Normal insulin signalling

Question 1

What does insulin secretion stop?

Answer 1

Gluconeogenesis
Glucogenolysis
Lipolysis
Ketogenesis
Proteolysis

Question 2

What does insulin secretion promote?

Answer 2

Glucose uptake
Glycolysis
Glycogen synthesis
Protein synthesis
Uptake of ions (K+, PO43-)

Question 3

How is insulin produced?

Answer 3

Preproinsulin
Loss of signal sequence
Proinsulin
Loss of C chain
Insulin

Question 4

What happens to the C chain?

Answer 4

Exported with no known physiological effect

Question 5

Where is insulin processed?

Answer 5

In the endoplasmic reticulum of the beta cell

Has high number of ER

Question 6

What is basal blood glucose?

Answer 6

5.5mM

Any higher stimulates insulin

Question 7

How is insulin secreted in response to glucose?

Answer 7

Glucose enters the beta cell
Enters glycolysis and Krebs
Produces ATP
Membrane depolarisation
Ca2+ influx
Signal to release insulin

Question 8

How does glucose enter the beta cell?

Answer 8

Via Glut2 transporter

Question 9

What enzyme first acts on glucose?

Answer 9

Glucokinase phosphorylates glucose to glucose-6-phosphate

Question 10

What is the effect on ATP production in the beta cell?

Answer 10

ATP has a negative effect on the ATP-sensitive K+ channel
Closes it
Causes depolarisation

Question 11

How does Ca2+ enter the beta cell?

Answer 11

Via the Ca2+ voltage gated channel

Question 12

What are the phases of insulin release?

Answer 12

First phase - stored granules released in response to glucose
Second phase - stores depleted and insulin must be synthesised

Question 13

Describe rare diabetes study 1

Answer 13

20 week scan identified complex congenital heart disease
Mother had previous miscarriages
Birth weight: 1.8kg
ECG: transposition off great arteries, cyanotic
Had cardiac surgery
Day 8: developed jaundice
Day 11: hyperglycaemia, metabolic acidosis
Insulin infusion

Question 14

What was the diagnosis of rare diabetes study 1?

Answer 14

GATA6 mutation

A transcription factor

Question 15

Why are transcription factors important?

Answer 15

Necessary for beta cell development

Question 16

How do beta cells develop?

Answer 16

Pluripotent stem cell
Endoderm
Pancreatic endoderm
Endocrine progenitor
Beta cells

Question 17

What is the result of a GATA6 mutation?

Answer 17

Diabetes

Liver, cardiac and pancreas abnormalities

Question 18

What is the role of GATA6?

Answer 18

Role in early embryological development

Question 19

Describe rare diabetes study 2

Answer 19

Healthy boy aged 14
Father has type 2 diabetes
No symptoms
No glycosuria
Fasting glucose 5.8mM/L
Strong family history of type 2 diabetes
No autoimmune biomarkers
Not fat

Question 20

What is the diagnosis of rare diabetes study 2?

Answer 20

Glucokinase mutation

Question 21

What is glucokinase?

Answer 21

Phosphorylates glucose to glucose-6-phosphate

Activated at 5.5mM/L

Question 22

What is the effect of a glucokinase mutation?

Answer 22

Activates late at 6 or 7mM/L glucose
Causes raised fasting glucose in a healthy child
Does not require treatment

Question 23

What is the glucose sensor of the beta cell?

Answer 23

Glucokinase

Question 24

Describe rare diabetes study 3

Answer 24

Baby born at 34+5 weeks
Developed diabetes at 7 days old
Mother also had diabetes at a young age
Treated with diluted insulatard

Question 25

What was the diagnosis of rare diabetes study 3?

Answer 25

Mutation in KCJNII gene (R210C)

Question 26

What is a KCJNII mutation?

Answer 26

Potassium channel fails to close in response to increased ATP levels

Question 27

How is a KCJNII mutation treated?

Answer 27

0.4mg/kg sulphonylurea glubenclamide daily

Question 28

What is permanent neonatal diabetes?

Answer 28

``` Rare 1 in 500,000 Diagnosed in first 3 months Genetically heterogenous 1/3rd of cases due to KCJNII mutations encoding the Kir6.2 subunit of K/ATP channel ```

Question 29

Describe rare diabetes study 4

Answer 29

Siblings Presented at 6 years with thirst, tired and losing weight Treated for type 1 diabetes 11 years: suffered optic atrophy

Question 30

What is Wolfram syndrome?

Answer 30

``` Diabetes insipidus, mellitus Optic atrophy Deafness 1 in 500,000 Autosomal recessive WFS1 encodes Wolframin protein Mutations in 85% of cases diabetes and optic atrophy under 15 years Wolframin localises to the endoplasmic reticulum C not cleaved from proinsulin Induces endoplasmic reticulum stress ```

Question 31

What are endoplasmic reticulum stress disorders?

Answer 31

A build up of unfolded or misfiled proteins Triggers unfolded protein response pathway If unresolvable, cell undergoes apoptosis

Question 32

Can Wolfram syndrome be treated?

Answer 32

Potential for small molecule chaperones to help endoplasmic reticulum stress