Insulin Biochemistry Flashcards
What cells secrete insulin?
Pancreatic beta cells
What is the location of the pancreatic beta cell?
In the pancreatic islets. The are located close to the blood vessel to allow them to detects the blood glucose concentration
How is insulin formed?
- Synthesised in the RER of the pancreatic beta cells as a larger preprohormone - PREPROINSULIN
- Cleaved to form insulin by Ca2+ dependent peptidases
What is the structure of the insulin hormone?
Two amino acid chains joined by two disulphide bridges
Where is insulin stored?
Within granules in the betacells until it is secreted into the bloodstream by exocytosis in response to the appropriate stimulus.
What is the main function of insulin?
To lower blood glucose concentration
How was the diagnostic criteria of diabetes mellitus determined?
They likelihood of development of diabetic retinopathy
What is the result of too much insulin?
Hypoglycaemia
What is the process of insulin secretion?
- Glucose enters the beta cell through GLUT2 Transporter and is phosphorylated by glucokinase
- The change in concentration leads to a dramatic change in glucokinase activity
- The increased metabolism of glucose leads to an increase in intracellular ATP concentration.
- This ATP inhibits the ATP-sensitive K+ channel and prevents K+ from leaving the cell. Depolarisation occurs.
- Depolarisation results in the opening of voltage gated Ca2+ channels.
- The increase in intracellular Ca2+ leads to fusion of secretory vesicles and the release of insulin
What occurs in relation to insulin in type 1 diabetes?
The beta cells are mostly lost
What level of blood glucose causes the beta cells to secrete insulin?
Above 5mM
This is because glucokinse is the main glucose phosphorylating enzyme and its Km lies close to 5mM
Why is the release of insulin biphasic?
The first phase prevents a sharp increase in blood glucose.
The second phase is more tuned to the body’s insulin requirement and is released in relation the the glucose intake
What are readily releaseable pools of insulin?
5% of insulin granules are immediately available for release in response to an increase in intracellular calcium
What are the two proteins in the KATP channels?
Kir6 (Inward Rectifier Subunit)
SUR1 (Sulphonylurea Receptor Regulatory Subunit)
What is the function of the SUR1 subunit of the KATP channel?
To regulate K+ flow
What can mutation in the KATP channel lead to?
Neonatal Diabetes
Congenital Hyperinsulinism
What is the treatment for neonatal diabetes?
SURs - directly inhibit KATP
What is the treatment for congenital hyperinsulinism?
Diazoxide - can help inhibit insulin secretion if the channels are still getting to the membrane by stimulating KATP
What are the potential problems with glucokinase activity in MODY2?
- Glucokinase activity is impaired by mutation
2. Glucose sensing defect - therefore threshold for insulin release is much higher
What is type 1 diabetes?
Loss of insulin secretion
What is MODY?
Defective glucose sensing in the pancreas and/or loss of insulin secretion
What is Type 2 Diabetes?
Initially hyperglycaemia with hyperinsulinaemia so the primary problem is reduced insulin sensitivity in tissues
What are the main target tissues of insulin?
Liver
Muscles
Adipose Tissue
What effects does insulin promote?
Amino acid uptake in muscles
DNA synthesis
Protein synthesis
Growth responses
Glucose uptake in muscle and adipose tissue
Lipogenesis in adipose tissue and liver
Glycogen synthesis in the liver and muscles
What are the inhibitory effects of insulin?
Inhibits Lipolysis
Inhibits gluconeogenesis in the liver
What is the most common association with insulin resistance?
Obesity.
Other causes may include - mutation in key signalling pathways and absence of adipose tissue
What is Donohue Syndrome?
Autosomal recessive mutation in the gene for the insulin receptor causing severe insulin resistance
What is Rabson Mendenhall Syndrome?
Autosomal recessive condition causing severe insulin resistance, hyperglycaemia and compensatory hyperinsulinaemia
What are ketone bodies?
These are formed in liver mitochondria and diffuse into the blood stream and peripheral tissues. They are important molecules for energy metabolism in the heart muscle and renal cortex.
What are the two main ketone bodies?
Acetoacetate
3-beta-hydroxybutate
What is the effect of insulin on ketone bosies?
Insulin normally inhibits lipolysis of fats. The reduces the amount of fat that is burned and reduces the risk of ketone body overload
Describe the process of ketone body formation…
Normally acetyl-CoA (from fatty acid oxidation) enters the TCA cycle. However if the supply of either pyruvate or oxaloacetate is limited then the TCA cannot proceed and acetyl Co-A is converted to ketones.
Having
How does the absence of insulin impact ketone body formation?
If there is an absence of insulin, this means that glucose is not removed from the blood by being taken up into tissues. This reduces glycolysis meaning that the body switches to fatty acid oxidation as a form of energy.
What does an excess of ketone bodies in the blood lead to?
Acidosis
What is euglycaemia?
Normal levels of glucose in the blood
What is the result of hypoinsulinaemia?
Diabetic Ketoacidosis
What is the result of hyperinsulinaemia?
Hypoglycaemic Coma
