treatment of t1 and t2 diabetes

Question 1

describe insulin synthesis

Answer 1

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

Question 2

what stimulates both insulin and glucagon?

Answer 2

aa

Question 3

how does glucose regulate insulin?

Answer 3

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

Question 4

which tissues are NOT insulin dependent?

Answer 4

CNS, peripheral nerves, vessels, renal medulla, and liver

Question 5

insulin stimulates three things

Answer 5

glycogen synthesis in liver
protein synthesis in muscle
lipogenesis in adipose

Question 6

insulin inhibits

Answer 6

ketogenesis and gluconeogenesis in the liver

Question 7

mechanism of insulin receptor

Answer 7

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

Question 8

when insulin is absent in diabetes, what runs opposed?

Answer 8

cortisol
epinephrine
norepinephrine
glucagon
GH
--all are opposed by insulin

Question 9

type 1 diabetes

Answer 9

juvenile onset
autoimmune destruction of B cells
prone to ketoacidosis; HLA associated and islet cell antibodies present
50% among monozygotic twins
INSULIN IS REQUIRED

Question 10

type 2 diabetes

Answer 10

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)

Question 11

how must insulin be administered?

Answer 11

not active orally –> IV or SQ

Question 12

insulin overdose can cause

Answer 12

hypoglycemia and brain damage(treat with glucose)

Question 13

insulin lispro

Answer 13

synthetic insulin analog,

absorbed more rapidly than regular insulin since it doesnt dimerize after injection –> can inject right before eating

Question 14

regular insulin

Answer 14

dimerizes after injection so administer 30 minutes before

Question 15

NPH insulin

Answer 15

intermediate acting; forms zinc protamine complex that slowly releases insulin at injection site

Question 16

insulin glargine

Answer 16

long acting synthetic insulin

causes precipitation upon injection –> slowly dissolves over time

no peak; onset after 1.5 hrs and lasts 24 hrs

Question 17

insulin detemir

Answer 17

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

Question 18

what two insulin preps are peakless?

Answer 18

glargine and detemir

Question 19

first drug to use with t2 diabetes?

Answer 19

metformin

Question 20

metformin

Answer 20

inhibits liver gluconeogenesis

doesnt cause hypoglycemia!

side effect: lactic acidosis

Question 21

if metformin doesnt work, you can add what?

Answer 21

an orally active hypoglycemic (glipizide) or a glitazone (pioglitazone) or sitagliptin

Question 22

three sulfonylureas?

Answer 22

oral hypoglycemics
tolbutamide
glyburide
glipizide

Question 23

sulfonylureas

Answer 23

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

Question 24

glyburide and glipizide

Answer 24

sulfonylureas that are 200x more potent than tolbutamide

**can cause hypoglycemia

Question 25

acarbose

Answer 25

alpha glucosidase inhibitor that slows intestinal carb breakdown
helps reduce hyperglycemia after a meal
side effects: gas, bloating, and diarrhea (undigested carbs)

Question 26

pioglitazone

Answer 26

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

Question 27

sitagliptin

Answer 27

oral inhibitor of DPP4(dipeptidyl peptidase 4) –> amplifies GLP1 (since it isnt being broken down) –> stimulates more insulin release and inhibits glucagon release

Question 28

what is DPP4?

Answer 28

dipeptidyl peptidase 4enzyme that breaks down GLP1, decreasing insulin release

when it is inhibited, insulin release increases

Question 29

what drugs inhibit DPP4?

Answer 29

sitagliptin and saxagliptin

Question 30

saxagliptin

Answer 30

DPP-4 inhibitor

Question 31

canagliflozin

Answer 31

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)