Biochemistry of Insulin Production, Secretion and Action Flashcards
At what blood glucose level is insulin produced?
Above 5mM
At what blood glucose level is glucagon released?
Below 5mM
Which cells in the pancreas are responsible for secreting insulin?
Beta cells
Which cells in the panreas release glucagon?
Alpha cells
What are the basic stages in the synthesis of the insulin hormone?
It is synthesised in the RER of beta cells
First preproinsulin is formed
The C peptide is cleaved from this molecules leaving two polypeptide chains (A and B) linked by disulfide bonds
What is the name given to a very fast and short acting insulin preparation?
Lispro
What is the name given to an ultra long acting insulin preparation?
Glargine
What must Lispro be used in conjunction with for continuous insulin infusion?
A longer-acting insulin preparation
(it is useful for around meals)
Using Lispo, has a major disadvantage which is the fact it is antigenic
True or false?
False
It is not antigenic
Why is glargine so long lasting?
It precipitates in the subcutaneous tissue
How does glucose enter beta cells and what occurs when it does?
GLUT2 transporters
Phosphorylated by glucokinase
Why does a change in glucose concentrations above 5mM lead to a dramatic change in glucokinase activity?
The Km for glucokinase is around 5mM of glucose
If there is an increased metabolism of glucose within beta cells, there will therefore be subsequent increase of what in the cell?
ATP
What is the consequence of a raised intracellular ATP within beta cells?
ATP inhibitis KATP channels
This causes depolarisation
When a pancreatic beta cell is depolarised via high intracellular ATP, what is the outcome?
Ca2+ voltage gated channels will open
This causes secretory vesicles to fuse with the cell membrane and release insulin
Normally the release of insulin is __________
Normally the release of insulin is biphasic
Why are two phases of insulin release usually required?
Only 5% of insulin granules are ready for release at the initial period
The reserve pool must undergo preparatory reactions in order to be ready for release
What is the term given to the pool of insulin that is ready for immediate release?
Readily releasable pool
Which two proteins does KATP consist of?
- KIR - Inward rectifier subunit (Kir6)
- Sulphonylurea receptor - Regulatory subunit (SUR1)
KATP can be directly inhibited by which class of drugs?
Sulphonylurea
Give two examples of drugs within the sulphonylurea drug class
- Gliclazide
- Glipizide
- Glibenclamide
- Glimepiride
What stimulates KATP and what is the outcome of this?
Diazoxide
Insulin secretion is inhibited
Which drug class can be used alongside metformin as an adjunct to first line treatment for type 2 DM?
SURs
A mutation in what will lead to neonatal diabetes?
Kir6.2
(this may lead to increased KATP activation or increase in numbers)
How can congenital neonatal diabetes be treated?
Sulfonylureas
Mutations in which things may lead to congenital hyperinsulinism?
- Kir6.2
- SUR1
Which treatment may help congenital hyperinsulinism?
Diazoxide
What is MODY?
Maturity onset diabetes of the young
What can cause MODY?
- Monogenic diabetes with beta cell genetic defect
- Familial form of early onset type II diabetes with defects in insulin secretion
- Mutations in at least 6 different genes other genes (there are around 150 genes)
What causes MODY2?
Mutations in the glucokinase genes
Impaired glucokinase function
Why does hyperglycaemia occur in those with MODY2?
There is a glucose sensing defect and the blood glucose threshold for insulin secretion is increased
Types 1 and 3 MODY are due to mutations in what?
HNF transcription factors
What are two key roles of HNF transcription factors?
- Pancreas foetal development and neogenesis
- Regulate beta cell differentiation and function
It is important to distinguish MODY patients from type 1 DM patients for what reason regarding treatment?
They can be treated with a sulfonylurea rather than insulin
Type 1 DM is characterised by a loss of what?
Insulin secreting beta cells
MODY is characterised by what?
Defective glucose sensing in the pancreas and/or loss of insulin secretion
Type 2 diabetes is characterised by what?
Reduced insulin sensitivity
(secondary to hyperglycaemia which causes hyperinsulinaemia)
What are the main positive effects (i.e. start things happening) of insulin?
- Amino acid uptake in muscle
- DNA synthesis
- Protein synthesis
- Growth responses
- Glucose uptake in muscle and adipose tissue
- Lipogenesis in adipose tissue and liver
- Glycogen synthesis in liver and muscle
What are the main negative effects (i.e. stop things happening) of insulin?
- Lipolysis
- Gluconeogenesis in liver
Insulin binds to which receptor?
Insulin receptor
What type of receptor is the insulin receptor?
A dimeric tyrosine kinase
Which subunits of the insulin receptor for the hormone binding domains?
Alpha subunits
Binding of insulin to the alpha subunits of the insulin has what immediate effect?
Autophosphorylation of the beta subunits
When the beta subunits of the insulin receptor become phosphorylated, what does this allow them to also phosphorylate?
Insulin receptor substrates (IRS)
Insulin receptor substrates can activate which two things?
- PI3K
- Ras
By activating PI3K, what is the outcome of this pathway?
Glycogen synthesis
By activating Ras, what is the outcome of this pathway?
Gene expression
(via MAP kinase pathway)
PI3K also activates which other protein which allows for what?
PKB
GLUT4 translocation into the cell membrane
What is the role of GLUT4 within the cell membrane?
Glucose uptake into cells
PKB and the MAP kinase pathway have one common outcome which is ____ _________
PKB and the MAP kinase pathway have one common outcome which is cell growth
What is insulin resistance?
A reduced ability to respond to physiological insulin levels
Insulin resistance is most associated with what?
Obesity
What is “Leprechaunism”, or Donohue syndrome, what causes it and what developmental abnormalities may be present?
A condition involving severe insulin resistance
Caused by a rare autosomal recessive genetic trait and mutations in the insulin receptor gene
Developmental abnormalities:
- Elfin facial appearance
- Growth retardation
- Abscence of subcutaneous fat and decreased muscle mass
What is Rabson-Mendenhall syndrome, what causes it and what developmental abnormalities may be present?
A condition involving severe insulin resistance, hyperglycaemia and compensatory hyperinsulinaemia
Caused by an autosomal recessive trait and mutations in the insulin receptor reducing sensitivity
Associated with fasting hypoglycaemia (due to hyperinsulinaemia) and diabetic ketoacidosis
Developmental abnormalities include:
- Abdominal distension with loss of subcutaneous fat
- Overcrowding of teeth and fissuring of the tongue
- Premature greying of the hair
- Acanthosis nigricans
- Clitoromegaly in females
Where are ketone bodies formed?
Liver mitochondria
What are ketone bodies dervied from?
Acetyl-CoA
(after beta oxidation)
Ketone bodies are useful for what?
Energy metabolism within heart and renal cortex tissues
(converted back to acetyl-CoA)
In which situations may ketone bodies be produced in excess?
- Starvation
- Diabetes
Why are ketone bodies produced in excess in certain situations?
- Oxaloacetate is consumed for gluconeogenesis when no other energy source is present
- The TCA cycle cannot “run” as the intermediates have been used up
- Acetyl-CoA build up which causes a subsequent rise in ketone bodies (they are equilibrium)
An accumulation of ketone bodies leads to what?
Acidosis
(coma and death eventually)
What can exacerbate a ketoacidosis?
High glucose excretion
(results in dehydration increasing acidotic effect)
Ketoacidosis is most associated with which condition under which circumstance?
Type 1 diabetes
When insulin is not injected and cells fail to receive glucose so fat breakdown occurs
Why does ketoacidosis generally not occur with type 2 diabetes?
- There are high insulin concentrations
- This inhibits hormone-sensitive lipase
- This prevents tryglyceride breakdown into glycerol and free fatty acids
