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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
Q

what is GIP?

A
  • 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
Q

where are K cells found and what do they synthesise?

A

found in:
- mucosa of the duodenum
- jejunum of the GIT

Synthesise GIP

27
Q

where is GLP-1 synthesised and released?

A

L-cells in ileum and colon

28
Q

what does GLP-1 do?

A
  • 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
Q

what does the gene that makes GLP-1 also make?

A

GLucagon
GLP-2

30
Q

What breaks the gene of GLP-1 down into the active form?

A

Prohormone convertase 1

31
Q

describe GLP-1’s structure

A
  • it is a GPCR
  • consisting of 7 TM helices
  • extracellular N-terminus
  • cytoplasmic c-terminus
32
Q

what are GPCRs

A

they are GEFs (Guanine nucleotide exchange factors)

33
Q

how do GPCRs work?

A

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
Q

describe the structure of GLP-1R extracellular domain (ECD)

A
  • 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
Q

how many Ga’s are there?

A

5, Ga: s, i, q, 12 and transducin

36
Q

what does Gas signalling pathway do ?

A

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
Q

what are the prolonged effects of GLP-1R activation?

A
  • ER stress reduction
  • Inhibition of Apoptosis
  • B-cell proliferation and neogenesis
  • increased insulin biosynthesis
38
Q

what is a GLP-1R drug?

A

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
Q

why does exenatide last longer than other peptiddes and GLP?

A

it is not cleaved by DPP4 due to a glycine residue therefore activates receptor for a longer period of time

40
Q

what is semaglutide?

A

-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
Q

whats special about semaglutide?

A
  • forms a series of aggregates that are concentration dependent
  • highest concentrations forms branched tree-like aggregates
42
Q

what secures high albumin affinity and GLP-1 receptor potency?

A
  • fatty acid moiety and the linking chemistry GLP-1
43
Q

What is DPP4?

A
  • 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
Q

what are two advantages of DPP4 inhibitors ?

A
  • do not inhibit gastic emptying (whereas GLP-1 agonists do)
  • have been shown to increase saiety, leading to decreased food intake
45
Q

describe some features of DPP4 inihibitors

A
  • standard small molecular inhibitors
  • dDPP8 and 9 are intracellular - adverse effects in animal models but none in human clinical trials
46
Q

name three DPP4 inhibitors

A
  • saxagliptin
  • sitagliptin
  • vildagliptin
47
Q

name as many GLP-1 agonists as you can ?

A

Exendatide
Lixisendatide
Taspoglutide
Liraglutide
Albglutide
Semaglutide

48
Q

where does glucose get reabsorbed back into the blood stream from?

A

proximal tubule
made up of three segments
S1 - close to bowmans capsule
S2 and S3 - have sodium-glucose linked transporters

49
Q

compare SGL1 and SGL2 transport

A

SGL1:
- proximal tubule
- 90% reabsorption
- high capacity
- low affinity

SGL2:
- distal end of proximal tubule
- 10% reabsorption
- low capacity
- high affinity

50
Q

where is SGLT1 located?

A

mostly small intestine,, some in kidney and heart

51
Q

where is SGLT2 located?

A

almost exclusively the kidney

52
Q

name a SGLT2 inhibitor and describe

A

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
Q

what is metformin?

A

a plant believed to make cells more sensitive to insulin

Molecular basis of disease (5 decks)

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