Biochemistry of Insulin Production, Secretion and Action Flashcards

1
Q

At what blood glucose level is insulin produced?

A

Above 5mM

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2
Q

At what blood glucose level is glucagon released?

A

Below 5mM

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3
Q

Which cells in the pancreas are responsible for secreting insulin?

A

Beta cells

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4
Q

Which cells in the panreas release glucagon?

A

Alpha cells

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5
Q

What are the basic stages in the synthesis of the insulin hormone?

A

It is synthesised in the RER of beta cells

First preproinsulin is formed

The C peptide is cleaved from this molecules leaving two polypeptide chains (A and B) linked by disulfide bonds

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6
Q

What is the name given to a very fast and short acting insulin preparation?

A

Lispro

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7
Q

What is the name given to an ultra long acting insulin preparation?

A

Glargine

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8
Q

What must Lispro be used in conjunction with for continuous insulin infusion?

A

A longer-acting insulin preparation

(it is useful for around meals)

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9
Q

Using Lispo, has a major disadvantage which is the fact it is antigenic

True or false?

A

False

It is not antigenic

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10
Q

Why is glargine so long lasting?

A

It precipitates in the subcutaneous tissue

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11
Q

How does glucose enter beta cells and what occurs when it does?

A

GLUT2 transporters

Phosphorylated by glucokinase

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12
Q

Why does a change in glucose concentrations above 5mM lead to a dramatic change in glucokinase activity?

A

The Km for glucokinase is around 5mM of glucose

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13
Q

If there is an increased metabolism of glucose within beta cells, there will therefore be subsequent increase of what in the cell?

A

ATP

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14
Q

What is the consequence of a raised intracellular ATP within beta cells?

A

ATP inhibitis KATP channels

This causes depolarisation

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15
Q

When a pancreatic beta cell is depolarised via high intracellular ATP, what is the outcome?

A

Ca2+ voltage gated channels will open

This causes secretory vesicles to fuse with the cell membrane and release insulin

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16
Q

Normally the release of insulin is __________

A

Normally the release of insulin is biphasic

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17
Q

Why are two phases of insulin release usually required?

A

Only 5% of insulin granules are ready for release at the initial period

The reserve pool must undergo preparatory reactions in order to be ready for release

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18
Q

What is the term given to the pool of insulin that is ready for immediate release?

A

Readily releasable pool

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19
Q

Which two proteins does KATP consist of?

A
  1. KIR - Inward rectifier subunit (Kir6)
  2. Sulphonylurea receptor - Regulatory subunit (SUR1)
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20
Q

KATP can be directly inhibited by which class of drugs?

A

Sulphonylurea

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21
Q

Give two examples of drugs within the sulphonylurea drug class

A
  1. Gliclazide
  2. Glipizide
  3. Glibenclamide
  4. Glimepiride
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22
Q

What stimulates KATP and what is the outcome of this?

A

Diazoxide

Insulin secretion is inhibited

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23
Q

Which drug class can be used alongside metformin as an adjunct to first line treatment for type 2 DM?

A

SURs

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24
Q

A mutation in what will lead to neonatal diabetes?

A

Kir6.2

(this may lead to increased KATP activation or increase in numbers)

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25
Q

How can congenital neonatal diabetes be treated?

A

Sulfonylureas

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26
Q

Mutations in which things may lead to congenital hyperinsulinism?

A
  1. Kir6.2
  2. SUR1
27
Q

Which treatment may help congenital hyperinsulinism?

A

Diazoxide

28
Q

What is MODY?

A

Maturity onset diabetes of the young

29
Q

What can cause MODY?

A
  1. Monogenic diabetes with beta cell genetic defect
  2. Familial form of early onset type II diabetes with defects in insulin secretion
  3. Mutations in at least 6 different genes other genes (there are around 150 genes)
30
Q

What causes MODY2?

A

Mutations in the glucokinase genes

Impaired glucokinase function

31
Q

Why does hyperglycaemia occur in those with MODY2?

A

There is a glucose sensing defect and the blood glucose threshold for insulin secretion is increased

32
Q

Types 1 and 3 MODY are due to mutations in what?

A

HNF transcription factors

33
Q

What are two key roles of HNF transcription factors?

A
  1. Pancreas foetal development and neogenesis
  2. Regulate beta cell differentiation and function
34
Q

It is important to distinguish MODY patients from type 1 DM patients for what reason regarding treatment?

A

They can be treated with a sulfonylurea rather than insulin

35
Q

Type 1 DM is characterised by a loss of what?

A

Insulin secreting beta cells

36
Q

MODY is characterised by what?

A

Defective glucose sensing in the pancreas and/or loss of insulin secretion

37
Q

Type 2 diabetes is characterised by what?

A

Reduced insulin sensitivity

(secondary to hyperglycaemia which causes hyperinsulinaemia)

38
Q

What are the main positive effects (i.e. start things happening) of insulin?

A
  1. Amino acid uptake in muscle
  2. DNA synthesis
  3. Protein synthesis
  4. Growth responses
  5. Glucose uptake in muscle and adipose tissue
  6. Lipogenesis in adipose tissue and liver
  7. Glycogen synthesis in liver and muscle
39
Q

What are the main negative effects (i.e. stop things happening) of insulin?

A
  1. Lipolysis
  2. Gluconeogenesis in liver
40
Q

Insulin binds to which receptor?

A

Insulin receptor

41
Q

What type of receptor is the insulin receptor?

A

A dimeric tyrosine kinase

42
Q

Which subunits of the insulin receptor for the hormone binding domains?

A

Alpha subunits

43
Q

Binding of insulin to the alpha subunits of the insulin has what immediate effect?

A

Autophosphorylation of the beta subunits

44
Q

When the beta subunits of the insulin receptor become phosphorylated, what does this allow them to also phosphorylate?

A

Insulin receptor substrates (IRS)

45
Q

Insulin receptor substrates can activate which two things?

A
  1. PI3K
  2. Ras
46
Q

By activating PI3K, what is the outcome of this pathway?

A

Glycogen synthesis

47
Q

By activating Ras, what is the outcome of this pathway?

A

Gene expression

(via MAP kinase pathway)

48
Q

PI3K also activates which other protein which allows for what?

A

PKB

GLUT4 translocation into the cell membrane

49
Q

What is the role of GLUT4 within the cell membrane?

A

Glucose uptake into cells

50
Q

PKB and the MAP kinase pathway have one common outcome which is ____ _________

A

PKB and the MAP kinase pathway have one common outcome which is cell growth

51
Q

What is insulin resistance?

A

A reduced ability to respond to physiological insulin levels

52
Q

Insulin resistance is most associated with what?

A

Obesity

53
Q

What is “Leprechaunism”, or Donohue syndrome, what causes it and what developmental abnormalities may be present?

A

A condition involving severe insulin resistance

Caused by a rare autosomal recessive genetic trait and mutations in the insulin receptor gene

Developmental abnormalities:

  1. Elfin facial appearance
  2. Growth retardation
  3. Abscence of subcutaneous fat and decreased muscle mass
54
Q

What is Rabson-Mendenhall syndrome, what causes it and what developmental abnormalities may be present?

A

A condition involving severe insulin resistance, hyperglycaemia and compensatory hyperinsulinaemia

Caused by an autosomal recessive trait and mutations in the insulin receptor reducing sensitivity

Associated with fasting hypoglycaemia (due to hyperinsulinaemia) and diabetic ketoacidosis

Developmental abnormalities include:

  1. Abdominal distension with loss of subcutaneous fat
  2. Overcrowding of teeth and fissuring of the tongue
  3. Premature greying of the hair
  4. Acanthosis nigricans
  5. Clitoromegaly in females
55
Q

Where are ketone bodies formed?

A

Liver mitochondria

56
Q

What are ketone bodies dervied from?

A

Acetyl-CoA

(after beta oxidation)

57
Q

Ketone bodies are useful for what?

A

Energy metabolism within heart and renal cortex tissues

(converted back to acetyl-CoA)

58
Q

In which situations may ketone bodies be produced in excess?

A
  1. Starvation
  2. Diabetes
59
Q

Why are ketone bodies produced in excess in certain situations?

A
  1. Oxaloacetate is consumed for gluconeogenesis when no other energy source is present
  2. The TCA cycle cannot “run” as the intermediates have been used up
  3. Acetyl-CoA build up which causes a subsequent rise in ketone bodies (they are equilibrium)
60
Q

An accumulation of ketone bodies leads to what?

A

Acidosis

(coma and death eventually)

61
Q

What can exacerbate a ketoacidosis?

A

High glucose excretion

(results in dehydration increasing acidotic effect)

62
Q

Ketoacidosis is most associated with which condition under which circumstance?

A

Type 1 diabetes

When insulin is not injected and cells fail to receive glucose so fat breakdown occurs

63
Q

Why does ketoacidosis generally not occur with type 2 diabetes?

A
  1. There are high insulin concentrations
  2. This inhibits hormone-sensitive lipase
  3. This prevents tryglyceride breakdown into glycerol and free fatty acids