Biochemistry

Question 1

Normal blood glucose level

Answer 1

5 milli molar (mM)

Question 2

Blood glucose levels rise above normal

Answer 2

Causes pancreatic Beta cells to release insulin. This causes increased glucose uptake and storage and hepatic glucose output is inhibited.

Question 3

Blood glucose levels fall below normal

Answer 3

Causes pancreatic alpha cells to release glucagon. Causes increased hepatic glucose output.

Question 4

Endocrine unit in the pancreas

Answer 4

Islet of Langerhan

Question 5

Types of cells in the islet of Langerhans and function

Answer 5

Beta cells- release insulin
Alpha cells- release glucagon
Gamma cells- release somatostatin
PP cells- secrete pancreatic polypeptide

Question 6

Role of Gamma and PP cells

Answer 6

Regulation

Question 7

How is insulin formed

Answer 7

Synthesised at the RER in beta cells of the pancreas. Synthesised first as preproinsulin and then cleaved to form insulin

Question 8

Structure of insulin

Answer 8

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.

Question 9

What is the significance of peptide C

Answer 9

The C chain is cleaved leaving the active form of insulin. Therefore peptide C can be recorded to measure insulin levels.

Question 10

Modified insulin

Answer 10

Insulin can be modified to be short or long acting.

Question 11

Insulin lispro

Answer 11

By switching two amino acids (lysine at B28 and proline at B29) you get short acting insulin.

Question 12

Insulin glargine

Answer 12

Used for prolonged action.

Glycine is added to the A chain. And adding two arginine residues to the B chain.

Question 13

Describe how insulin is secreted from beta cells.

Answer 13

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.

Question 14

Characteristics of the release of insulin

Answer 14

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.

Question 15

The K+ ATP dependent channel structure

Answer 15

Made up of two proteins
An inward rectifier subunit- KIR6
A sulphonylurea regulatory subunit- SUR1.
These both make the functional channel.

Question 16

Drugs that act on the K+ ATP dependent channel.

Answer 16

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.

Question 17

Mutations in the K+ ATP dependent channel

Answer 17

Mutations in KIR6 can cause neonatal diabetes.

Some mutations in KIR6 or SUR1 lead to congenital hyperinsulism

Question 18

MODY

Answer 18

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.

Question 19

MODY caused by glucokinase 2 mutations

Answer 19

Means that blood glucose levels have to get quite high before insulin is released.
Due to impairment of glucokinase enzyme.

Question 20

MODY caused by HNF transcription mutations

Answer 20

These play key roles in development of the pancreas in the feotus.
They also regulate B cell differentiation and function

Question 21

Treatment of MODY

Answer 21

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).

Question 22

How to distinguish between MODY and type 1 diabetes

Answer 22

Familial screening.

Question 23

Biological functions of insulin

Answer 23

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

Question 24

Binding of insulin causes

Answer 24

A signal transduction pathway leading to activation of cellular responses.

Question 25

The insulin receptor structure

Answer 25

A dimeric tyrosine kinase.

Consists of two extracellular alpha subunits and two transmembrane Beta subunits connected by disulphide bonds.

Question 26

Binding of insulin to the alpha subunit

Answer 26

Causes the beta subunits to phosphorylate themselves (autophosphorylation) thus activating the catalytic activity of the receptor

Question 27

Describe the biochemical pathway that is caused by insulin binding to a receptor.

Answer 27

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.

Question 28

Ketone bodies

Answer 28

Formed in the liver mitochondria
Derived from acetly coA
Diffuse into the bloodstream and peripheral tissues

Question 29

Significance of ketone bodies in starvation and diabetes.

Answer 29

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.

Question 30

Which type of diabetes is ketoacidosis associated with?

Answer 30

Type 1- when insulin is not released- cells fail to get enough glucose and therefore break down fat.