Glucose Homeostasis and causes of T1DM

Question 1

what does glucose do?

Answer 1

• provides energy

- can cause hyperglycaemia which leads to DM

Question 2

provides energy:

Answer 2

• ubiquitous source of energy
• glycogen is stored glucose in the liver
• cannot be substituted in the CNS from FA
• can substitute at birth

Question 3

Important values:

Answer 3

• HYPO - <3mmol/L
• NORMAL - 4-6mmol/L
• POST PRANDIAL (2 hours after eating) - 8mmol/L
• HYPER - > 10mmol/L

Question 4

Diabetes Mellitus:

Answer 4

chronic disease
cannot produce insulin
cannot use the insulin produced 
persistant hyperglycaemia 
loss of glucose can lead to osmotic diuresis

Question 5

What happens if you get DM:

Answer 5

thirst increases, urine increase, dehydration, coma, death

Question 6

Homeostasis of hyperglycaemia

Answer 6

increase glucose intake - food or liver converts glycogen
beta cells from Islets of Langerhans
insulin action by liver, adipocytes, CNS and muscles - decrease glucose levels due to uptake

Question 7

glucose homeostasis

Answer 7

1. CNA - energy expenditure and appetite regulation - obesity
2. leptin - signals brain to stop eating - released from adipolysis
3. GI tract - glucose uptake and incretin effect

Question 8

integrated physiological system

Answer 8

1. intake of food into stomach
2. glucose released and sent to pancreas
3. pancreas releases beta cells from islets of langerhans
4. uptakes by beta cells

Question 9

increase in insulin

Answer 9

1. allows glucose uptake
2. allows glucose to be converted to triglycerides
3. allows glucose to be converted to glycogen in the liver

Question 10

what does insulin do

Answer 10

prevents lipolysis in fat cells and fatty acid uptake by liver to promote gluconeogenesis

liver supports increase serum levels of glucose

acts locally in islets to switch off glucagon synthesis
glucagon produced by alpha islet cells in the pancreas acts to convert glycogen in the liver to glucose

Question 11

T1DM

Answer 11

occurs in childhood - 5-15 yrs
caused by destruction or damage by autoantibodies of the islet beta cells in the pancreas
not genetically predetermined by genetic susceptibility
environmental priming can cause early onset
treatment by insulin injections - no cure

Question 12

stages of T1DM

Answer 12

1. genetic susceptibility
2. environmental influences
3. initial CD8+ (T cell) and APC involvement, B cell autoantibodies and epitope spreading

Question 13

genetic susceptibility

Answer 13

specific genetic constitution is required - certain combination of genes?
need a genetic trigger
identical twins of parents with T1DM will eventually express autoanitbodies against beta cells - but one may get it at 4 and another at 15

Question 14

T1DM susceptibility genes

Answer 14

major histocompatibility complex
insulin
cytokines 
receptors
signalling molecules 
risk of 1 gene mutating = diabetes

Question 15

what is major histocompatibility complex

Answer 15

set of cell surface proteins that allows the immune system to recognise foreign bodies

Question 16

environmental influences

Answer 16

triggers lead to auto-antibody response against islets antigens
timing between priming and detection is not consistent

Question 17

timing between priming and detection is not consistent

Answer 17

1. hit and run triggers - no molecular trace of source

2. multiple environmental insults

Question 18

viral infections

Answer 18

abundant levels of HLA class I and INF alpha in islets of recent T1DM cells suggests a viral footprint suggesting infection of cells - no evidence but a cause

Question 19

bacterial infections

Answer 19

composition of bacteria in the gut - hylobacter pylori

Question 20

What happens with viral infections

Answer 20

accumulation of INF alpha (interferons) stimulates cytokines (CD8+ t-cells)
upregulation of MHC class I which enables CD8+ to attack
when INF-alpha and MHC class I collide the beta cells have problems
inappropriate expression of Beta cells antigen on surface which is detected as foreign

Question 21

early stages of type 1

Answer 21

expression of proteins that should be recognised as host on the surface of a beta cell

some proteins are associated with insulin molecule and some are part of secretory packages that contain insulin

due to viral or bacterial infection proteins inappropriately displayed on the surface

T cell within close proximity will have a receptor against it

binds and Fas ligand becomes activated to Fas receptor and causes apoptosis of beta cell

Question 22

clinical diabetes

Answer 22

progression is irreversible
clinical onset is later on after 80% of islet cells are lost
loss of C-peptide
takes 8 years for it to happen