Biochemistry of glucose and insulin Flashcards
1
Q
What happens at <5mM blood glucose?
A
Pancreatic alpha cells release glucagon
2
Q
What happens at >5mM of blood glucose?
A
- Pancreatic beta cells release insulin
- Hepatic glucose output is inhibited
3
Q
What are the cells of the pancreatic islets?
A
- beta cells
- alpha cells
- delta cells
- PP cells
4
Q
What do beta cells secrete?
A
Insulin
5
Q
What do alpha cells secrete?
A
glucagon
6
Q
What do delta cells secrete?
A
Somatostatin
7
Q
What do PP cells secrete?
A
Pancreatic peptide
8
Q
What pancreatic secretions are involved in the regulation of exocrine function?
A
Somatostatin and pancreatic peptide
9
Q
In the synthesis of insulin, what is the first structure?
A
Preproinsulin
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
11
Q
Describe the structure of insulin
A
Two polypeptide chains linked together by disulphide bonds
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
13
Q
Name a ultra fast/ultra short acting insulin
A
Lispo (HUMALOG)
14
Q
Name a short acting insulin
A
Regular insulin
15
Q
Name the intermediate acting insulins
A
NPH (isophane) and lente
16
Q
Which works more quickly, NPH (isophane) or lente?
A
NPH
17
Q
Name a long acting insulin
A
Ultralente
18
Q
Name an ultra long acting insulin
A
Glargine
19
Q
In lispo, where does lysine occur?
A
B28
20
Q
In lispo, where does proline occur?
A
B29
21
Q
Is lispo (humalog) a monomer or polymer?
A
Monomer
22
Q
True or false
Lispo (humalog) is antigenic
A
FALSE
It is NOT antigenic
23
Q
When should lispo (humalog) be injected?
A
Within 15 minutes of beginning a meal
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
25
Describe glargine
Recombinant insulin analog that precipitates in the neutral environment of subcutaneous tissue
26
Does glargine have peaks in its action?
No it is peakless
It has a prolonged action
27
How is glargine administered?
As a single dose at bedtime
28
How does the structure of glargine differ from lispo (humalog)?
* Two arginines are added to chain
* Glycene added instead of asparagine at 21
29
How does glucose enter beta cells?
Through the GLUT2 glucose transporter
30
After the glucose enters the beta cells, what happens?
It is phosphorylated by glucokinase
31
Where does glucokinase's Km for glucose lie and what does this mean?
The physiological range of concentrations
A change of glucose concentration leads to a dramatic change in glucokinase activity
32
What does an increase in the metabolism of glucose lead to in the cell?
An increase in intracellular ATP concentration
33
In the cell, what does ATP inhibit and what does this lead to?
Inhibits the ATP-sensitive K+ channel (KATP)
This causes depolarisation of the cell membrane
34
What does the depolarisation of the cell membrane cause in the secretion of insulin?
Voltage-gated calcium ion channels open, causing the internal calium ion concentration to increase
35
What does an increase in intracellular calcium ion cause?
Fusion of secretory vesicles with the cell membrane and INSULIN IS RELEASED
36
What does fusio of secretory vesicles with the cell membrane cause in the secretion of insulin pathway?
The secretion of insulin!!
37
Why does depolarisation of the cell membrane occur in the secretion of insulin pathway?
The inhibition of KATP causes a build up of potassium ions. This depolarises the cell membrane
38
How many phases are there of insulin release?
2
39
Explain why insulin release is biphasic
* 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
40
How many proteins do KATP channels consist of and what are they?
2
KIR6 and SUR1
41
What is the inward rectifier subunit in KATP?
KIR6
42
What is KIR 6?
KATP pore subunit
43
What is SUR1 in KATP?
Regulatory subunit
44
What type of structure is a KATP channel?
Octometric structure
45
What directly inhibits KATP?
The sulphonylurea class of drugs e.g. tolbutamide and glibenclamide
46
What is KATP stimulated by?
Diazoxide
47
What does stimulation of KATP cause?
Inhibition in insulin secretion
48
What can mutations in KIR6 cause?
Neonatal diabetes
49
How can KIR6 mutations lead to neonatal diabetes?
* Activated KATP channels or increased KATP numbers
* beta cells secrete insulin in response to tolbutamide
50
What can some KIR6 and SUR1 mutations lead to?
Congenital hyperinsulinism
51
What does MODY stand for?
maturity onset diabetes of the young
52
Define MODY
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
How can a mutation in glucokinase lead to MODY?
* 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
What play key roles in pancreas foetal development and neogenesis and can cause MODY?
Hepatocyte nuclear factor 4a and hepatocyte nuclear factor 1a
55
What is the role of HNF-4a and HNF-1a?
regulate beta cell differentiation and function
56
Name the transcription factors that can cause MODY
* HNF-4a
* HNF-1a
* IPF1 (insulin promotor factor 1)
* HNF - 1b
* neuro D1 (neurogenic differentiation factor 1)
57
What does robust genetic screening to differentiate between type I and MODY allow and why is this important?
MODy patients to be treated with sulphonylureas instead of insulin
MODY patients usually have some beta cell function)
58
Is insulin an anabolic or catabolic hormone?
Anabolic
59
What are the biological effects of insulin when it is secereted (switched 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 liver and muscle
60
What are the biological effects of insulin being suppressed (switched off)?
* Lipolysis
* Gluconeogenesis
61
What are the three parts of a signalling cascade?
1. Reception
2. Transduction
3. Response
62
In a signalling cascade, where does reception occur?
At the cell membrane
63
In a signalling cascade, where do transduction and response occur?
Cytoplasm
64
What does protein phosphorylation do?
Provides a reversible method for altering protein function
65
What has been found to happen to transgenic mice with inactive KATP channels?
Hyperinsulinaemic
66
How are proteins phosphorylated?
Phosphorylated by ATP catalysed by protein kinase
67
What enzyme catalyses the reaction from a phosphorylated protein back to a protein?
Phosphatase
68
Where can proteins get phosphorylated?
On any hydroxyl group
69
True or false
Phosphorylation causes a large negative charge onto the protein structure
True
70
What is the receptor for insulin?
Dimetric tyrosine kinase
71
Describe the composition of dimetric tyrosine kinase
* 2 extracellular alpha subunits with insulin binding domains
* 2 transmembrane beta subunits
* linked by disulphide bonds
72
How is the catalytic activity of dimetric tyrosine kinase activated?
Binding of insulin to the alpha subunit causes the beta subunits to phosphorylate themselves (autophosphorylation)
73
Where does insulin bind to?
Alpha units of tyrosine kinase
74
What happens after the beta units on tyrosine kinase are autophosphorylated in the insulin signalling pathway?
Insulin receptor subunits (IRS1) are phosphorylated
75
What does phosphorylated IRS1 do?
Activate Ras/MAP Kinase pathway and PI3K pathways
76
Describe Ras/MAPK pathway
Ras --\> MAP Kinase pathway --\> Gene expression
77
Describe the PI3K pathway
PI3K --\> PKB --\> glycogen synthesis
78
What does PKB stimulate?
GLUT 4 translocation
79
What occurs after GLUT4 translocation in the insulin signalling pathways?
Glucose is taken up and cell growth is stimulated
80
Describe the 7 stages of the insulin signalling pathway
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
What does near complete absence of adipose tissue result in?
Insulin resistance
82
Is type 2 diabetes thought to be polygenic or monogenic?
Polygenic with a large input from environmental factors
83
A family with severe insulin resistance and diabetes may be due to a mutation in what gene?
AKT2
84
What type of disorder is Donohue syndrome (Leprechaunism) in terms of genetics?
Rare autosommal recessive
85
What is Donohue syndrome caused by?
Mutations in the gene for insulin receptor
Causes severe insulin resistance, defects in insulin binding or insulin receptor signalling
86
What are the symptoms of Donohue syndrome?
* Elfin facial appearance
* Growth retardation
* Absence of subcutaneous fat with decreased muscle mass
87
What is Rabson Mendenhall syndrome in terms of genetics?
Rare autosomal recessive disorder
88
What are the signs and symptoms of Rabson Mendenhall syndrome?
* Severe insulin resistance
* Hyperglycaemia with compensatory hyperinsulinaemia
* Acanthosis nigericans (hyperpigmentation)
* DKA
89
What may obesity linked insulin resistance be due to?
Reduced insulin signalling
90
What have severe cases of Rabson Mendenhall syndrome been linked to?
Mutations in the insulin receptor that decrease sensitivity
91
Where are ketone bodies formed?
Mitochondria of the liver
92
Where are ketone bodies derived from?
Acetyl CoA from beta oxidation
93
What are ketone bodies an important molecule of?
Energy metabolism for heart muscle and renal cortex
94
Describe the kreb cycle
* Carbohydrate --\> pyruvate ---\> oxaloactetate
* Citrate
* alpha-keto-glutarate
* Succinyl CoA
* Fumarate (then back to oxaloacetate
95
What enters the kreb cycle if fat and carbohydrate degradation are balanced?
Acetyl-CoA (from oxidation of fatty acids)
96
When glucose is not readily available, what is oxidised to produce energy?
Fatty acids
97
If there is excess acetyl-CoA due to the increased oxidation of fatty acids, what happens?
The excess acetyl-CoA is converted into ketone bodies causing the blood ketone concentration to increase
98
What does an accumulation of ketones in the blood cause?
Acidosis
99
How does increased glucose excretion exacerbate acidosis?
Dehydrates the patient, increasing the acid concentration therefore increasing acidosis
100
What type of diabetes is DKA associated with?
Type I
101
What happens in type I diabetes when insulin is not injected?
The cells fail to recieve enough glucose and switch to fat breakdown. This can cause DKA
102
Why is DKA not normally seen in type 2 diabetes?
The increased concentration of insulin in type 2 inhibits the hormone-sensitive enzyme, lipase
103
What is the function of lipase?
An enzyme that breaks down stored triglycerides into glycerol and free fatty acids.
104
How does lipase relate to type 2 diabetes?
As it is inhibited there is no excessive breakdown of fat resources. This is why DKA does not occur in type 2 diabetes
