Diabetes and Drug Targets Flashcards
what is gestational diabetes
pregnant women whom have not been previously diagnosed with diabetes exhibit high levels of blood glucose sugar
what is the cause of gestational diabetes
occurs in the third trimester due to changes in renal absorbtion
what do alpha/beta cells in the ilses of Langerhan release
beta - insulin
alpha - glucagon
what is a unique feature of the pancreas
it is an endocrine and exocrine organ
what does insulin bind to
the insulin receptor
what can conformational change of the insulin receptor cause
convert glucose to glycogen
convert glucose to pyruvate - converted into fatty acids
if there is a quite high blood glucose sugar level, what can the conformational change in insulin receptor cause
intracellular vesicles - glucose transporter-4 can fuse to the membrane to uptake more glucose to be converted into glycogen/fatty acids
what is the function of the hydrophobic terminus of insulin
prevents it from escaping the ribosome into the cytoplasm
what is the function of the translocon in terms of insulin production
recognises the signal sequence of insulin and allows it to enter the ER lumen
then it cleaves the signal sequence
what is the pH of the ER lumen, Golgi apparatus and secretory vessels
ER lumen - 7.2
Golgi - 6-6.7
secretory vesicles - 5.7
why is the gradual decrease in pH from ER to vesicles important in insulin secretion
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
how is mature insulin packaged
into a zinc-bound monomer
a hexagonal shape with 2 zinc and 6 insulin
how is zinc introduced for packaging and why is it a risk factor
Znt8 is a Zn+2 transporter
in Type 1 diabetes it will recognise Znt8 as a foreign protein and destroy it
what are the 3 states in which insulin hexamers can exist
R6
T6
T3R3
what was used in the formation of R6 crystals and why, and why is it not in use anymore
phenol was used as an antibacterial agent in R6 preparation
not used anymore because it is toxic
what plays an important role in the chemical and physical stability of insulin
the intrinsic flexibility at the ends of the B chains
what is a function of the hexameric packaging of insulin
stabilises insulin and prevents degradation
what are additives to insulin hexamers
protamine
phenols/metacresol
zinc chloride
what is the function of protamine for insulin hexamers
a protein extracted from fish sperm nucleus
regulates interactions between hexamers and dimers
slows the release of insulin
function of zinc chloride for insulin hexamers
stabilise the hexamer
zinc ions are the predominant quaternary structure of pharmacological insulin
what are the 3 general forms of insulin
fast acting analogous
slow acting analogous
very slow acting analogous
how does lispro sway insulin into fast acting
impairs dimerisation
moves the equilibrium to monomeric and active form
why is Aspart a fast acting insulin releaser
because there are charge repulsion at the dimer interface
equilibrium favours the monomeric/active forms
why is glulisine a fast acting insulin
decreased zinc-free association
leads to decreased hexamer formation
equilibrium favours active form
what breaks disaccharides into monosaccharides
alpha-glucosidases
what is involved in the intestinal lumen uptake of glucose/galactose
SGLT1
along with the uptake of Na+
what is responsible for intestinal lumen fructose uptake
GLUT5
what does is the SGLT1 mediated influx of Na+ involved in
Na+/K+-ATPase
what transports monosaccharides into the bloodstream
GLUT2
features and function of acarbose
a pseudotetrasaccharide
unsaturated cyclitol component of the molecule identified as essential for alpha-glucosidase inhibitory activity
how does acarbose inhibit alpha-glucosidase
binds reversibly/competitively to oligosaccharide binding site of alpha-glucosidase
what can/ can’t inhibit alpha-amylase and why
can - cyclitol
can’t - miglitol - because it is smaller
role of alpha-amylase compared to alpha-glucosidase
alpha-amylase - breaks down complex carbohydrates in the gut
alpha-glucosidase - converts di into monosaccharides for absorption
what is the problem with alpha-amylase/glucosidase inhibitors
they are effective
so polysaccharides end up in the colon
lots of bacteria there to feed off it
bacteria produce toxic levels of CO2
how is the level of blood glucose detected by cells
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
what is responsible for sensing the ratio of ATP to ADP
KATP
a K+ ion channel
how does an increase in the ATP to ADP ratio affect KATP
causes KATP inhibition
what does KATP inhibition lead to
no K+ influx
leads to depolarisation
what is cell depolarisation detected by
voltage-dependent Ca2+ channels
how does depolasrisation lead to insulin secretion
voltage-dependent Ca2+ channels open
Ca2+ influx
Ca2+ binds to insulin carrying secretory vesicles
initiates insulin export
what is the structure of KATP
tetrameric structure
binding of ATP closes the channel
4 channel (Kir6.2) subunits and 4 regulatory (SUR1) subunits
what do the regulatory subunits of KATP bind to and what do they cause
sulphonyl urea compounds
reduce K-ATP channel activity
what are features of the SUR1 (regulatory) subunits
3 transmembrane domains (TMD0/1/2)
TMD1/2 possess ADP binding sites
what is the function of PIP2 in terms of KATP
keeps the K+ channels in an open conformation
how does the increase in ATP and decrease in ADP lead to closed K+ channels
the ADP bound to the sulphonyl urease subunit falls off
leads to PIP2 being displaced by ATP
leads to closure of the K+ channel
what is main factor driving insulin release
50-70% of insulin secreted is due to the incretin effect
what is the incretin effect
incretins are hormones released from the GI tract into circulation in response to nutrient ingestion
enhances glucose-stimulated insulin secretion
what are the hormones that account for the incretin effect
gastric inhibitory peptide (GIP)
Glucagon Like Peptide-1 (GLP-1)
features of GIP
derived from a proprotein encoded by the GIP gene
circulates as a biologically active amino acid peptide
what synthesises GIP and where is it located
synthesised by K cells
found in:
- mucosa duodenum
- jejunum of the GI tract
function of GIP
induces insulin secretion and lipolysis
is insulinotropic - stimulates/affects the production/release of insulin
what causes insulin secretion in a diabetic state
only GLP-1
what type of receptor is the GLP-1 receptor
G-protein coupled receptor
