Lecture 17 - Causes of Diabetes Flashcards
What secretes insulin?
the beta cells in the pancreas
Where does the pancreas sit?
in the abdominal cavity behind the stomach
Where are the beta cells contained within the pancreas?
In pancreatic islets which contain alpha, beta and delta cells
What cells secrete glucagon?
alpha cells
When is insulin released?
in response to high blood glucose levels
What does an increase in blood glucose lead to?
an increase of glucose uptake into the cell
What does increased glucose in the cell cause?
higher levels of ATP, which increases the ATP”ADP ratio
What does increased ATP:ADP cause?
closure of the ATP-sensitive K+ channels, which causes membrane depolarisation
What does membrane depolarisation cause?
activation of voltage gates Ca2+ channels, causing increased Ca2+ inside the cell
What does increased cytosolic Ca2+ cause?
fusion of insulin granules with the plasma membrane, causing release of insulin
What does insulin increase?
glucose uptake, glycolysis, glycogen synthesis, fatty acid/triglyceride synthesis, amino acid uptake and protein synthesis
What does insulin decrease?
glycogen breakdown, gluconeogenesis, lipolysis, proteolysis
What are the effects of insulin mediated via?
activation of insulin signalling pathways in target cells
What does insulin binding to the insulin receptor do?
activates many different signalling pathways to bring about its effects on metabolism and growth
What does insulin signalling involve?
protein phosphorylation
What does binding of insulin to the insulin receptor (IR) lead to?
auto phosphorylation of the receptor (receptor phosphorylates itself)
What do phosphorylates residues on the IR act as?
binding sites for insulin receptor substrate (IRS)
What does IR phosphorylate?
4 tyrosine residues in IRS proteins
What binds to phosphorylated residues?
The lipid kinase, phosphoinositide 3-kinase
What does the lipid kinase phosphoinositide 3-kinase do?
converts PIP2 to PIP3
What does binding of PIP3 do?
activates PKD1
What does PKD1 do?
phosphorylates and activates kinases such as PKB/Akt
What does PKB/Akt do?
diffuse through the cell and activate processes such as glucose transport and glycogen synthesis
What does insulin stimulate?
glucose transport into adipocytes and skeletal muscle
What does insulin binding to receptor on adipocytes and skeletal muscle cells do?
activates the insulin signalling pathway, leading to fusion of GLUT4 containing vesicles to the membrane
What happens when GLUT4 vesicles fuse with the membrane?
GLUT4 inserts itself into the cell surface where it can take up those glucose molecules into the cells
How does insulin repress gluconeogenesis?
by inhibiting transcription factor Fox01
Where is Fox01 synthesised?
in the cytosol
Where is Fox01 targetted?
to the nucleus
What does Fox01 do?
regulates expression of genes that mediate gluconeogenesis (PEPCK, G6Pase)
What does PKB do to Fox01?
phosphorylates it
What does phosphorylation of Fox01 do?
prevents it from entering the nucleus, leading to a loss of expression of gluconeogenic genes and hence a loss of glucose production
How does loss of insulin secretion or insulin resistance lead to hyperglycaemia?
as a result of loss of insulin stimulated uptake into target cells (skeletal muscle, adipocytes)
loss of insulin-mediated repression of gluconeogenesis (and glycogen breakdown) in the liver
What happens in type 1 diabetes?
is a chronic autoimmune disease in which destruction of beta cells results in insulin deficiency and hyperglycaemia
Who does type 1 diabetes generally occur in?
susceptible individuals, likely as a result of an environmental trigger
What has been identified as a cause of type 1 diabetes?
susceptibility genes and possible triggers (e.g. enteroviruses)
How much higher is the risk of T1D for first degree relatives of someone with the disease?
~15 times higher
What is the HLA region?
a critical susceptibility locus for T1D
What does the HLA region contain?
genes that encode components of major histocompatibility complex and is a key component of the immune system
How many people with the HLA gene variant develop T1D?
only 5%
Where is the HLA gene region?
chromosome 6
What do the HLA genes have strongest known association with?
T1D
What is a significant risk factor for development of T1D?
presence of autoantibodies against beta cell antigens
Examples of autoantibodies?
glutamic acid decarboxylate 65 (GAD-65)
insulin
ICA512
ZnT8 (zinc transporter 8)
How many people test positive for these antibodies? And how many of those develop T1D?
3-5% of general population test positive and only 20% of those develop T1D
What does the presence of 2 antibodies do?
increases risk of developing T1D within next 10 years to 75%
Why is it difficult to identify precipitating events for T1D?
these might occur many years before onset of symptoms
several precipitating events might be involved
What have been implicated as a possible precipitating event?
Enteroviruses such as coxsackie virus
Why is the coxsackie virus thought to be a precipitating factor?
striking similarity between the 2C protein of the coxsackie virus and GAD65 suggests molecular mimicry might be involved in aetiology of T1D
leading to beta cell destruction
When do clinical onset (symptoms) of T1D typically occur?
until you have lost ~90% of beta cell mass, there is no way back from this
Why is it important to identify before clinical onset?
to identify people at risk and intervene before they have lost so much of their beta cell mass
Treatment of type 1 diabetes?
insulin injections for the rest of their life
careful monitoring of diet and regular blood tests to check glucose levels
What are high blood glucose levels as a result of in type 2 diabetes?
insulin resistance of target tissues
insufficient production/secretion of insulin (beta cell dysfunction)
What is one of the first things to develop in T2D?
insulin resistance - the cells in the body no longer respond to insulin as they should
Why is there not really a change in blood glucose levels as insulin resistance begins?
the beta cells secrete more insulin to overcome the resistance and keep blood glucose levels normal
What happens after a while of producing excess insulin?
there is too much stress on the beta cells and they become dysfunctional and die
What is the amount of insulin secreted by beta cells established by?
the prevailing insulin sensitivity
What happens when the body is in an insulin sensitive state?
beta cells secrete a low amount of insulin
What happens when the body goes into a insulin resistant state?
the beta cells sense this and respond by secreting more insulin
this gives insulin resistance but normal blood glucose levels
Strong link between insulin resistance and…?
obesity
What does protein tyrosine phosphatase 1B (PTPB1) do?
dephosphorylates the insulin receptor, leading to a loss of insulin receptor substrate binding
What does PTEN (phosphatase and tensin homologue) do?
dephosphorylates PIP3 back to PIP2, switches off insulin signalling
What does PKC do?
serine phosphorylates IRS proteins and when it serine phosphorylates IRS proteins, this prevents the insulin receptor from activating tyrosine phosphorylation on IRS proteins
What is a consequence of obesity?
the amount of triglycerols exceeds the storage capacity of adipose cells and as a result fat starts to accumulate in other tissues such as liver and muscle
What does excess fat lead to?
increased levels of the intracellular lipid signalling intermediates diaglycerol (DAG) and ceramide (a component of sphingolipids) in the cytoplasms of cells
What are DAG and ceramide formed from?
fatty acids
What does ceramide do?
inactivates PKB
What does diaglycerol do?
key second messenger leading to the activation of PKC
What is adiponectin?
is secreted from adipocytes and promotes insulin sensitivity
What does adiponectin do?
binds to adiponectin receptor on target cells, and activates ceramidase, which converts ceramide into sphingosine
What does sphingosine do?
reduces levels of ceramide inside of the cells (interferes with PKB)
What happens to adiponectin secretion in obesity?
it is decreased, which contributes to insulin resistance
What does decreased conversion of ceramide do?
ceramide accumulates inside the cells and interferes with insulin signalling to increase insulin resistance
What is obesity?
a pro-inflammatory condition in which hypertrophied adipocytes and adipose resident immune cells both contribute to increased circulating levels of pro-inflammatory cytokines
What does adipose tissue in lean individuals secrete?
anti-inflammatory and insulin sensitising adipokines such as adiponectin
What is released in obesity?
pro-inflammatory cytokines such as TNF alpha (tumour necrosis factor alpha)
What does TNF alpha have?
different effects that contribute to insulin resistance
What does TNF alpha increase?
expression of PTP1B, which can dephosphorylate the insulin receptor, preventing IRS binding
What does TNF alpha activate?
JNK (Jun-N-terminal kinase, which causes serine phosphorlyation and inactivation of IRS proteins
What is thought to contribute to type 2 diabetes
loss of beta cell mass and loss of insulin secretory capacity
What is dysregulation of insulin secretion linked to?
accumulation of fat in pancreas
What % of beta cell mass decrease after 5 years diagnosis of T2D?
25% decrease
What % of beta cell mass decrease after >15 years diagnosis of T2D?
50%
What happens when beta cells synthesise more insulin?
the endoplasmic reticulum is put under stress and can no longer fold and process new insulin
What happens when the endoplasmic reticulum is put under stress?
activates unfolded protein response (UPR)
What does unfolded protein response result in?
apoptosis and beta cell death
What is type 2 classed as?
a complex polygenic disorder (caused by a combination of genetic and lifestyle factors)
What have GWAS studies identified that happen more freqently in type 2 diabetes?
many gene polymorphisms (SNPs) (>75 risk genetic loci have been indentified
