Diabetes and Drug Targets

Question 1

what is gestational diabetes

Answer 1

pregnant women whom have not been previously diagnosed with diabetes exhibit high levels of blood glucose sugar

Question 2

what is the cause of gestational diabetes

Answer 2

occurs in the third trimester due to changes in renal absorbtion

Question 3

what do alpha/beta cells in the ilses of Langerhan release

Answer 3

beta - insulin
alpha - glucagon

Question 4

what is a unique feature of the pancreas

Answer 4

it is an endocrine and exocrine organ

Question 5

what does insulin bind to

Answer 5

the insulin receptor

Question 6

what can conformational change of the insulin receptor cause

Answer 6

convert glucose to glycogen
convert glucose to pyruvate - converted into fatty acids

Question 7

if there is a quite high blood glucose sugar level, what can the conformational change in insulin receptor cause

Answer 7

intracellular vesicles - glucose transporter-4 can fuse to the membrane to uptake more glucose to be converted into glycogen/fatty acids

Question 8

what is the function of the hydrophobic terminus of insulin

Answer 8

prevents it from escaping the ribosome into the cytoplasm

Question 9

what is the function of the translocon in terms of insulin production

Answer 9

recognises the signal sequence of insulin and allows it to enter the ER lumen
then it cleaves the signal sequence

Question 10

what is the pH of the ER lumen, Golgi apparatus and secretory vessels

Answer 10

ER lumen - 7.2
Golgi - 6-6.7
secretory vesicles - 5.7

Question 11

why is the gradual decrease in pH from ER to vesicles important in insulin secretion

Answer 11

the pI (overall charge) of insulin is 5.1
if the pI is close to the pH it will precipitate out of solution - controlled manner
can be reversed

Question 12

how is mature insulin packaged

Answer 12

into a zinc-bound monomer
a hexagonal shape with 2 zinc and 6 insulin

Question 13

how is zinc introduced for packaging and why is it a risk factor

Answer 13

Znt8 is a Zn+2 transporter
in Type 1 diabetes it will recognise Znt8 as a foreign protein and destroy it

Question 14

what are the 3 states in which insulin hexamers can exist

Answer 14

R6
T6
T3R3

Question 15

what was used in the formation of R6 crystals and why, and why is it not in use anymore

Answer 15

phenol was used as an antibacterial agent in R6 preparation
not used anymore because it is toxic

Question 16

what plays an important role in the chemical and physical stability of insulin

Answer 16

the intrinsic flexibility at the ends of the B chains

Question 17

what is a function of the hexameric packaging of insulin

Answer 17

stabilises insulin and prevents degradation

Question 18

what are additives to insulin hexamers

Answer 18

protamine
phenols/metacresol
zinc chloride

Question 19

what is the function of protamine for insulin hexamers

Answer 19

a protein extracted from fish sperm nucleus
regulates interactions between hexamers and dimers
slows the release of insulin

Question 20

function of zinc chloride for insulin hexamers

Answer 20

stabilise the hexamer
zinc ions are the predominant quaternary structure of pharmacological insulin

Question 21

what are the 3 general forms of insulin

Answer 21

fast acting analogous
slow acting analogous
very slow acting analogous

Question 22

how does lispro sway insulin into fast acting

Answer 22

impairs dimerisation
moves the equilibrium to monomeric and active form

Question 23

why is Aspart a fast acting insulin releaser

Answer 23

because there are charge repulsion at the dimer interface
equilibrium favours the monomeric/active forms

Question 24

why is glulisine a fast acting insulin

Answer 24

decreased zinc-free association
leads to decreased hexamer formation
equilibrium favours active form

Question 25

what breaks disaccharides into monosaccharides

Answer 25

alpha-glucosidases

Question 26

what is involved in the intestinal lumen uptake of glucose/galactose

Answer 26

SGLT1 along with the uptake of Na+

Question 27

what is responsible for intestinal lumen fructose uptake

Answer 27

GLUT5

Question 28

what does is the SGLT1 mediated influx of Na+ involved in

Answer 28

Na+/K+-ATPase

Question 29

what transports monosaccharides into the bloodstream

Answer 29

GLUT2

Question 30

features and function of acarbose

Answer 30

a pseudotetrasaccharide unsaturated cyclitol component of the molecule identified as essential for alpha-glucosidase inhibitory activity

Question 31

how does acarbose inhibit alpha-glucosidase

Answer 31

binds reversibly/competitively to oligosaccharide binding site of alpha-glucosidase

Question 32

what can/ can't inhibit alpha-amylase and why

Answer 32

can - cyclitol can't - miglitol - because it is smaller

Question 33

role of alpha-amylase compared to alpha-glucosidase

Answer 33

alpha-amylase - breaks down complex carbohydrates in the gut alpha-glucosidase - converts di into monosaccharides for absorption

Question 34

what is the problem with alpha-amylase/glucosidase inhibitors

Answer 34

they are effective so polysaccharides end up in the colon lots of bacteria there to feed off it bacteria produce toxic levels of CO2

Question 35

how is the level of blood glucose detected by cells

Answer 35

when glucose enters a cell there is an increase in ATP to ADP the ATP to ADP ratio in cells is used to detect the level of blood glucose

Question 36

what is responsible for sensing the ratio of ATP to ADP

Answer 36

KATP a K+ ion channel

Question 37

how does an increase in the ATP to ADP ratio affect KATP

Answer 37

causes KATP inhibition

Question 38

what does KATP inhibition lead to

Answer 38

no K+ influx leads to depolarisation

Question 39

what is cell depolarisation detected by

Answer 39

voltage-dependent Ca2+ channels

Question 40

how does depolasrisation lead to insulin secretion

Answer 40

voltage-dependent Ca2+ channels open Ca2+ influx Ca2+ binds to insulin carrying secretory vesicles initiates insulin export

Question 41

what is the structure of KATP

Answer 41

tetrameric structure binding of ATP closes the channel 4 channel (Kir6.2) subunits and 4 regulatory (SUR1) subunits

Question 42

what do the regulatory subunits of KATP bind to and what do they cause

Answer 42

sulphonyl urea compounds reduce K-ATP channel activity

Question 43

what are features of the SUR1 (regulatory) subunits

Answer 43

3 transmembrane domains (TMD0/1/2) TMD1/2 possess ADP binding sites

Question 44

what is the function of PIP2 in terms of KATP

Answer 44

keeps the K+ channels in an open conformation

Question 45

how does the increase in ATP and decrease in ADP lead to closed K+ channels

Answer 45

the ADP bound to the sulphonyl urease subunit falls off leads to PIP2 being displaced by ATP leads to closure of the K+ channel

Question 46

what is main factor driving insulin release

Answer 46

50-70% of insulin secreted is due to the incretin effect

Question 47

what is the incretin effect

Answer 47

incretins are hormones released from the GI tract into circulation in response to nutrient ingestion enhances glucose-stimulated insulin secretion

Question 48

what are the hormones that account for the incretin effect

Answer 48

gastric inhibitory peptide (GIP) Glucagon Like Peptide-1 (GLP-1)

Question 49

features of GIP

Answer 49

derived from a proprotein encoded by the GIP gene circulates as a biologically active amino acid peptide

Question 50

what synthesises GIP and where is it located

Answer 50

synthesised by K cells found in: - mucosa duodenum - jejunum of the GI tract

Question 51

function of GIP

Answer 51

induces insulin secretion and lipolysis is insulinotropic - stimulates/affects the production/release of insulin

Question 52

what causes insulin secretion in a diabetic state

Answer 52

only GLP-1

Question 53

what type of receptor is the GLP-1 receptor

Answer 53

G-protein coupled receptor