Type 1 DM: overview and therapeutic approaches

Question 1

What is the composition of islet cells? 5

Answer 1

Endocrine tissue, alpha cells, beta cells, delta cells and gamma cells

Question 2

How many people in the UK are affected by DM and what percentage is type 1/2?

Answer 2

2.9 million 90% type 2

Question 3

How much beta cell mass is lost in type 1 DM?

Answer 3

50-80%

Question 4

What 7 things occur if type 1 is left untreated?

Answer 4

1) increased glucagon 2) gluconeogenic 3)breakdown of protein 4)switch to fat oxidation 5) increased ketone bodies 6) ketoacidosis 7)diabetic coma

Question 5

What are the long term needs of DM1?

Answer 5

Requirement for life long insulin replacement

Question 6

What are secondary complications of DM1?

Answer 6

Macrovasculature - atherosclerosis Microvasculature - nephropathy and retinopathy Nervous system - neuropathy

Question 7

What is type 1 DM?

Answer 7

Autoimmune destruction of pancreatic B cells. Immune cell infiltraition onto pancreatic islets. Effects largely specific to beta cells - b cell apoptosis and loss of b cell mass

Question 8

what agent is used to induce DM1 in rodents and why?

Answer 8

STZ (streptozotocin) and used bc toxicity is largely specifc to b cells

Question 9

What do environmental triggers have to do with DM1?

Answer 9

They are essential in tipping the balance in genetically predisposed individuals

Question 10

What gene loci have been studied for DM1?

Answer 10

HLA genes esp those for MHC on chromosome 6

Question 11

viral infection vp1?

Answer 11

vp1 is an enteroviral capsid protein that over 60% DM1 cases had vp1 positive islets

Question 12

How could viral infection trigger DM? 4

Answer 12

1) direct cell damage (cytolysis) 2) viral persistance (prolonged localised inflammation 3)bystander activation (damage to b cells by virus induced t cell activation ) 4)molecular mimicry

Question 13

What is TEDDY?

Answer 13

The Environmental Determinants of Diabetes in the Young

Question 14

What did TEDDY find in relation to virus’?

Answer 14

Found no evidence for viral infection as a cause for rapid-onset DM1

Question 15

What is the pathophysiology of immune cell infiltraton? 4

Answer 15

1) infiltration of mononuclear cells 2)direct cell:cell killing 3) secretion of inflammatory mediators 4)anti-islet antibodies

Question 16

Pathophysiology of inflammatory cytokines?

Answer 16

They are secreted by infiltrating immune cells (mainly macros and t cells) and bind to cell surface receptors on islet cells. they have multiple and diverse effects on cellular function. they act synergistically.

Question 17

Name four reactive oxygen species

Answer 17

hydrogen peroxide, superoxide, hydroperoxyl and hydroxyl

Question 18

name two reactive nitrogen species

Answer 18

nitric oxide and… other nitrogen oxides -.- well done dave

Question 19

What is the interplay like between ROS/RNS?

Answer 19

COMPLEX MY DEAR

Question 20

What are two sources of reactive species?

Answer 20

exogenous - secretion from macrophages and endogenous - cytokine induced expression

Question 21

What are two antioxidant defence mechanisms?

Answer 21

catalase and reduced expression in beta cells

Question 22

Which apoptotic pathway is involved?

Answer 22

intrinsic

Question 23

Why do we research basic cellular mechanisms?

Answer 23

to model systems.

Question 24

Why do we need to understand immunological mechanisms?

Answer 24

early intervention with immunosuppressant

Question 25

Why do we research b cell apop?

Answer 25

for strategies to improve b cell survival in transplantation

Question 26

Beta cell regeneration?

Answer 26

‘reprogramming’ non beta cells

Question 27

6 problems with transplantation?

Answer 27

1) # of donor pancreas’ 2)islet stress 3)re-vascularisation 4)host rejection 5) glucotoxicity 6) recurrent autoimmunity