Biochemistry of Insulin

Question 1

pancreatic islets

Answer 1

also called islet of langerhans

found throughout the pancreas

Question 2

what do the B, a, gamma and PP cells do in pancreatic islet

Answer 2

B - secrete insulin

a - secrete glucagon

gamma - secrete somatostatin

PP - secrete pancreatic polypeptide

Question 3

synthesis of insulin

Answer 3

syntehsised in the RER of pancreatic B cell, as a larger single chain preprohormone, called preproinsulin

cleaved to form insulin, which contains two polypeptide chains linked by disulphide bonds

there is a connecting C peptide, which is a byproduct of cleavage and has no known physiological function

Question 4

use of insulin lispro

Answer 4

ultra fast/short acting

used to allow blood glucose control during meal - injected within 15 min of beginning meal

must be used in combination with longer acting preparations unless used in continuous infusion

Question 5

what sructural change has occured in inuslin Lispro

Answer 5

lysine and proline amino acids have been switched

Question 6

insulin glargine

Answer 6

recombinant insulin analogue that has a peakless prolonged action

used to maintain blood glucose over night - single dose before bedtime

Question 7

how does glucose enter the B cells

Answer 7

through GLUT2 glucose transported by diffusion

Question 8

describe the secretion of insulin

Answer 8

glucose enters B cell through GLUT2 (diffusion) and is phosphorylated by glucokinase

inc metabolism of glucose leads to an increase in intracellular ATP concentration

ATP inhibits K channel K_ATP - leads to depolarisation of the cell and opening of voltage gated Ca²⁺ channels

increase in internal Ca²⁺ concentation leads to release of insulin

Question 9

glucokinase activity

Answer 9

glucokinase’s K_M for glucose lies in the physiological range of glucose concentration

(in hyperglycaemia glucose conc outwith K_M of glucokinase and B cells lose ability to sense changes in glucose)

Question 10

how many ATP does one molecule of glucose produce

Answer 10

36

Question 11

carbohydrate metabolism

Answer 11

Question 12

what can be used as a marker of B cells

Answer 12

insulin - these are the only cells that make and secrete insulin

Question 13

at what blood glucose level should insulin be made and secreted at

Answer 13

>5mM

Question 14

describe the pattern of insulin release

Answer 14

biphasic

• 5% insulin granules are immediately available for release - the RRP (readily releasable pool)
• reserve pool must be prepared before it is mobilised and released

Question 15

what is insulin secretion like in poorly controllled T2DM

Answer 15

weaknes and flattens - down regulation of sensing process due to limited glucokinase acitivty

Question 16

sulphonylurea drug action

Answer 16

mimic the action of ATP on K_ATP channel to depolarise the B cell and stimulate Ca channel opening and thus insulin release

Question 17

K_ATP channel

Answer 17

consists of 2 proteins: pore subunit (Kir6) and regulatory subunit (SUR1)

both are required to form a functional channel

channel is an octomeric structure

Question 18

what drug inhibits insulin secretion

Answer 18

diazoxide - stimulates K_ATP

Question 19

why are sulphonylurea drugs second line therapy for T2DM

Answer 19

B cells are already under a lot of stress - pharmacologically inducing them to work harder would be counterintuitive

useful in patients who have trouble injecting insulin or when glucose control has been improved and the stress on the B cells lessened

Question 20

mutations in Kir6

Answer 20

can lead to neonatal diabetes

either due to constitutively activated K_ATP channels or an increase in K_ATP numbers = insulin not produced and an increase in blood glucose

in some of these patients the B cells are responsive to SURs

Question 21

what can some Kir6 or SUR1 mutations lead to

Answer 21

hyperinsulinism

• diazoxide can inhibit insulin secretion

Question 22

MODY

Answer 22

monogenic - genetic defect in B cell function

familial form early onset type 2 diabetes

Question 23

what mutations cause MODY

Answer 23

can be caused by AuD mutations in at least 6 different genes on glucokinase or on several transcription factors

Question 24

what mutation is MODY2 due to

Answer 24

mutations on glucokinase - impaired glucokinase activity, meaning it is less responsive to rising levels of glucose

Question 25

HNF transcription factors

Answer 25

play key roles in pancreas foetal development and neogenesis

also regulate B cell differentiation and function

Question 26

what is MODY treated with

Answer 26

SURs rather than insulin as there is usually still some B cell function

Question 27

what type of hormone is insulin

Answer 27

anabolic

Question 28

insulin receptor binding

Answer 28

binds to tyrosine kinase receptor a subunit - causing the B subunit to dimerise and autophosphorylate, thus activating the catalytic activity of the receptor

• PI3K - PKB - glycogen synthesis
• Ras - MAPK pathway - gene expression

both result in cell growth

Question 29

define insulin resistance

Answer 29

cell sensitivity to insulin has changed (rather than resistance)

Question 30

does adipose functionality mediate insulin sensivity

Answer 30

yes - it is a key mediator

near complete absence of adipose results in insulin resistance

Question 31

leprechaunism

Answer 31

Donohue Syndrome

rare AuR trait that is characterised by mutations in the gene for insulin receptor - defects in insulin binding or receptor signalling

results in severe insulin resistance

developmental abnormalities: elfin facial appearnace, growth retardation, absence of subcutaenous fat, dec muscle mass

Question 32

Rabson Medenhall Syndrome

Answer 32

rare AuR trait that is characterised by severe insulin resistance, hyperglycaemia and compensatory hyperinsulinaemia

developmental abnormalities, and acanthosis nigricans

Due to the hyperinsulinaemia there is fasting hypoglycaemia and diabetic ketoacidosis

Question 33

symptoms of diabetic ketoacidosis

Answer 33

vomiting, dehydration, inc HR and distinctive smell on breath

Question 34

diabetic ketoacidosis

Answer 34

results from a shortage of insulin, in which the body starts burning fats producing ketone bodies

Question 35

ketone bodies

Answer 35

found in the liver mitochondria

derived from acetyl CoA, which is from B oxidation of fatty acids

diffuse into the blood stream and peripheral tissues

important molecules of energy metabolism for heart muscle and renal cortex as they can be converted back to acetyl CoA, which enters the TCA cycle

Question 36

ketone body formation

Answer 36

if fat and carbohydrate degradation are balanced, fatty acid oxiation yields acetyl CoA which enters the TCA cycle

in glucose limiting conditions (eg starvation and diabetes), oxaloacetate is not available for the conversion of acetyl CoA to citric acid - therefore ketone body formation occurs

FFA are released from adipose tissue (lipolysis) and are converted to ketone bodies by B oxidation

Question 37

what can accumulation of lots of ketone bodies lead to

Answer 37

acidosis

Question 38

what effect does low levels of insulin have on glucagon level

Answer 38

elevation of glucagon level - increased release of glucose by the liver

high glucose excretion leads to polyuria, dehydration and polydipsia

this exacerbates the acidosis

Question 39

treatment of diabetic ketoacidosis

Answer 39

insulin and rehydration

Question 40

what can DK lead to

Answer 40

coma and death

Question 41

what type of diabetes is DKA a danger in

Answer 41

type 1 DM if insulin supplementation is missed

more rare in T2DM, as there is still inhibition of lipolysis, but can occur as insulin resistance and deficiency increases