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Endocrine > Biochemistry of Insulin > Flashcards

Biochemistry of Insulin Flashcards

1
Q

what type of hormone is insulin?

A

anabolic peptide

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2
Q

describe the therapeutic window of insulin?

A

narrow

can be deadly if given at wrong time or wrong amounts

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3
Q

how can insulin cause death?

A

can induce a hypoglycaemic coma

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4
Q

what cells make insulin?

A

beta cells in islets in pancreas

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5
Q

what cells are present within pancreatic islets?

A

beta cells - secrete insulin
alpha - secrete glucagon
delta - secrete somatostatin
PP - secrete polypeptide

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6
Q

where is insulin synthesised in the cell?

A

rough ER

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7
Q

how is insulin formed?

A

preproinsulin cleaved to form insulin

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8
Q

describe the structure of insulin

A

2 polypeptide chains linked by disulphide bonds

connecting ā€œCā€ peptide which is a byproduct of cleavage but has no function

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9
Q

what are the types of insulin preparations available?

A 
ultra fast/ultra short-acting
short-acting
intermediate-acting
long-acting
ultra-long-acting
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10
Q

describe an ultra fast/ultra fast acting insulin and its use

A

insulin lispro
monomeric and not antigenic
rapid action
should be injected within 15 mins of beginning a meal and in combination with longer acting preparation for type 1 diabetes unless used for continuous infusion

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11
Q

describe an ultra-long acting insulin and its use

A

insulin glargine
recombinant insulin analog which precipitates in the neutral environment of subcutaneous tissue
peakless prolonged action
administered as single bed time dose

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12
Q

how is insulin secreted?

A

glucose enters beta cell through GLUT2 transporter via concentration gradient
glucose is phosphorylated by glucokinase
metabolism of glucose leads to an increase in intracellular ATP concentration (TCA cycle etc)
ATP inhibits the ATP sensitive K+ channel (KATP)
Inhibition of KATP leads to depolarisation of the cell membrane
depolarisation of the cell membrane results in opening of voltage gates Ca2+ channels
Ca2+ increase causes fusion of secretory vesicles with the cell membrane and release of insulin

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13
Q

which enzyme senses glucose and how is its activity controlled?

A

glucokinase

change in glucose concentration causes change in activity

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14
Q

how is glucokinase affected in diabetes?

A

the Km of glucokinase is within the normal range of blood glucose so if this goes outwith normal range (i.e diabetes), glucokinase activity with be reduced

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15
Q

when is insulin secretion stimulated in beta cells?

A

when blood glucose rises above normal level (5mM)

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16
Q

how are beta cells affected in diabetes?

A

type 1 = beta cells are lost (attacked by immune system)

other types = beta cells lose ability to sense changes in glucose (glucose conc outwith Km of glucokinase)

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17
Q

describe the pattern of insulin release

A

biphasic
1st phase = fast release of insulin granules in response to any increase in glucose, immediate and ready for release (5% of insulin store)
2nd phase = reserve pool, needs preparation to be released, occurs after 1st if glucose isnā€™t controlled by 1st phase

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18
Q

why are there 2 phases of insulin secretion and how is this affected in type 2 diabetes?

A

so you donā€™t use complete insulin store for every slight change in glucose
secretion flattens and weakens in T2DM due to downregulation of sensing process

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19
Q

how is insulin secretion regulated pharmacologically?

A

restore glucose to physiological level - should enhance insulin secretion
some drugs mimic action of the ATP to depolarise beta cells (e.g SURs)

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20
Q

what makes up the K ATP channel?

A

2 proteins
- inward rectifier (Kir) = pore subunit
- sulphonylurea (SUR) = regulatory subunit
channel exists as an octometric structure

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21
Q

what genes are responsible for the K ATP channel subunits?

A 
Kir = Kir6
SUR = SUR1
22
Q

how is K ATP regulated?

A

ATP inhibits by binding to the Kir subunit

Diazoxide stimulates by binding to SUR

23
Q

how do SURs work and when are they used?

A

same effect as ATP in inhibiting K ATP by binding to SUR subunit
second line therapy for type 2 diabetes - if cant inject insulin or have improved control and lessened stress on islets

24
Q

how can genes be involved in diabetes?

A

mutations in Kir6 and SUR1
Kir6 mutation = neonatal diabetes as constantly activates K ATP channels or increase in amount
Kir6 or SUR1 = congenital hyperinsulinism

25
Q

how is neonatal diabetes managed?

A

SURs

26
Q

how is congenital hyperinsulinism managed?

A

diazoxide can inhibit insulin secretion if channels are still getting to the membrane

27
Q

what is MODY?

A

maturity onset diabetes of the young
monogenic diabetes with genetic defect in Beta cell function
familial form of early onset type 2
defective glucose sensing in the pancreas and/or loss of insulin secretion

28
Q

what causes MODY?

A

primary defect in insulin secretion due to mutations in at least 6 different genes (glucokinase, transcription factors etc)

29
Q

how is glucokinase affected in MODY?

A

activity impaired

causes glucose sensing defect where blood glucose threshold for insulin secretion is increased

30
Q

how are HNF transcription factors involved in MODY?

A

play key roles in pancreas foetal development and neogenesis

regulate beta cell differentiation and function (GLUT2 expression, insulin secretion etc)

31
Q

how is MODY diagnosed and managed?

A

differentiated from type 1 via genetic screening

managed with SURs instead of insulin as patients usually have some beta cell function

32
Q

what is type 2 diabetes?

A

initially hyperglycaemia with hyperinsulinaemia so problem is reduced insulin sensitivity in tissues

33
Q

which biological processes does insulin switch on?

A 
amino acid uptake in muscle
DNA synthesis
protein synthesis
growth response
glucose uptake in muscle and fat
lipogenesis in fat and liver
glycogen synthesis in liver and muscle
34
Q

what biological processes does insulin switch off?

A

lipolysis

gluconeogenesis in the liver

35
Q

what does insulin regulate?

A

gene expression

36
Q

what type of receptor is the insulin receptor?

A

receptor kinase

type of tyrosine kinase

37
Q

what happens when insulin binds to its receptor?

A

binds to alpha subunit causing beta subunits to dimerise and phosphorylate themselves, activating the catalytic activity of the receptor

38
Q

what commonly causes insulin resistance?

A

due to reduced insulin sensing and/or signalling
usually due to obesity but can be due to a complete lack of adipose tissue
type 2 = polygenic (obesity and insulin resistance)
mutation in signalling pathways (e.g MODY)

39
Q

name a genetic mutation which can cause severe insulin resistance

A

AKT2 mutation

40
Q

what is leprechaunism?

A

autosomal recessive genetic disorder of severe insulin resistance due to mutation in gene for insulin receptor
causes defects in insulin binding or insulin receptor signalling

41
Q

what are the features of leprechaunism?

A 
elfin facial appearance
growth retardation
absence of subcutaneous fat
decreased muscle mass
short stature
42
Q

what is Rabson Mendenhall syndrome?

A

autosomal recessive genetic condition of severe insulin resistance, hyperglycaemia and compensatory hyperinsulinaemia
some cases linked to insulin receptor mutation

43
Q

what are the features of Rabson Mendenhall syndrome?

A

developmental abnormalities
acanthosis nigricans (hyperpigmentation)
fasting hypoglycaemia due to hyperinsulinaemia
DKA more common

44
Q

what are the symptoms of diabetic ketoacidosis (DKA)?

A

vomiting
dehydration
increased heart rate
acetone smell on breath

45
Q

what is the function of ketone bodies?

A

diffuse into bloodstream and to peripheral tissues
important molecules of energy metabolism for heart muscle and renal cortex, then converted back to acetyl CoA which enters the TCA cycle

46
Q

where are ketone bodies formed?

A

in liver mitochondria

derived from acetyl CoA from beta oxidation of fats

47
Q

how are ketones affected by diabetes?

A

low levels of insulin inhibits lipolysis and prevents ketone body overload
DKA can occur in type 1 if insulin is missed

48
Q

why is DKA rare in type 2?

A

as there is still inhibition of lipolysis as insulin is being produced
can still occur as insulin resistance and deficiency increases alongside glucagon increase

49
Q

how are ketones formed?

A

carbohydrates and fatty acids act as fuel for TCA
carbohydrates form pyruvate which forms acetyl CoA
fatty acids are oxidised to also form acetyl CoA
acetyl CoA enters TCA which eventually forms oxaloacetate which recombines with acetyl CoA to restart TCA
if oxaloacetate is limited (e.g no glycolysis occurring) then the acetyl CoA is diverted to form ketones

50
Q

how do glucose limiting conditions (diabetes, starvation) cause DKA?

A

if glucose unavailable, fatty acids are oxidised to provide energy and excess acetyl CoA converted to ketone bodies
blood levels of ketones increases
accumulation of ketones leads to acidosis
high glucose excretion causes dehydration and exacerbates acidosis
leads to coma and possibly death

51
Q

how is DKA treated?

A

insulin and rehydration

52
Q

which diabetes type is autoimmune?

A

type 1

Endocrine (45 decks)

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