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Y2 Endocrine > Biochemistry of glucose and insulin > Flashcards

Biochemistry of glucose and insulin Flashcards

1
Q

What happens at <5mM blood glucose?

A

Pancreatic alpha cells release glucagon

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2
Q

What happens at >5mM of blood glucose?

A
  • Pancreatic beta cells release insulin
  • Hepatic glucose output is inhibited
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3
Q

What are the cells of the pancreatic islets?

A
  • beta cells
  • alpha cells
  • delta cells
  • PP cells
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4
Q

What do beta cells secrete?

A

Insulin

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5
Q

What do alpha cells secrete?

A

glucagon

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6
Q

What do delta cells secrete?

A

Somatostatin

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7
Q

What do PP cells secrete?

A

Pancreatic peptide

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8
Q

What pancreatic secretions are involved in the regulation of exocrine function?

A

Somatostatin and pancreatic peptide

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9
Q

In the synthesis of insulin, what is the first structure?

A

Preproinsulin

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10
Q

Describe how insulin is synthesised

A
  • preproinsulin (long, single chain) is cleaved in the RER of pancreatic beta cells
  • Preproinsulin is cleaved to form proinsulin and a single peptide
  • Proinsulin is cleaved again to form C-peptide and insulin
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11
Q

Describe the structure of insulin

A

Two polypeptide chains linked together by disulphide bonds

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12
Q

What is the physiological function of connecting (C) peptide?

A

It is a biproduct of cleavage but there is NO known physiological function

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13
Q

Name a ultra fast/ultra short acting insulin

A

Lispo (HUMALOG)

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14
Q

Name a short acting insulin

A

Regular insulin

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15
Q

Name the intermediate acting insulins

A

NPH (isophane) and lente

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16
Q

Which works more quickly, NPH (isophane) or lente?

A

NPH

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17
Q

Name a long acting insulin

A

Ultralente

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18
Q

Name an ultra long acting insulin

A

Glargine

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19
Q

In lispo, where does lysine occur?

A

B28

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20
Q

In lispo, where does proline occur?

A

B29

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21
Q

Is lispo (humalog) a monomer or polymer?

A

Monomer

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22
Q

True or false

Lispo (humalog) is antigenic

A

FALSE

It is NOT antigenic

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23
Q

When should lispo (humalog) be injected?

A

Within 15 minutes of beginning a meal

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24
Q

Lispo (humalog) has a short duration of action. What does this mean in terms of how it is used?

A

It must be used in combination with a longer-acting preparation for type I diabetes, unless it is used for continuous infusion

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25
Q

Describe glargine

A

Recombinant insulin analog that precipitates in the neutral environment of subcutaneous tissue

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26
Q

Does glargine have peaks in its action?

A

No it is peakless

It has a prolonged action

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27
Q

How is glargine administered?

A

As a single dose at bedtime

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28
Q

How does the structure of glargine differ from lispo (humalog)?

A
  • Two arginines are added to chain
  • Glycene added instead of asparagine at 21
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29
Q

How does glucose enter beta cells?

A

Through the GLUT2 glucose transporter

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30
Q

After the glucose enters the beta cells, what happens?

A

It is phosphorylated by glucokinase

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31
Q

Where does glucokinase’s Km for glucose lie and what does this mean?

A

The physiological range of concentrations

A change of glucose concentration leads to a dramatic change in glucokinase activity

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32
Q

What does an increase in the metabolism of glucose lead to in the cell?

A

An increase in intracellular ATP concentration

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33
Q

In the cell, what does ATP inhibit and what does this lead to?

A

Inhibits the ATP-sensitive K+ channel (KATP)

This causes depolarisation of the cell membrane

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34
Q

What does the depolarisation of the cell membrane cause in the secretion of insulin?

A

Voltage-gated calcium ion channels open, causing the internal calium ion concentration to increase

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35
Q

What does an increase in intracellular calcium ion cause?

A

Fusion of secretory vesicles with the cell membrane and INSULIN IS RELEASED

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36
Q

What does fusio of secretory vesicles with the cell membrane cause in the secretion of insulin pathway?

A

The secretion of insulin!!

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37
Q

Why does depolarisation of the cell membrane occur in the secretion of insulin pathway?

A

The inhibition of KATP causes a build up of potassium ions. This depolarises the cell membrane

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38
Q

How many phases are there of insulin release?

A

2

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39
Q

Explain why insulin release is biphasic

A
  • 5% of insulin granules are immediately available for release
    • RRP (readily releasable pool)
  • Reserve pool must undergo preparatory reactions to become mobilised and available for release
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40
Q

How many proteins do KATP channels consist of and what are they?

A

2

KIR6 and SUR1

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41
Q

What is the inward rectifier subunit in KATP?

A

KIR6

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42
Q

What is KIR 6?

A

KATP pore subunit

43
Q

What is SUR1 in KATP?

A

Regulatory subunit

44
Q

What type of structure is a KATP channel?

A

Octometric structure

45
Q

What directly inhibits KATP?

A

The sulphonylurea class of drugs e.g. tolbutamide and glibenclamide

46
Q

What is KATP stimulated by?

A

Diazoxide

47
Q

What does stimulation of KATP cause?

A

Inhibition in insulin secretion

48
Q

What can mutations in KIR6 cause?

A

Neonatal diabetes

49
Q

How can KIR6 mutations lead to neonatal diabetes?

A
  • Activated KATP channels or increased KATP numbers
  • beta cells secrete insulin in response to tolbutamide
50
Q

What can some KIR6 and SUR1 mutations lead to?

A

Congenital hyperinsulinism

51
Q

What does MODY stand for?

A

maturity onset diabetes of the young

52
Q

Define MODY

A

A familial form of early onset type II diabetes (monogenic diabetes with genetic defect in beta cell function) with primary defects in beta cell function and as such insulin secretion

53
Q

How can a mutation in glucokinase lead to MODY?

A
  • Activity of glucokinase is impaired
  • Glucose sensing defect - blood glucose threshold for insulin secretion increases (the lood glucose levels need to get much higher before insulin is released)
54
Q

What play key roles in pancreas foetal development and neogenesis and can cause MODY?

A

Hepatocyte nuclear factor 4a and hepatocyte nuclear factor 1a

55
Q

What is the role of HNF-4a and HNF-1a?

A

regulate beta cell differentiation and function

56
Q

Name the transcription factors that can cause MODY

A
  • HNF-4a
  • HNF-1a
  • IPF1 (insulin promotor factor 1)
  • HNF - 1b
  • neuro D1 (neurogenic differentiation factor 1)
57
Q

What does robust genetic screening to differentiate between type I and MODY allow and why is this important?

A

MODy patients to be treated with sulphonylureas instead of insulin

MODY patients usually have some beta cell function)

58
Q

Is insulin an anabolic or catabolic hormone?

A

Anabolic

59
Q

What are the biological effects of insulin when it is secereted (switched on)?

A
  • 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 liver and muscle
60
Q

What are the biological effects of insulin being suppressed (switched off)?

A
  • Lipolysis
  • Gluconeogenesis
61
Q

What are the three parts of a signalling cascade?

A
  1. Reception
  2. Transduction
  3. Response
62
Q

In a signalling cascade, where does reception occur?

A

At the cell membrane

63
Q

In a signalling cascade, where do transduction and response occur?

A

Cytoplasm

64
Q

What does protein phosphorylation do?

A

Provides a reversible method for altering protein function

65
Q

What has been found to happen to transgenic mice with inactive KATP channels?

A

Hyperinsulinaemic

66
Q

How are proteins phosphorylated?

A

Phosphorylated by ATP catalysed by protein kinase

67
Q

What enzyme catalyses the reaction from a phosphorylated protein back to a protein?

A

Phosphatase

68
Q

Where can proteins get phosphorylated?

A

On any hydroxyl group

69
Q

True or false

Phosphorylation causes a large negative charge onto the protein structure

A

True

70
Q

What is the receptor for insulin?

A

Dimetric tyrosine kinase

71
Q

Describe the composition of dimetric tyrosine kinase

A
  • 2 extracellular alpha subunits with insulin binding domains
  • 2 transmembrane beta subunits
  • linked by disulphide bonds
72
Q

How is the catalytic activity of dimetric tyrosine kinase activated?

A

Binding of insulin to the alpha subunit causes the beta subunits to phosphorylate themselves (autophosphorylation)

73
Q

Where does insulin bind to?

A

Alpha units of tyrosine kinase

74
Q

What happens after the beta units on tyrosine kinase are autophosphorylated in the insulin signalling pathway?

A

Insulin receptor subunits (IRS1) are phosphorylated

75
Q

What does phosphorylated IRS1 do?

A

Activate Ras/MAP Kinase pathway and PI3K pathways

76
Q

Describe Ras/MAPK pathway

A

Ras –> MAP Kinase pathway –> Gene expression

77
Q

Describe the PI3K pathway

A

PI3K –> PKB –> glycogen synthesis

78
Q

What does PKB stimulate?

A

GLUT 4 translocation

79
Q

What occurs after GLUT4 translocation in the insulin signalling pathways?

A

Glucose is taken up and cell growth is stimulated

80
Q

Describe the 7 stages of the insulin signalling pathway

A
  1. Insulin binds to alpha subunits
  2. Beta subunits are autophosphorylated
  3. Insuli receptor subunits (IRS) are phosphorylated
  4. IRS activate the Ras/MAPK pathway and gene expression
  5. IRS activate PI3K, PKB and glycogen synthesis
  6. PKB stimulates GLUT4 translocation
  7. Glucose is taken up and cell growth is stimulated
81
Q

What does near complete absence of adipose tissue result in?

A

Insulin resistance

82
Q

Is type 2 diabetes thought to be polygenic or monogenic?

A

Polygenic with a large input from environmental factors

83
Q

A family with severe insulin resistance and diabetes may be due to a mutation in what gene?

A

AKT2

84
Q

What type of disorder is Donohue syndrome (Leprechaunism) in terms of genetics?

A

Rare autosommal recessive

85
Q

What is Donohue syndrome caused by?

A

Mutations in the gene for insulin receptor

Causes severe insulin resistance, defects in insulin binding or insulin receptor signalling

86
Q

What are the symptoms of Donohue syndrome?

A
  • Elfin facial appearance
  • Growth retardation
  • Absence of subcutaneous fat with decreased muscle mass
87
Q

What is Rabson Mendenhall syndrome in terms of genetics?

A

Rare autosomal recessive disorder

88
Q

What are the signs and symptoms of Rabson Mendenhall syndrome?

A
  • Severe insulin resistance
  • Hyperglycaemia with compensatory hyperinsulinaemia
  • Acanthosis nigericans (hyperpigmentation)
  • DKA
89
Q

What may obesity linked insulin resistance be due to?

A

Reduced insulin signalling

90
Q

What have severe cases of Rabson Mendenhall syndrome been linked to?

A

Mutations in the insulin receptor that decrease sensitivity

91
Q

Where are ketone bodies formed?

A

Mitochondria of the liver

92
Q

Where are ketone bodies derived from?

A

Acetyl CoA from beta oxidation

93
Q

What are ketone bodies an important molecule of?

A

Energy metabolism for heart muscle and renal cortex

94
Q

Describe the kreb cycle

A
  • Carbohydrate –> pyruvate —> oxaloactetate
  • Citrate
  • alpha-keto-glutarate
  • Succinyl CoA
  • Fumarate (then back to oxaloacetate
95
Q

What enters the kreb cycle if fat and carbohydrate degradation are balanced?

A

Acetyl-CoA (from oxidation of fatty acids)

96
Q

When glucose is not readily available, what is oxidised to produce energy?

A

Fatty acids

97
Q

If there is excess acetyl-CoA due to the increased oxidation of fatty acids, what happens?

A

The excess acetyl-CoA is converted into ketone bodies causing the blood ketone concentration to increase

98
Q

What does an accumulation of ketones in the blood cause?

A

Acidosis

99
Q

How does increased glucose excretion exacerbate acidosis?

A

Dehydrates the patient, increasing the acid concentration therefore increasing acidosis

100
Q

What type of diabetes is DKA associated with?

A

Type I

101
Q

What happens in type I diabetes when insulin is not injected?

A

The cells fail to recieve enough glucose and switch to fat breakdown. This can cause DKA

102
Q

Why is DKA not normally seen in type 2 diabetes?

A

The increased concentration of insulin in type 2 inhibits the hormone-sensitive enzyme, lipase

103
Q

What is the function of lipase?

A

An enzyme that breaks down stored triglycerides into glycerol and free fatty acids.

104
Q

How does lipase relate to type 2 diabetes?

A

As it is inhibited there is no excessive breakdown of fat resources. This is why DKA does not occur in type 2 diabetes

Y2 Endocrine (6 decks)

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