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Biomed Season Finale > Diabetes and Drug Targets > Flashcards

Diabetes and Drug Targets Flashcards

1
Q

what is gestational diabetes

A

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

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2
Q

what is the cause of gestational diabetes

A

occurs in the third trimester due to changes in renal absorbtion

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3
Q

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

A

beta - insulin
alpha - glucagon

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4
Q

what is a unique feature of the pancreas

A

it is an endocrine and exocrine organ

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5
Q

what does insulin bind to

A

the insulin receptor

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6
Q

what can conformational change of the insulin receptor cause

A

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

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7
Q

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

A

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

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8
Q

what is the function of the hydrophobic terminus of insulin

A

prevents it from escaping the ribosome into the cytoplasm

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9
Q

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

A

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

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10
Q

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

A

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

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11
Q

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

A

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

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12
Q

how is mature insulin packaged

A

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

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13
Q

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

A

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

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14
Q

what are the 3 states in which insulin hexamers can exist

A

R6
T6
T3R3

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15
Q

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

A

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

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16
Q

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

A

the intrinsic flexibility at the ends of the B chains

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17
Q

what is a function of the hexameric packaging of insulin

A

stabilises insulin and prevents degradation

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18
Q

what are additives to insulin hexamers

A

protamine
phenols/metacresol
zinc chloride

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19
Q

what is the function of protamine for insulin hexamers

A

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

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20
Q

function of zinc chloride for insulin hexamers

A

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

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21
Q

what are the 3 general forms of insulin

A

fast acting analogous
slow acting analogous
very slow acting analogous

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22
Q

how does lispro sway insulin into fast acting

A

impairs dimerisation
moves the equilibrium to monomeric and active form

23
Q

why is Aspart a fast acting insulin releaser

A

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

24
Q

why is glulisine a fast acting insulin

A

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

25
Q

what breaks disaccharides into monosaccharides

A

alpha-glucosidases

26
Q

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

A

SGLT1
along with the uptake of Na+

27
Q

what is responsible for intestinal lumen fructose uptake

A

GLUT5

28
Q

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

A

Na+/K+-ATPase

29
Q

what transports monosaccharides into the bloodstream

A

GLUT2

30
Q

features and function of acarbose

A

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

31
Q

how does acarbose inhibit alpha-glucosidase

A

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

32
Q

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

A

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

33
Q

role of alpha-amylase compared to alpha-glucosidase

A

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

34
Q

what is the problem with alpha-amylase/glucosidase inhibitors

A

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

35
Q

how is the level of blood glucose detected by cells

A

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

36
Q

what is responsible for sensing the ratio of ATP to ADP

A

KATP
a K+ ion channel

37
Q

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

A

causes KATP inhibition

38
Q

what does KATP inhibition lead to

A

no K+ influx
leads to depolarisation

39
Q

what is cell depolarisation detected by

A

voltage-dependent Ca2+ channels

40
Q

how does depolasrisation lead to insulin secretion

A

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

41
Q

what is the structure of KATP

A

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

42
Q

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

A

sulphonyl urea compounds
reduce K-ATP channel activity

43
Q

what are features of the SUR1 (regulatory) subunits

A

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

44
Q

what is the function of PIP2 in terms of KATP

A

keeps the K+ channels in an open conformation

45
Q

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

A

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

46
Q

what is main factor driving insulin release

A

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

47
Q

what is the incretin effect

A

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

48
Q

what are the hormones that account for the incretin effect

A

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

49
Q

features of GIP

A

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

50
Q

what synthesises GIP and where is it located

A

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

51
Q

function of GIP

A

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

52
Q

what causes insulin secretion in a diabetic state

A

only GLP-1

53
Q

what type of receptor is the GLP-1 receptor

A

G-protein coupled receptor

54
Q
A

Biomed Season Finale (11 decks)

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