Type 1 DM: overview and therapeutic approaches Flashcards
What is the composition of islet cells? 5
Endocrine tissue, alpha cells, beta cells, delta cells and gamma cells
How many people in the UK are affected by DM and what percentage is type 1/2?
2.9 million 90% type 2
How much beta cell mass is lost in type 1 DM?
50-80%
What 7 things occur if type 1 is left untreated?
1) increased glucagon 2) gluconeogenic 3)breakdown of protein 4)switch to fat oxidation 5) increased ketone bodies 6) ketoacidosis 7)diabetic coma
What are the long term needs of DM1?
Requirement for life long insulin replacement
What are secondary complications of DM1?
Macrovasculature - atherosclerosis Microvasculature - nephropathy and retinopathy Nervous system - neuropathy
What is type 1 DM?
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
what agent is used to induce DM1 in rodents and why?
STZ (streptozotocin) and used bc toxicity is largely specifc to b cells
What do environmental triggers have to do with DM1?
They are essential in tipping the balance in genetically predisposed individuals
What gene loci have been studied for DM1?
HLA genes esp those for MHC on chromosome 6
viral infection vp1?
vp1 is an enteroviral capsid protein that over 60% DM1 cases had vp1 positive islets
How could viral infection trigger DM? 4
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
What is TEDDY?
The Environmental Determinants of Diabetes in the Young
What did TEDDY find in relation to virus’?
Found no evidence for viral infection as a cause for rapid-onset DM1
What is the pathophysiology of immune cell infiltraton? 4
1) infiltration of mononuclear cells 2)direct cell:cell killing 3) secretion of inflammatory mediators 4)anti-islet antibodies
Pathophysiology of inflammatory cytokines?
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.
Name four reactive oxygen species
hydrogen peroxide, superoxide, hydroperoxyl and hydroxyl
name two reactive nitrogen species
nitric oxide and… other nitrogen oxides -.- well done dave
What is the interplay like between ROS/RNS?
COMPLEX MY DEAR
What are two sources of reactive species?
exogenous - secretion from macrophages and endogenous - cytokine induced expression
What are two antioxidant defence mechanisms?
catalase and reduced expression in beta cells
Which apoptotic pathway is involved?
intrinsic
Why do we research basic cellular mechanisms?
to model systems.
Why do we need to understand immunological mechanisms?
early intervention with immunosuppressant
Why do we research b cell apop?
for strategies to improve b cell survival in transplantation
Beta cell regeneration?
‘reprogramming’ non beta cells
6 problems with transplantation?
1) # of donor pancreas’ 2)islet stress 3)re-vascularisation 4)host rejection 5) glucotoxicity 6) recurrent autoimmunity
