell function
reduced insulin output
predispose to type 2

Question 16

insulin hormone

Answer 16

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

Question 17

insulin signalling defects

Answer 17

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

Question 18

insulin resistance

Answer 18

type 2 gene defects result in resistance to insulin

polymorphisms found in reduced beta cell mass and impaired beta cell function

Question 19

insulin resistance associations

Answer 19

FTO gene which codes for FTO enzyme

obesity

Question 20

IRS and PPARG

Answer 20

reduced insulin secretion

resistance pushes the beta cells harder

Question 21

insulin and obesity

Answer 21

cytokines and inflammation of pancreas

independent genetic impact on beta cell function and insulin production

Question 22

environment and type 2

Answer 22

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

Question 23

environmental risks

Answer 23

snacking
poor diet
thermogenesis
exercise

Question 24

treatments

Answer 24

calorie control diet

insulin injections

Question 25

pregnancy

Answer 25

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