Biochemistry of Insulin

Question 1

what type of hormone is insulin?

Answer 1

anabolic peptide

Question 2

describe the therapeutic window of insulin?

Answer 2

narrow

can be deadly if given at wrong time or wrong amounts

Question 3

how can insulin cause death?

Answer 3

can induce a hypoglycaemic coma

Question 4

what cells make insulin?

Answer 4

beta cells in islets in pancreas

Question 5

what cells are present within pancreatic islets?

Answer 5

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

Question 6

where is insulin synthesised in the cell?

Answer 6

rough ER

Question 7

how is insulin formed?

Answer 7

preproinsulin cleaved to form insulin

Question 8

describe the structure of insulin

Answer 8

2 polypeptide chains linked by disulphide bonds

connecting “C” peptide which is a byproduct of cleavage but has no function

Question 9

what are the types of insulin preparations available?

Answer 9

ultra fast/ultra short-acting
short-acting
intermediate-acting
long-acting
ultra-long-acting

Question 10

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

Answer 10

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

Question 11

describe an ultra-long acting insulin and its use

Answer 11

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

Question 12

how is insulin secreted?

Answer 12

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

Question 13

which enzyme senses glucose and how is its activity controlled?

Answer 13

glucokinase

change in glucose concentration causes change in activity

Question 14

how is glucokinase affected in diabetes?

Answer 14

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

Question 15

when is insulin secretion stimulated in beta cells?

Answer 15

when blood glucose rises above normal level (5mM)

Question 16

how are beta cells affected in diabetes?

Answer 16

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)

Question 17

describe the pattern of insulin release

Answer 17

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 isn’t controlled by 1st phase

Question 18

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

Answer 18

so you don’t use complete insulin store for every slight change in glucose
secretion flattens and weakens in T2DM due to downregulation of sensing process

Question 19

how is insulin secretion regulated pharmacologically?

Answer 19

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

Question 20

what makes up the K ATP channel?

Answer 20

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

Question 21

what genes are responsible for the K ATP channel subunits?

Answer 21

Kir = Kir6
SUR = SUR1

Question 22

how is K ATP regulated?

Answer 22

ATP inhibits by binding to the Kir subunit

Diazoxide stimulates by binding to SUR

Question 23

how do SURs work and when are they used?

Answer 23

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

Question 24

how can genes be involved in diabetes?

Answer 24

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

Question 25

how is neonatal diabetes managed?

Answer 25

SURs

Question 26

how is congenital hyperinsulinism managed?

Answer 26

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

Question 27

what is MODY?

Answer 27

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

Question 28

what causes MODY?

Answer 28

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

Question 29

how is glucokinase affected in MODY?

Answer 29

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

Question 30

how are HNF transcription factors involved in MODY?

Answer 30

play key roles in pancreas foetal development and neogenesis | regulate beta cell differentiation and function (GLUT2 expression, insulin secretion etc)

Question 31

how is MODY diagnosed and managed?

Answer 31

differentiated from type 1 via genetic screening | managed with SURs instead of insulin as patients usually have some beta cell function

Question 32

what is type 2 diabetes?

Answer 32

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

Question 33

which biological processes does insulin switch on?

Answer 33

``` 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 ```

Question 34

what biological processes does insulin switch off?

Answer 34

lipolysis | gluconeogenesis in the liver

Question 35

what does insulin regulate?

Answer 35

gene expression

Question 36

what type of receptor is the insulin receptor?

Answer 36

receptor kinase | type of tyrosine kinase

Question 37

what happens when insulin binds to its receptor?

Answer 37

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

Question 38

what commonly causes insulin resistance?

Answer 38

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)

Question 39

name a genetic mutation which can cause severe insulin resistance

Answer 39

AKT2 mutation

Question 40

what is leprechaunism?

Answer 40

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

Question 41

what are the features of leprechaunism?

Answer 41

``` elfin facial appearance growth retardation absence of subcutaneous fat decreased muscle mass short stature ```

Question 42

what is Rabson Mendenhall syndrome?

Answer 42

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

Question 43

what are the features of Rabson Mendenhall syndrome?

Answer 43

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

Question 44

what are the symptoms of diabetic ketoacidosis (DKA)?

Answer 44

vomiting dehydration increased heart rate acetone smell on breath

Question 45

what is the function of ketone bodies?

Answer 45

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

Question 46

where are ketone bodies formed?

Answer 46

in liver mitochondria | derived from acetyl CoA from beta oxidation of fats

Question 47

how are ketones affected by diabetes?

Answer 47

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

Question 48

why is DKA rare in type 2?

Answer 48

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

Question 49

how are ketones formed?

Answer 49

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

Question 50

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

Answer 50

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

Question 51

how is DKA treated?

Answer 51

insulin and rehydration

Question 52

which diabetes type is autoimmune?

Answer 52

type 1