treatment of t1 and t2 diabetes Flashcards
describe insulin synthesis
occurs in pancreatic B cells
preproinsulin –> proinsulin –> packaged into immature granules by the golgi –> inside the granule proinsulin forms disulfide bridges and proteolytic cleavage removes C peptide –> mature granule contains insulin, Zn2+, and C-peptide
what stimulates both insulin and glucagon?
aa
how does glucose regulate insulin?
glucose is taken up by B cells –> undergoes phosphorylation and glycolysis –> ATP production increases –> ATP inhibits K channels and allows depolarization –> ca influx –> release of insulin
which tissues are NOT insulin dependent?
CNS, peripheral nerves, vessels, renal medulla, and liver
insulin stimulates three things
glycogen synthesis in liver
protein synthesis in muscle
lipogenesis in adipose
insulin inhibits
ketogenesis and gluconeogenesis in the liver
mechanism of insulin receptor
receptor made of 2alpha(extracellular) and 2beta(membrane spanning) units –> 2 molecules bind to alphas –> activates tyrosine kinase on beta intracellular side –> TK phosphorylates the IRS (insulin receptor substrate) and that activates enzymes for storage
TK also causes glucose transporters to relocate to membrane to enhance glucose uptake
when insulin is absent in diabetes, what runs opposed?
cortisol epinephrine norepinephrine glucagon GH --all are opposed by insulin
type 1 diabetes
juvenile onset autoimmune destruction of B cells prone to ketoacidosis; HLA associated and islet cell antibodies present 50% among monozygotic twins INSULIN IS REQUIRED
type 2 diabetes
onset after 30yo
obese, ketoacidosis resistant; there is some insulin present –> glucose is more stable
not HLA associated; 95-100% among monozygotic twins
treat w diet exercise and oral hypoglycemics (sulfonylureas)
how must insulin be administered?
not active orally –> IV or SQ
insulin overdose can cause
hypoglycemia and brain damage(treat with glucose)
insulin lispro
synthetic insulin analog,
absorbed more rapidly than regular insulin since it doesnt dimerize after injection –> can inject right before eating
regular insulin
dimerizes after injection so administer 30 minutes before
NPH insulin
intermediate acting; forms zinc protamine complex that slowly releases insulin at injection site
insulin glargine
long acting synthetic insulin
causes precipitation upon injection –> slowly dissolves over time
no peak; onset after 1.5 hrs and lasts 24 hrs
insulin detemir
no peak, long acting insulin
injected 2x/day for smooth insulin background
precipitates on injection and dissolves over time
onset in 1-2 hrs; lasts 24 hrs
what two insulin preps are peakless?
glargine and detemir
first drug to use with t2 diabetes?
metformin
metformin
inhibits liver gluconeogenesis
doesnt cause hypoglycemia!
side effect: lactic acidosis
if metformin doesnt work, you can add what?
an orally active hypoglycemic (glipizide) or a glitazone (pioglitazone) or sitagliptin
three sulfonylureas?
oral hypoglycemics
tolbutamide
glyburide
glipizide
sulfonylureas
oral hypoglycemics (glyburide, glipizide, and tolbutamide) to treat t2 diabetes directly stimulate insulin release from B cells by binding to K channels and inhibiting K efflux (like ATP)--> increased uptake of glucose
glyburide and glipizide
sulfonylureas that are 200x more potent than tolbutamide
**can cause hypoglycemia
acarbose
alpha glucosidase inhibitor that slows intestinal carb breakdown
helps reduce hyperglycemia after a meal
side effects: gas, bloating, and diarrhea (undigested carbs)
pioglitazone
decreases insulin resistance by activating nuclear PPARgamma receptor (peroxisome proliferator activated receptor gamma) –> activates insulin responsive genes –> increased synthesis and translocation of glucose transporters in skeletal muscle and adipose which decreases liver production of glucose
sitagliptin
oral inhibitor of DPP4(dipeptidyl peptidase 4) –> amplifies GLP1 (since it isnt being broken down) –> stimulates more insulin release and inhibits glucagon release
what is DPP4?
dipeptidyl peptidase 4enzyme that breaks down GLP1, decreasing insulin release
when it is inhibited, insulin release increases
what drugs inhibit DPP4?
sitagliptin and saxagliptin
saxagliptin
DPP-4 inhibitor
canagliflozin
oral SLGT2 inhibitor(Na-glucose cotransporter)
allows glucose(and water) to be excreted –> reduces hgba1c, fasting glucose, body weight, and systemic BP
side effects: genital bacterial infections and UTIs; diuretic effect (water loss)
