Normal insulin signalling Flashcards

1
Q

What does insulin secretion stop?

A
Gluconeogenesis
Glucogenolysis
Lipolysis
Ketogenesis
Proteolysis
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2
Q

What does insulin secretion promote?

A
Glucose uptake
Glycolysis
Glycogen synthesis
Protein synthesis
Uptake of ions (K+, PO43-)
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3
Q

How is insulin produced?

A
Preproinsulin
Loss of signal sequence
Proinsulin
Loss of C chain
Insulin
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4
Q

What happens to the C chain?

A

Exported with no known physiological effect

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5
Q

Where is insulin processed?

A

In the endoplasmic reticulum of the beta cell

Has high number of ER

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6
Q

What is basal blood glucose?

A

5.5mM

Any higher stimulates insulin

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7
Q

How is insulin secreted in response to glucose?

A
Glucose enters the beta cell
Enters glycolysis and Krebs
Produces ATP
Membrane depolarisation
Ca2+ influx
Signal to release insulin
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8
Q

How does glucose enter the beta cell?

A

Via Glut2 transporter

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9
Q

What enzyme first acts on glucose?

A

Glucokinase phosphorylates glucose to glucose-6-phosphate

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10
Q

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

A

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

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11
Q

How does Ca2+ enter the beta cell?

A

Via the Ca2+ voltage gated channel

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12
Q

What are the phases of insulin release?

A

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

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13
Q

Describe rare diabetes study 1

A

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

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14
Q

What was the diagnosis of rare diabetes study 1?

A

GATA6 mutation

A transcription factor

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15
Q

Why are transcription factors important?

A

Necessary for beta cell development

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16
Q

How do beta cells develop?

A
Pluripotent stem cell
Endoderm
Pancreatic endoderm
Endocrine progenitor
Beta cells
17
Q

What is the result of a GATA6 mutation?

A

Diabetes

Liver, cardiac and pancreas abnormalities

18
Q

What is the role of GATA6?

A

Role in early embryological development

19
Q

Describe rare diabetes study 2

A
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
20
Q

What is the diagnosis of rare diabetes study 2?

A

Glucokinase mutation

21
Q

What is glucokinase?

A

Phosphorylates glucose to glucose-6-phosphate

Activated at 5.5mM/L

22
Q

What is the effect of a glucokinase mutation?

A

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

23
Q

What is the glucose sensor of the beta cell?

A

Glucokinase

24
Q

Describe rare diabetes study 3

A

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

25
Q

What was the diagnosis of rare diabetes study 3?

A

Mutation in KCJNII gene (R210C)

26
Q

What is a KCJNII mutation?

A

Potassium channel fails to close in response to increased ATP levels

27
Q

How is a KCJNII mutation treated?

A

0.4mg/kg sulphonylurea glubenclamide daily

28
Q

What is permanent neonatal diabetes?

A
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
29
Q

Describe rare diabetes study 4

A

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

30
Q

What is Wolfram syndrome?

A
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
31
Q

What are endoplasmic reticulum stress disorders?

A

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

32
Q

Can Wolfram syndrome be treated?

A

Potential for small molecule chaperones to help endoplasmic reticulum stress