Diabetes Flashcards
What is the features of T1D?
- cause
- age onset
- BMI
- onset time
- family history
- insulin level
- life expectancy
- cause - autoimmune insulin producing beta cell destruction
- age onset - young
- BMI - thinner
- onset time - sudden (days/weeks)
- family history - less influence as spontaneous in 85%
- insulin level - low
- life expectancy - reduced by 5-14 years
What is the features of T2D?
- cause
- age onset
- BMI
- onset time
- family history
- insulin level
- life expectancy
- cause - insulin resistance + beta cell defects
- age onset - older
- BMI - obese
- onset time - longer (months/years)
- family history - strong
- insulin level - high
- life expectancy - reduced by 6 years
What is your normal blood glucose level (in mmol/L)?
4-7 mmol/L
which cells are present in pancreas?
alpha and beta cells
what is produced in alpha and beta cells?
alpha - glucagon
beta - insulin
How is blood glucose level maintained or regulated?
The normal blood glucose level (BGL) is maintained by insulin and glucagon
- Insulin absorb glucose -> lowers BGL
- Glucagon secretes glucose -> glucose increases BGL
Which are the 3 main tissues that insulin acts on to lower blood glucose?
liver, adipose and muscle
How does glucagon secrete glucose?
converts glycogen to glucose
How does insulin mediate its inhibitory effect to lower the BGL?
Insulin mediates its inhibitory effect to lower the BGL by acting on:
1. Liver - prevents glucose production by stopping glycogen breakdown
2. Fat - inhibits lipolysis, therefore promoting lipogenesis
3. Muscle - increases the glucose uptake
Altogether, lowering the BGL
How does glucagon mediate its stimulatory effect to increase the BGL?
Glucagon mediates it stimulatory effect to increase BGL by acting on
1. Liver - promotes the glycogen breakdown to secrete glucose
Outline the insulin signalling pathway
- insulins binds the insulin receptor (TRK) on the plasma membrane + binding leads to dimerisation and auto-phosphorylation
- phosphorylation of adaptor protein (IRS1)
- the PIP2 converts to PIP3
- PIP3 then binds PKB/Akt
- the binding results in glut4 translocation to the plasma membrane
- the glucose molecules enter the cells of adipocytes and skeletal muscle through glut 4 via facilitated diffusion
Outline the glucagon pathway
- Acts on liver via glucagon receptor (GPCR) to increase cAMP and PKA
- the increase in cAMP and PKA leads to
2a. inhibition of glycolysis and glycogenesis
2ai. glycolysis - breakdown of glucose to pyruvate
2aii. glycogenesis - formation of glycogen
together, decreasing the glycogen formation - stimulates gluconeogenesis and glycogenolysis
3a. gluconeogenesis - formation of new glucose
3b. glycogenolysis - breakdown of glycogen into glucose
where is insulin stored in beta cells?
in the granules of cytoplasm of beta cells
What is the response of insulin to glucose?
- the response is marked against x and y axis i.e. the levels of insulin (pg/min/islet) for 11mM of glucose in 60 mins
- it is essentially marked by two phases
1. First phase/ transient phase - it is a rapid short lived spike in insulin level due to the insulin secretion probably from the granules adjacent to cell membrane representing the first spike at 10 mins on graph
2. Second phase - if BGL is high, then the rise in insulin level continue, representing the plateau for 45 mins on graph
what nutrients/factors stimulate the insulin release?
- amino acids
- fatty acids
- GPR40
- GLP-1
how is insulin secreted in beta cells of pancrea?
- glucose is taken up by GLUT2
- post uptake of glucose, it is converted into pyruvate though glycolysis
- once pyruvate is formed in cytoplasm it gets converted into Acety CoA in the mitochondria
- Acetyl CoA enters the Krebs cycle in which ATP and H+ ions are release
- the K+ channels on plasma membrane are sensitive to ATP
- high levels of ATP leads to close of K+ channels resulting in depolarisation
- the depolarisation further then open the Ca2+ channels
- increase in Ca2+ levels leads to insulin release
what neuronal factors stimulate the insulin release?
- parasympathetic innervation
2. sympathetic innervation
how does parasympathetic innervation stimulate the insulin release?
- increases insulin
- by release Ach (acetylcholine)
- Ach acts on DAG -> PKC -> Ca2+ -> insulin release
- therefore, lower BGL
how does sympathetic innervation stimulate the insulin release?
- decreases insulin
- by inhibiting cAMP and therefore reducing PKA and ultimately reduce in Ca2+ levels
- resulting in decreased insulin release
- therefore, increases the BGL
what is glucokinase?
- member of hexokinase family (hexokianse IV or D)
- essential for glucose metabolism
- converts glucose to glucose 6 phosphate
what are the properties of glucokinase?
- sets the threshold for glucose stimulated/depedent insulin release
- phosphorylates glucose to form glucose 6 phosphate (glycolysis)
- hexokinase IV - low affinity for glucose (S0.5 8-10mM) - ensures insulin secretion only when glucose increases above the basal level
- lack of inhibition by product (like glucose 6 phosphate unlike other hexokinase)
how are beta cells specialised to allow glucose regulated insulin release?
- presence of glucokinase
- low affinity of Glut2 for glucose
- vascularised islets
- tightly controlled/highly static numbers of beta cells
- highly differentiated beta cells
what are the consequences of diabetes (secondary diseases)?
- macrovascular - myocardial infarction, stroke, peripheral gangrene
- microvascular - retinopathy, nephropathy (kidney failure), neuropathy or foot ulcers
what type of receptors do insulin and glucagon act on?
- insulin receptor - receptor tyrosine kinase (RTK)
2. glucagon receptor - G protein coupled receptor (GPCR)
Define Diabetes Mellitus
Hyperglycemia (high BGL) due to insufficient insulin secretion
what is clinical definition of diabetes mellitus?*
fasting BGL over 7mmol/L (normal BGL 6mmol/L)
Is diabetes monogenic or polygenic?
diabetes is caused by single gene defects (beta cell defect) therefore, it is is monogenic
what are the common mutations found in neonatal diabetes?
KCNJ11 and ABCC8 - mutations in K+ channels
how are K+ channels involved in blood glucose regulation?
K+ channels are significantly involved in blood glucose regulation via depolarisation of the membrane resulting in Ca2+ influx which ultimately releases insulin
what is MODY?
Maturity Onset Diabetes of the Young
which are the six genes that account for 87% of UK MODY?
- HFN1A
- HFN1B
- HFN4A
- IPF1 (PDX-1)
- NEUROD1
- Glucokinase
10% of people have T1D and 90% of people have T2D?
A. True
B. False
A. True
Define T1D and T2D wrt to insulin and glucose
T1D - low insulin + high glucose
T2D - high insulin + high glucose
Define T2D
Hyperglycaemia (high BGL) due to insufficient insulin secretion
Why there is low insulin secretion despite of high levels of insulin in T2D?
- increased (peripheral) insulin resistance
2. beta cell defects
In T2D, there can be very high levels of insulin secretion but due to insulin resistance BGL remains high?
A. True
B. False
A. True
what are the defects in blood glucose regulation of T2D due to insulin resistance?
- Pancreas - stop releasing insulin
- Liver - glucose production is increased
- muscle - reduced glucose uptake
- fat - lipolysis promoted, forming fatty acids
what are the symptoms of T1D?
The 4T's 1. Toilet 2. Thinner 3. Tired 4. Thirsty \+ ketoacidosis