Pharmacology 4: Diabetes and obesity Flashcards
tment which must be given immediately for diabetic ketoacidosis?
insulin-IV at a fixed rate for DKA
rehydration- IV replacement fluids, with K+ in fluid as insulin drives K+ into cells via Na+/H+ exchange stimulation and subsequent increased Na+ pump activity, so patient would otherwise become hypokalaemic very quickly, putting them at risk of cardiac arrythmias.
classes of oral hypoglycaemic drugs?
those which increase sensitivity to insulin (insulin sensitisers): biguanides e.g. metformin, thiazolineinediones (glitazones) e.g. pioglitazone.
those which stimulate insulin release: sulfonylureas e.g. tolbutamide and glipizide, and meglitinides e.g. nateglinide.
glucagon like peptide-1 analogues
dipeptidyl peptidase-4 (DPP4) inhibitors (gliptins)
alpha-Glucosidase inhibitors
how do thiazolineinediones (glitazones) work?
agonsitically bind to peroxisome proliferator-activated receptor-gamma (PPAR-gamma)= transcription factor- regulates AT differentiation and role in lipid met., which binds with another nuclear receptor- retinoid X receptor, complex upregulates wide set of genes- in liver, SM and AT, with products important in insulin signalling and so increase insulin sensitivity in AT and muscle.
increase glucose uptake
reduce glucose synthesis in liver, muscle and AT
suppress hepatic gluconeogenesis, and so reduce hepatic glucose output
how do sulfonylureas work?
antagonise beta cell K+/ATP channel activity, causing decrease in K+ current, which cause depolarisation, which then increases Ca2+ entry into cell, which governs fusion rate of insulin vesicles with beta cell membrane, and their release into circulation.
Meglitidines also work in this way.
Orlistat is a drug used to treat obesity, how does it work?
gastric and pancreatic lipase inhibitor, so reduces dietary fat conversion to FA and glycerol for absorption.
SEs of orlistat?
soft fatty stools, flatus, unpleasant faecal discharge or faecal incontinence
Sibutramine is used to treat obesity, how does it work?
NA and serotonin (5-HT) reuptake inhibitor. Suppresses appetite anf some additional reduction in hyperglycaemia rate of glucose met, poss. due to increased thermogenesis.
SEs of sibutramine
increase HR and BP- CVS risk factors present and being treated in obese diabetics
example of drug used to delay carbohydrate absorption by gut?
alpha-glucosidase inhibitors e.g. acarbose- inhibits bdown of carbohydrates to glucose
SEs: runny stools, flatulence- as carbs fermented by gut bacteria, abdominal pain, diarrhoea
effects of insulin in body, other than decreasing blood glucose levels?
STORAGE promotion hormone
- stimulates hepatic glycogen prod via increasing glucokinase activity, glycolysis, and inhibits glycogenolysis and gluconeogenesis
- stimulates hepatic FA synthesis-for transport as lipoproteins- increase circulating free FA, promote clearance of circulating free FA
- inhibition of fat b.down in hepatocytes (lipolysis)- lipase inhibition
- increase aa uptake by muscle
3 modes of action of metformin?
increase sensitivity of cells to insulin, and so stimulates glucose uptake by AT and skeletal muscle
inhibits hepatic gluconeogenesis
reduced absorption of glucose from gut
describe the process of insulin production
synthesised initially as preproinsulin- exported into ER where signal peptide cleaved by signal peptidase, to create proinsulin- folds via disulphide bond formation and is transported to secretory vesicles where cleavage via endopeptidase produces insulin (A and B peptides with 2 S-S bridges) and C peptide= released in endogenous amounts from secretory vesicle.
how is insulin secretion by pancreatic beta cells stimulated by increased glucose?
glucose met. increases IC ATP/ADP ratio.
glucose enters beta cells via GLUT2 transporter- facilitated diffusion, enters glycolytic pathway after conversion to glucose 6-phosphate by hexokinase. increase ATP closes K+/ATP sensitive channel, causing cell depolarisation, Ca2+ influx and fusion of insulin vesicles with cell membrane.
why is insulin secretion prevented by low blood glucose?
low ATP:ADP in pancreatic beta cells as low glucose met, which opens K+/ATP channel, maintaining cells in a hyperpolarised state that prevents Ca2+ influx.
how does insulin act on it target tissues e.g. AT, muscle and liver?
via a tyrosine-kinase linked receptor: binds to EC domain and activates TK, causing autophosphorylation of tyrosine and phosphorylation of intracellular insulin receptor substrate proteins. These protiens recruit 2nd messenger proteins important for insulin action.
how is glucose reabsorbed by the kidneys and how is the process affected in diabetes?
PCT: high-capacity, low-affinity Na+-glucose co-transporter= SGLT2 on apical membrane= secondary AT using Na+ gradient generated by Na+K+ATPase, generates conc gradient for glucose that allows facilitated diffusion across BL membrane via GLT2.
straight PT: high affinity, low-capacity 2Na+-glucose co-transporter (SGLT1), GLT1 on BL membrane.
diabetes= excess glucose filtered, renal threshold exceeded so excess glucose unable to be reabsorbed and is excreted in urine. Glucose increase osmolarity of filtrate, reducing H20 reabsorption- remains with glucose and is excreted.
renal threshold for glucose?
200mg/100ml
despite high glucose in type 1 diabetes, why do glycogenolysis and gluconeogenesis proceed unchecked?
unavailability of insulin to promote glucose uptake into tissues, coupled with unopposed actions of counter-regulatory hormones e.g. cortisol and glucagon- increase PEPCK and fructose 1,6-bisphosphatase activity, causing starvation like response.
how does obesity link to insulin resistance?
insulin receptor desensitisation
ectopic accumulation of lipid into liver and muscle
obesity-induced inflammation
how does insulin suppress appetite?
insulin and leptin stimulate the inhibitory primary neurone that releases POMC to inhibit appetite, and inhibit the stimulatory pathway where NPY and agouti-related peptide are released to stimulate appetite.
only aspect of insulin functioning which differs depending on which insulin you give to a patient?
rate of insulin absorption into blood following SC injection, which depends on insulin solubility and local circulation
this is dependent on aa sequence
formulation of drug different, can use recombinant DNA technology
why might insulin requirement in an individual need to be increasef?
stress
infection
trauma
during puberty