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Molecular basis of disease > Diabetes > Flashcards

Diabetes Flashcards

1
Q

what are the three general forms of insulin drugs?

A

1) Fast-acting insulin analogues
2) Long acting insulin analogues
3) Very long acting insulin analogues

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2
Q

Name three rapid acting insulin drugs? and there universal mechanism of action

A

Shift from the stored form to the monomeric active form

  • Lispro (Humalog)
  • Aspart (Novolog)
  • Gluisine (Apidra)
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3
Q

Explain how lispro works

A

Impairs dimerisation
Mutation from Proline to lysine
Pro B28 to Lys
LysB29 to Pro
- just shifts equilibrium to more of the monomeric insulin

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4
Q

Explain how aspart works?

A

Charge repulsion at dimer interface
Mutation from proline to aspartate
- so shifts towards the break down into monomers

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5
Q

Explain how Glulisine (Apidra) works?

A

Decreased zinc-free association
AsnB3 to Lys
LysB29 to Glu

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6
Q

name two long term acting insulin drugs?

A

Glargine (Lantus)

Detemir (Levemir)

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7
Q

how does glargine work?

A

long-term acting
ArgB31-ArgB32 tag
AsnA21 to Gly
Causes a shift in pi to pi 7 leads to isoelectric precipitation on injection

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8
Q

how does Detemir work?

A

Long-term acting
Modification of LysB29 by a tethered fatty acid
Stabilisation of hexamer and binding to serum albumin

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9
Q

what is the only absorbable form of carbohydrates in the GIT?

A

monosaccharides

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10
Q

what breaks disaccharides into monosaccharides?

A

membrane-bound a-glucosidases and lactase

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11
Q

what breaks down polysaccharides into disaccharides?

A

salvia and pancreatic a-amylases

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12
Q

Describe intestinal alpha-glucosidases

A
  • alpha-glucosidase is tethered to the brush border membrane via a transmembrane helix
  • contains two catalytic domains
  • there are two types (MGAM and SI)
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13
Q

what is acarbose?

A
  • a pseudotetrasaccharide
  • a natural microbial product derived from culture broths of acitnoplanes strain SE 50
  • Unsaturated cyclitol component of the molecule has been identified as essential for a-glucosidase inhibitory activity
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14
Q

how does acarbose bind?

A
  • binds reversibly, competitively and in a dose dependent manner to the oligosaccharide binding site of a-glucosidase enzymes in the brush border of the small intestinal mucosa
  • therefore hydrolysis is prevented (prevenst full polysaccharide breakdown)
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15
Q

how does miglitol work?

A
  • inhibits glycoside hydrolase enzymes called alpha-glycosidases
  • systemically absorbed but is not metabolised and is secreted by the kidneys
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16
Q

how does voglibose work

A
  • Alpha-glucosidase inhibitor
  • it is a saccharide
  • competively inhibits enzymes needed to digest carbohydrates (specifically in the brush border of small intestines)
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17
Q

what is the catalytic part of intestinall alpha-glucosidase?

A

catalytic nucleophile D443 and acid/ base catalyst D542

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18
Q

what drugs cannot inhibit pancreatic alpha-amylase?

A

Miglitol
Voglibose

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19
Q

what is the function of alpha-amylase?

A

to break down complex carbohydrates in the gut

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20
Q

what is the role of alpha-glucosidase?

A

to break down smaller polysacchardie units to monosaccharides for absorption

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21
Q

what is the resting membrane potential?

A

-70mV

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22
Q

what is the incretin effect?

A

Incretins are hormones that are secreted from the GIT into theh circulation in response to nutrient ingestion that enhance glucose-stimulated insulin secretion

23
Q

how much of the total insulin is secreted?

A

50-70% due to the incretin effect

24
Q

what two hormones account for the incretin effect in humans?

A

Gastric Inhibitory Peptide (GIP)
Glucagon-Like Peptide-1 (GLP-1)

25
what is GIP?
- derived from a 153-amino acid proprotein - encoded by the GIP gene - circulates as an active 42 amino acid peptide - synthesised by K cells
26
where are K cells found and what do they synthesise?
found in: - mucosa of the duodenum - jejunum of the GIT Synthesise GIP
27
where is GLP-1 synthesised and released?
L-cells in ileum and colon
28
what does GLP-1 do?
- stimulates insulin release from B-cells - Potent inhibition of gastric emptying - potent inhibition of glucagon secretion - reduction of food intake and body weight - significant effects on b-cell growth and survival - insulinotropic actions preserved in T2DM
29
what does the gene that makes GLP-1 also make?
GLucagon GLP-2
30
What breaks the gene of GLP-1 down into the active form?
Prohormone convertase 1
31
describe GLP-1's structure
- it is a GPCR - consisting of 7 TM helices - extracellular N-terminus - cytoplasmic c-terminus
32
what are GPCRs
they are GEFs (Guanine nucleotide exchange factors)
33
how do GPCRs work?
1) ligand binds and activates GEF activity of GPCR 2) GPCR exchanged GTP for GDP on the G-protein a-subunit 3) The activated G-protein a-subunit dissociates and is free to move into the cytoplasm and signal
34
describe the structure of GLP-1R extracellular domain (ECD)
- a groove in tghe ECD provides a binding site for the C-terminal section of the GLP-1 helix - ECD consists of mostly beta sheet and one alpha helix
35
how many Ga's are there?
5, Ga: s, i, q, 12 and transducin
36
what does Gas signalling pathway do ?
activates plasma membrane adenylul cyclases, increasing cellular cAMP which stimulates phosphorylation of target proteins by cAMP-dependant protein kinase (signalling can be covalently activated by chorea toxin)
37
what are the prolonged effects of GLP-1R activation?
- ER stress reduction - Inhibition of Apoptosis - B-cell proliferation and neogenesis - increased insulin biosynthesis
38
what is a GLP-1R drug?
Exenatide - is a synthetic version of the extendin-4 pepride from glia monster (spiders and snakes). - has a 50% amino acid homology to GLP-1 and has a longer half-life in vivo
39
why does exenatide last longer than other peptiddes and GLP?
it is not cleaved by DPP4 due to a glycine residue therefore activates receptor for a longer period of time
40
what is semaglutide?
-chemically similar to human GLP-1 (94% similarity) - only differences are two AA substitutions (Ala and Lys replaced by 2-aminoisobutyric acid and arginine) - AA substitution at position 8 stops breakdown by DPP4
41
whats special about semaglutide?
- forms a series of aggregates that are concentration dependent - highest concentrations forms branched tree-like aggregates
42
what secures high albumin affinity and GLP-1 receptor potency?
- fatty acid moiety and the linking chemistry GLP-1
43
What is DPP4?
- part of serine protease family - exists as homodimeric membrane bound and soluble forms - major role in glucose metabolism ans responsible for the degredation of incretins such as GLP-1 - works as a suppressor in the development of some cancer and tumours - may play a protecctive role in heart and kidney ischemia-repurfusion injury by antiapoptotic, immunological and antioxidative changes
44
what are two advantages of DPP4 inhibitors ?
- do not inhibit gastic emptying (whereas GLP-1 agonists do) - have been shown to increase saiety, leading to decreased food intake
45
describe some features of DPP4 inihibitors
- standard small molecular inhibitors - dDPP8 and 9 are intracellular - adverse effects in animal models but none in human clinical trials
46
name three DPP4 inhibitors
- saxagliptin - sitagliptin - vildagliptin
47
name as many GLP-1 agonists as you can ?
Exendatide Lixisendatide Taspoglutide Liraglutide Albglutide Semaglutide
48
where does glucose get reabsorbed back into the blood stream from?
proximal tubule made up of three segments S1 - close to bowmans capsule S2 and S3 - have sodium-glucose linked transporters
49
compare SGL1 and SGL2 transport
SGL1: - proximal tubule - 90% reabsorption - high capacity - low affinity SGL2: - distal end of proximal tubule - 10% reabsorption - low capacity - high affinity
50
where is SGLT1 located?
mostly small intestine,, some in kidney and heart
51
where is SGLT2 located?
almost exclusively the kidney
52
name a SGLT2 inhibitor and describe
Dapagliflozin - selective SGL2 inhibitor with 1000x selectivity over SGLT1 - In human trials showed good efficacy but they do not inhibit > 30-50% of the filtered glucose load
53
what is metformin?
a plant believed to make cells more sensitive to insulin

Molecular basis of disease (5 decks)

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