Biochemistry Flashcards
Normal blood glucose level
5 milli molar (mM)
Blood glucose levels rise above normal
Causes pancreatic Beta cells to release insulin. This causes increased glucose uptake and storage and hepatic glucose output is inhibited.
Blood glucose levels fall below normal
Causes pancreatic alpha cells to release glucagon. Causes increased hepatic glucose output.
Endocrine unit in the pancreas
Islet of Langerhan
Types of cells in the islet of Langerhans and function
Beta cells- release insulin
Alpha cells- release glucagon
Gamma cells- release somatostatin
PP cells- secrete pancreatic polypeptide
Role of Gamma and PP cells
Regulation
How is insulin formed
Synthesised at the RER in beta cells of the pancreas. Synthesised first as preproinsulin and then cleaved to form insulin
Structure of insulin
Made up of two polypeptides (A and B) held together by another peptide (C peptide). The two functional peptides are A and B, peptide C has no known function.
What is the significance of peptide C
The C chain is cleaved leaving the active form of insulin. Therefore peptide C can be recorded to measure insulin levels.
Modified insulin
Insulin can be modified to be short or long acting.
Insulin lispro
By switching two amino acids (lysine at B28 and proline at B29) you get short acting insulin.
Insulin glargine
Used for prolonged action.
Glycine is added to the A chain. And adding two arginine residues to the B chain.
Describe how insulin is secreted from beta cells.
Glut 2 transporter allows glucose to move into the cell.
Glucose becomes phosphorylated to form glucose bisphosphate
The glucose bisphosphate then undergoes glycolysis to produce ATP
The intracellular concentration of ATP increases. This blocks the ATP sensitive K+ channel.
Blockage of this channel means K+ cant move out of the cell- therefore intracellular K+ rises depolarising the cell
Depolarisation activates voltage gated calcium channels and calcium moves into the cell. This causes vesicles containing insulin to fuse with the membrane and be released.
Characteristics of the release of insulin
It is biphasic.
Only 5% of insulin is released in phase 1.
The rest are released in phase 2 however this reserve pool has to undergo modification before it can be released.
The K+ ATP dependent channel structure
Made up of two proteins
An inward rectifier subunit- KIR6
A sulphonylurea regulatory subunit- SUR1.
These both make the functional channel.
Drugs that act on the K+ ATP dependent channel.
Some drugs directly inhibit the KATP+ channel- this means intracellular K+ will rise and therefore more insulin will be released- called sulphonylurea e.g. tolbutamide
Some drugs stimulate the K+ATP channel and therefore inhibit insulin secretion e.g. diazoxide.
Mutations in the K+ ATP dependent channel
Mutations in KIR6 can cause neonatal diabetes.
Some mutations in KIR6 or SUR1 lead to congenital hyperinsulism
MODY
Maturity Onset Diabetes of the Young
Monogenic diabetes with a genetic defect in B cells. Familial form of type II diabetes.
Can be caused by mutations in 6 different genes- glucokinase and several HNF transcription factors.
MODY caused by glucokinase 2 mutations
Means that blood glucose levels have to get quite high before insulin is released.
Due to impairment of glucokinase enzyme.
MODY caused by HNF transcription mutations
These play key roles in development of the pancreas in the feotus.
They also regulate B cell differentiation and function
Treatment of MODY
MODY is often misdiagnosed as type 1 diabetes. Treatment for type 1 diabetes is insulin. However treatment for MODY is sulphonylurea (to get the K+ATP channel to work).
How to distinguish between MODY and type 1 diabetes
Familial screening.
Biological functions of insulin
Turns on:
Amino acid uptake in muscle
DNA and protein synthesis
Growth responses
Glucose uptake in muscle and adipose tissue
Lipogenesis in adipose tissue and liver
Glycogen synthesis in the liver and muscle
Turns off:
Lipolysis
Gluconeogenesis
Binding of insulin causes
A signal transduction pathway leading to activation of cellular responses.
The insulin receptor structure
A dimeric tyrosine kinase.
Consists of two extracellular alpha subunits and two transmembrane Beta subunits connected by disulphide bonds.
Binding of insulin to the alpha subunit
Causes the beta subunits to phosphorylate themselves (autophosphorylation) thus activating the catalytic activity of the receptor
Describe the biochemical pathway that is caused by insulin binding to a receptor.
Insulin binds to the alpha subunit. This causes phosphorylation of the beta subunit and this subsequently causes phosphorylation of insulin receptor subunits (IRS).
Activation of these activates the Ras/MAPK pathway and gene expression.
Also it activates PI3K, PKB and glycogen synthesis.
PKB stimulates Glut 4 translocation to the membrane which allows glucose uptake into the cell. This means cellular growth can occur.
Ketone bodies
Formed in the liver mitochondria
Derived from acetly coA
Diffuse into the bloodstream and peripheral tissues
Significance of ketone bodies in starvation and diabetes.
When oxaloacetate is being used to generate new glucose (gluconeogenesis)- the TCA cycle uses fatty acids instead. These fatty acids form acetyl coA. Excess acetyl coA is converted into ketone bodies.
If ketone levels rise in the blood can cause acidosis.
Which type of diabetes is ketoacidosis associated with?
Type 1- when insulin is not released- cells fail to get enough glucose and therefore break down fat.
