Diabetes Flashcards
what are the three general forms of insulin drugs?
1) Fast-acting insulin analogues
2) Long acting insulin analogues
3) Very long acting insulin analogues
Name three rapid acting insulin drugs? and there universal mechanism of action
Shift from the stored form to the monomeric active form
- Lispro (Humalog)
- Aspart (Novolog)
- Gluisine (Apidra)
Explain how lispro works
Impairs dimerisation
Mutation from Proline to lysine
Pro B28 to Lys
LysB29 to Pro
- just shifts equilibrium to more of the monomeric insulin
Explain how aspart works?
Charge repulsion at dimer interface
Mutation from proline to aspartate
- so shifts towards the break down into monomers
Explain how Glulisine (Apidra) works?
Decreased zinc-free association
AsnB3 to Lys
LysB29 to Glu
name two long term acting insulin drugs?
Glargine (Lantus)
Detemir (Levemir)
how does glargine work?
long-term acting
ArgB31-ArgB32 tag
AsnA21 to Gly
Causes a shift in pi to pi 7 leads to isoelectric precipitation on injection
how does Detemir work?
Long-term acting
Modification of LysB29 by a tethered fatty acid
Stabilisation of hexamer and binding to serum albumin
what is the only absorbable form of carbohydrates in the GIT?
monosaccharides
what breaks disaccharides into monosaccharides?
membrane-bound a-glucosidases and lactase
what breaks down polysaccharides into disaccharides?
salvia and pancreatic a-amylases
Describe intestinal alpha-glucosidases
- alpha-glucosidase is tethered to the brush border membrane via a transmembrane helix
- contains two catalytic domains
- there are two types (MGAM and SI)
what is acarbose?
- 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
how does acarbose bind?
- 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)
how does miglitol work?
- inhibits glycoside hydrolase enzymes called alpha-glycosidases
- systemically absorbed but is not metabolised and is secreted by the kidneys
how does voglibose work
- Alpha-glucosidase inhibitor
- it is a saccharide
- competively inhibits enzymes needed to digest carbohydrates (specifically in the brush border of small intestines)
what is the catalytic part of intestinall alpha-glucosidase?
catalytic nucleophile D443 and acid/ base catalyst D542
what drugs cannot inhibit pancreatic alpha-amylase?
Miglitol
Voglibose
what is the function of alpha-amylase?
to break down complex carbohydrates in the gut
what is the role of alpha-glucosidase?
to break down smaller polysacchardie units to monosaccharides for absorption
what is the resting membrane potential?
-70mV
what is the incretin effect?
Incretins are hormones that are secreted from the GIT into theh circulation in response to nutrient ingestion that enhance glucose-stimulated insulin secretion
how much of the total insulin is secreted?
50-70% due to the incretin effect
what two hormones account for the incretin effect in humans?
Gastric Inhibitory Peptide (GIP)
Glucagon-Like Peptide-1 (GLP-1)
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
where are K cells found and what do they synthesise?
found in:
- mucosa of the duodenum
- jejunum of the GIT
Synthesise GIP
where is GLP-1 synthesised and released?
L-cells in ileum and colon
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
what does the gene that makes GLP-1 also make?
GLucagon
GLP-2
What breaks the gene of GLP-1 down into the active form?
Prohormone convertase 1
describe GLP-1’s structure
- it is a GPCR
- consisting of 7 TM helices
- extracellular N-terminus
- cytoplasmic c-terminus
what are GPCRs
they are GEFs (Guanine nucleotide exchange factors)
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
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
how many Ga’s are there?
5, Ga: s, i, q, 12 and transducin
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)
what are the prolonged effects of GLP-1R activation?
- ER stress reduction
- Inhibition of Apoptosis
- B-cell proliferation and neogenesis
- increased insulin biosynthesis
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
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
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
whats special about semaglutide?
- forms a series of aggregates that are concentration dependent
- highest concentrations forms branched tree-like aggregates
what secures high albumin affinity and GLP-1 receptor potency?
- fatty acid moiety and the linking chemistry GLP-1
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
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
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
name three DPP4 inhibitors
- saxagliptin
- sitagliptin
- vildagliptin
name as many GLP-1 agonists as you can ?
Exendatide
Lixisendatide
Taspoglutide
Liraglutide
Albglutide
Semaglutide
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
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
where is SGLT1 located?
mostly small intestine,, some in kidney and heart
where is SGLT2 located?
almost exclusively the kidney
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
what is metformin?
a plant believed to make cells more sensitive to insulin
