Diabetes P2 Flashcards
What does intake of carbohydrates tell the liver?
-inh glycogenolysis
-inh gluconeogenesis
-stim glycogen synth
-stim GLC uptake
-stim glycolysis
What does protein intake tell the liver?
-stim AA transport in liver and muscles
-stim protein synth
-inhibit release of AA from muscles
What ion is affected by insulin?
-potassium
-favors movements of K into cells
-lots of insulin treatment causes hypokalemia (K+ leaves blood for cells)
-also promotes growth and development
What is IGF?
-insulin-growth factor
-backup system for insulin
-IGF1 and IGF2
-secreted by liver, cartilage and tissue in response to growth hormone
-its receptor is very similar to insulin receptor
What is another name for IGFs?
-somatomedins
What are glucose transporters?
-helps glucose enter cell
-1-7
-GLUT1 in brain = insulin insensitive
-GLUT2 in beta cells
-GLUT4 in muscle and adipose
How are insulin secretions regulated?
-direct feedback of plasma glucose levels on beta cells or alpha cells
-tells the pancreas to secrete either glucagon or insulin to raise or lower blood glucose
What are three major drug groups that regulate insulin secretions?
-sulfonylurea
-biguanides
-thiazolidinediones
how does the sympathetic and parasympathetic NS affect the pancreas?
-symp: inhibits insulin secretion
-parasymp: increases insulin secretion
What GI secretions regulate insulin secretions?
-glucagon
-glucagon derivatives
-secretin
-cholecystokinin
-gastric inhibitory peptide
What is the incretin effect?
-when glucose is given orally it better stimulates insulin production than IV
What are two important incretin hormones?
-Glucose-dependent insulinotropic polypeptide (GIP)
-glucagon-like peptide 1
What are some characteristics of glucagon-like polypeptide 1?
-synth in L cells in ileum and colon
-stimulates insulin, suppresses glucagon
-slows gastric emptying
-increase beta cell mass
-increases insulin sensitivity
-long-term effects not fully known
-for type 2 diabetes
-30-31aa, derived from proglucagon
What are some characteristics of glucose-dependent insulinotropic peptide?
-42aa
-derived from proGIP
-secreted by K cells in duodenum and jejunum
What is GLP-1 degraded by?
-dipeptidyl peptidase 4 (DPP-4)
-after parenteral admin
What are two drug types that avoid DPP4?
-GLP-1 receptor agonists
-DPP4 inhibitors
What is the mechanism of action of insulin?
-binds to tyrosine kinase receptors
-phosphorylation cascade = translocate GLUT4 to PM
-induces transcription of genes for catabolism
-promotes the uptake of K+ into cells
What does insulin tell the muscle?
increase:
-glc transport
-glycolysis
-glycogen
-protein synth
What does insulin tell the adipose tissue?
increase
-glc transport
-increase lipogenesis
-decrease intracellular lipolysis
How is insulin given to best mimic regular non-diabetic insulin?
-combinations of short-acting and long/intermediate-acting
-short-acting gives the peak
-intermediate-acting gives the basal level
Difference between lispro and regular insulin and glulisine?
-lispro given 15min before meal and peak effect at 30-90min after
-regular insulin peak effect 50-120 min later
-glulisine can be taken 15 min before to 20 min after meal
What is lente insulin?
-amorphous insulin
-zinc ion
-slow onset but better sustained
-cannot be given IV
What is isophane NHP insulin?
-neutral protamine Hagedorn insulin
-crystalline zinc
-protamine: delays onset and prolongs effectiveness
Where in the body is the insulin pump?
-the fatty layer under the skin
What is ultralente insulin?
-zinc insulin suspension
-large particles that dissolve
-delayed onset
what is insulin glargine?
-precipitation at the injection site
-prolonged action
-no peak gives baseline insulin
What is detemir insulin?
-insulin with a FA complex
-slow dissolution
What are the adverse effects of insulin?
-hypoglycemia (insulin overdose, alcohol)
-hypokalemia
-lipodystrophy
-weight gain
-injection complications
What are the signs and symptoms of hypoglycemia?
-tachycardia
-confusion
-sweating
-drowsiness
-coma
-death
How is type 2 diabetes mellitus treated?
-lifestyle changes
-oral hypoglycemic drugs (lower glucose levels, may cause hypoglycemia)
What are oral hypoglycemics?
-agents useful in type 2 diabetes treatment
-newly diagnosed pt respond well
-never indicated for T1D
What are the drug classes for T2D?
-sulfonylureas
-biguanides
-thiazolidinediones
-alpha-glucosidase inhibitors
-meglitinides
What are sulphonylureas?
-work on ppancreas
-stimulates the release of insulin from islet cells
-increase receptor sensitivity
-adverse effect: hypoglycemia from not enough food or too much meds
What is a common issue of insulin?
hypoglycemia is the number one problem with drugs that promote insulin release
MOA of sulfonylureas
-release insulin from beta cells
-binds to SUR1 subunit and block the ATP-sensitive K+ channel in b-cell -> depolarization causes Ca influx -> insulin secretion
-also reduce glucagon
What is the pharmacokinetics of sulfonylureas?
-binds to plasma proteins
-met and exc in liver
tolbutamide
-sulfonylureas
-short-acting
-associated with 2.5x increase in cardiovascular mortality
-banned in canada
glyburide
-sulfonylureas
-intermediate-acting
glipizide
-sulfonylureas
-intermediate-acting
glimepiride
-sulfonylureas
-long-acting
What are the adverse effects of sulfonylureas?
-weight gain
-hyperinsulinemia
-hypoglycemia
-hepatic or renal insufficiency would make risks worse
-may increase cardiovascular events
Which organelle is important in diabetes?
-mitochondria
-we inherit only mothers mitochondria
-if mother has type 2 diabetes, then you will probably have type 2 diabetes
slide 60 drug interactions
remember any two in each box
Which drugs reduce the effects of sulfonylureas?
-diuretics
-corticosteroids
-niacin
Which drugs increase the effects of sulfonylureas?
-beta-blockers
-monoamine oxide inhibitors
-salicylates
Metformin
-biguanide
-insulin sensitizer
What are biguanides?
-works on the liver and occasionally muscle/adipose
-decrease hepatic gluconeogen
What is the MOA of metformin?
-reduces plasma glucose
-inh hepatic gluconeogen
-slows abs of sugars
-reduces hyperlipidemia
-decreases appetite
-reduces cardiovascular mortality
What are the adverse effects of metformin?
-hypoglycemia in combination medication
-rarely lactic acidosis
Why can you not have hypoglycemia when on metformin?
-does not promote insulin secretion
What is AMP Kinase?
-regulator for metabolism
What is the inhibitory pathway of AMPK?
decreases in ATP:AMP -> activates AMP kinase -> inhibits ATP consuming pathways (protein, glycogen, FA synthesis) -> consumes less ATP -> brings ATP:AMP ratio back
What is the activating pathway from AMPK?
stimulates ATP producing pathways
-glycolysis, beta-ox, glc uptake
-produces more ATP
-brings ATP:AMP back up
How does metformin work in a hepatocyte?
-enters cell via SLC22A1 transporter -> inhibits mito complex 1 -> less ATP -> high AMP -> gluconeogenesis suppressed -> reduced glucogenic enzymes -> reduced gene expression
-also suppresses fat metabolism and improves insulin receptor function
What are a-glucosidase inhibitors?
-for type 2 diabetes
-work on GI tract
-oligosaccharide derivatives
-inhibits an enzyme of the intestinal brush border
Acarbose
-a-glucosidase inhibitor
-poorly absorbed
-stays in intestinal lumen
miglitol
-a-glucosidase inhibitor
-absorbed and excreted by kidney
-effects intestinal lumen
MOA of a-glucosidase inhibitors
-taken beginning of a meal
-inhibits a-glucosidase = membrane-bound enzyme in the intestine
-hydrolyses oligosach to monosach -> absorbed -> blunts post-prandial glucose rise -> rises modestly and stays slightly elevated
What are thiazolidinediones?
-work on the liver and peripheral tissue
-insulin sensitizers
-increase insulin sensitivity of PPARy receptors in cell nucleus
-does not promote insulin secretion
-insulin required for function
-decreases insulin resistance by inhibiting gluconeogen
What are the adverse effects of thiazolidinediones?
-fluid retention
-headache
-weight gain
-NOT hypoglycemia
pioglitazone
-thiazolidinedione
-can be taken with insulin
rosiglitazone
-thiazolidinedione
What is the MOA of thiazolidinediones?
-activate peroxisome proliferator-activated receptor-gamma
-when ligand binds -> increases insulin sensitivity in adipocytes, hepatocytes and muscle
-elevates HDL levels
What is PPAR-y?
-when ligand is bound, it regulates adipocyte production, FA secretion, and glucose met
-liver: decreases FA and gluconeogen, increases insulin action
-muscle: increases insulin action
-liver: increases b-cell mass and insulin secretion
-pancreas: increases FA uptake, decreases lipolysis
Which drug can you not take with rosiglitazone?
-insulin
-causes severe edema
What are meglitinides?
-work on pancreas
-new class of oral hypoglycemics
-work similar to sulfonylureas
-stimulate release of insulin from islet cells
-short-acting
What does secretagogue mean?
-a substance that causes another substance to be secreted
repaglinide
-meglitinide analog
-secretagogue
nateglinide
-meglitinide analogs
-secretagogue
MOA of meglitinide analogs?
-bind to ATP sensitive K channels -> mimick prandial and post-prandial insulin release -> very short acting
What are the adverse effects of meglitinide analogs?
-hyopglycemia (but less than sulfonylureas
-drugs that inhibit CYP3A4 prolong effects
-interactions with other drugs
What is incretin therapy?
-naturally occurring hormones secreted by the gut
-increases when food is digested
what two drugs block cyp3a4?
-fluconazole
-erythromycin
What does DPP-4 enzymes do?
rapidly degrades active incretins when released
How does januvia (sitagliptin) work?
-food ingested -> incretins released -> januvia inhibits DPP-4 -> less incretins degraded -> increases insulin and reduces glucagon
What is SGLT 1 and 2?
-both: responsible for renal glucose reabsorption
-1: minor; in intestinal mucosa and proximal straight tubule in nephron
-2: major; in proximal convoluted tubule in nephron
How do sodium-glucose cotransporters work?
-let in sodium and glucose into cell
What is the difference between the three types of SGLTs?
-SGLT1:in GI and kidney; high affinity cotransporter
-SGLT2: in kidney; low affinity cotransporter
-SGLT3: throughout body; not glucose transporter
What are some SGLT2 inhibitors?
-dapagliflozin
-canagliflozin
-empagliflozin
-ipragliflozin
dapagliflozin
-SLGT2 inhibitor
canagliflozin
-SLGT2 inhibitor
empagliflozin
-SLGT2 inhibitor
What are the adverse effects of SLGT2 inhibitors?
-increase in genital infections (high glucose environment = bacteria grow)
-decrease in BP and weight
-increase in cancer: but not rly anymore?
What is the difference between standard and intensive treatment of diabetes?
more frequent hypoglycemic events
What is HbA1c used for?
-hemoglobin A1c
-good measure of glucose control
