L17 - Tx of T2DM COPY Flashcards
INSULIN ACTION
i) name three things it affects the metabolism of?
ii) name its three major target tissues and the target cells in each
iii) name something that can cause impaired glucose tolerance? what effect does this have on baseline plasma glucose?
iv) what happens to your insulin sensitivity as your glucose tolerance gets impaired?
i) carbohydrates, fat and protein
ii) affects liver = hepatocytes, adipose tissue = adipocytes and skeletal muscle = muscle cells
iii) obesity can cause impaired gluc tol
- causes higher baseline glucose
iv) insulin sensitivity decreases as increased glucose tolerance
EFFECTS OF INSULIN
i) what is the net effect of insulin? (2)
ii) name three processes that insulin decreases in hepatocytes and one thing that it increases
iii) what effect does it have on GLUT4 in muscle cells? name six things this allows
iv) name two things that insulin decreases in muscle cells
v) name three effects insulin has on adipocytes
i) decreases blood sugar (causes hypoglycaemia) and increase fuel storage in muscle, fat tissue and liver
ii) decreases gluconeogeneis, glycogenolysis and ketogenesis and increases glycogen synthesis
iii) increases GLUT4 translocation to the memebrane therefore cells take up more glucose
- increase glucose uptake, glucose oxidation, glycogen synthesis, amino acid uptake and protein synthesis (build muscle mass)
iv) decrease in glycogenolysis and amino acid release
v) increases glucose uptake, increases triglyceride synthesis and decreases free fatty acid/glycerol release (as dont need FFA -> glucose)
T2DM TX OPTIONS
i) which drug can decrease insulin resistance by mimicking effects of insulin?
ii) name three drugs that can help overcome beta cell dysfunction
iii) what treatment may need to be given due to loss of beta cell mass?
iv) which class of drugs work on the kidney to inhibit glucose reabsorption?
v) which four methods to try and reduce hyperglycaemia should be tried first?
i) metformin
ii) sulphonyurea, DDP-4 inhibitors, GLP-1 analogues
iii) insulin for loss of beta cell mass
iv) SGLT2 inhibitors prevent renal absorption of glucose
v) firstly try, change in diet, exercise and treatment for obesity and dyslipidaemia
SULPHONYUREAS
i) give three examples
ii) what form are they active in?
iii) what % are bound to plasma protein?
iv) how do they work in relation to insulin release?
i) gliclazide, glipizide and glimperide
ii) all are orally active
iii) all plasma prot bound (90-99%)
iv) increase insulin release by inhibiting ATP dependent potassium channels
SULPHONYUREAS - MECH OF ACTION
i) which channel do they bind? what effect does this have on the channel? how does this lead to insulin release?
ii) explain how glucose normally causes insulin release in a cell (5 steps involving glucose, ATP, K+ and Ca2+)
iii) are the effects of sulphoyureas dependent or independent of ATP? do they bind the channel on the same or different site?
i) SUs bind the ATP dependent K+ channel on b cell
- this causes the channel to close (stops K+ leaving the cell)
- build up of K+ causes Ca2+ VG channels to open and Ca floods in
- increase in Ca causes release of insulin from granules via exocytosis
ii) glucose moves into cell via GLUT 2
- increase in glycolysis which generates ATP
- ATP binds the K+ channel and causes it to close
- build up of K+ causes Ca channel to open and Ca floods in
- fusion of insulin granules with plas mem = insulin release
iii) SUs effects are ATP independent and they bind a different site on the channel
PHARMACODYNAMICS & USES OF SULPHONYUREAS
i) what is their primary mech of action?
ii) name three secondary and non major mechs of action
iii) which type of diabetes is it useful in? why?
iv) can it be used in combo with other anti diabetic drugs?
v) what is the major side effect? how common is this?
vi) name three drugs that potentiate SU action? explain each
vii) name two drugs that can decrease glucose tolerance and enhance effects of SUs
i) stimulation of endogenous insulin release by binding ATP dep K+ channels on beta cells (inhibits channel opening)
ii) sensitises beta cells to glycose, decreases lipolysis and decreases clearance of insulin by the liver by increasing its half life
iii) useful in T2DM only as T1DM dont have beta cells
iv) yes
v) hypoglycaemia is major SE but this is rare
vi) allopurinol - inhibits SU excretion so inc half life
- aspirin - can displace SU protein binding to increases levels in the blood
- alcohol - can impact on SU breakdown
vii) oral contraceptives and corticosteroids can enhance effects of SUs
METFORMIN
i) what choice of treatment is this?
ii) what type of drug class is it?
iii) name two things it does not do that SUs do
iv) what is its primary mechanism of action? (2)
i) first choice
ii) biguanide
iii) doesn’t stimulate insulin release or cause hypoglycaemia
iv) increase glucose uptake in muscles and decrease glucose production by the liver
METFORMIN - PRIMARY MECH OF ACTION
i) what does it cause supression of? through what mechanism?
ii) which mitochondrial complex does it inhibit? name two things that this causes in relation to AMP, ATP and F16BP
iii) which protein kinase does it activate? what does this cause in relation to SHP, G6P and PEPCK?
i) supression of hepatic glucose production by gluconeogenesis
ii) inhibits mitochondrial complex I which decreases ATP synthesis (and therefore gluconeogenesis, which req ATP)
- increases AMP:ATP ratio which inhibits F16BP (also req for GNG) (AMP inhibits F16BP)
iii) activates AMP activated protein kinase (AMPK)
- AMPK causes increased expression of SHP (nuclear TF)
- SHP inhibits expression of hepatic gluconeogenic genes PEPCK and G6P
METFORMIN - SECONDARY MECH OF ACTION
i) how may it affect insulin sensitivity? what likely mediates this?
ii) how does it affect peripheral glucose uptake? what GLUT transporter is increase via AMPK?
iii) how does it affect heart muscle? is this dependent or independent of AMPK?
iv) how does it affect fatty acid oxidation? is this AMPK mediated?
v) name a minor efefct on the GI tract
i) increase insulin sensitivity by improving insulin binding to its reeptors - mediated by AMPK
ii) increase peripheral glucose uptake by increase GLUT4 translocation to the membrane
- AMPK mediated
iii) causes metabolic changes in heart muscle to make it more likely to use glucose - independent of AMPK
iv) increases fatty acid oxidaton by decreasing insulin induced supression of FA oxidation = AMPK mediated
v) decreases glucose uptake from the GI tract
PROPERTIES OF METFORMIN
i) what cells does it have its major effects on?
ii) where is it active?
iii) does it bind plasma proteins?
iv) where is it excreted via? is it changed or unchanged?
v) what is its approx half life?
vi) name another conditions it can be used to treat
i) hepatocytes
ii) orally active
iii) does not bind plasma proteins
iv) excreted unchanged in the urine
v) half life of 1.5-4.5 hrs
vi) can be given in PCOS - helps metabolic disturbance
ADVERSE EFFECTS AND CONTRAINDIC OF METFORMIN
i) what adverse effect may occur in patients with renal impairment? how common is this?
ii) name five common side effects
iii) which two vitamins absorption can be decreased with chronic metformin use?
iv) name two conditions that need immediate stoppage of metformin use? why is this?
v) name four contraindications for metformin
i) lactic acidaemia (rare)
ii) nausea, abdominal discomfort, dirrhoea, metallic taste in mouth and anorexia
iii) B12 and folate
iv) MI and septicaemia - metformin can alter metabolic processes of the heart
v) hepatic disease, hx of lactic acidosis, cardiac failure, chronic hypoxic lung disease (due to acidosis risk)
THIAZOLIDINEDIONES/GLITAZONE
i) what is the only one that remains approved?
ii) which receptor does it activate? which two processes are these receptors involved in and what does activation ultimately cause in relation to insulin
iii) what effect do glitazones have on GNG, glucose output and triglyceride prod in the liver?
iv) what effect do they have on glucose uptake and util in skel muscle
v) what effect do they have on glucose uptake and fatty acid output in adipose tissue?
vi) what effect do they have on adipocytes? what does this allow?
i) pioglitazone
ii) activates PPAR-g receptors which are involved in transcrip of insulin responsive genes and regulation of adipocyte lipid metabolism
- cause cells to be more sensitive to insulin
iii) decrease GNG, glucose output and tryglyc prod in liver
iv) increase glucose uptake and util in skel muscle
v) increase glucose uptake and decreased FA output in adipose tissue
vi) cause differentiation of adipocytes - increased fat cells so they can store more glucose
GLITAZONE PKs
i) how many times a day is pioglitazone taken? how is it taken?
ii) how long does it take for plasma levels to peak?
iii) what is the plasma half life?
iv) where is it metabolised? how is it excreted (2)
i) once or twice orally
ii) 3 hours
iii) 3-7 hrs
iv) metab in liver and excreted in faeces (2/3) and urine (1/3)
ADVERSE EFFECTS AND INTERACTIONS OF GLITAZONES
i) what two things can be caused by glitazones promoting amiloride sens sodium reabs in the CD?
ii) how may weight change?
iii) do they cause lactic acidosis?
iv) what organ may be damaged?
v) what drugs may they lower the efficacy of?
i) fluid retention and mild anaemia
ii) can cause dose related weight gain
iii) no acidosis - even in patients with renal impairement
iv) may cause liver damage - need blood tests to monitor
v) may lower efficacy of oral contraceptives
GLUCAGON LIKE PEPTIDE-1 (GLP-1)
i) why is there increase in plasma insulin levels on oral admin rather than IV glucose admin?
ii) what does GLP release from the GI tract cause?
iii) what type of molecule is GLP? how is it removed?
i) oral glucose goes via the GI tract and affects insulin release mediated by GLP1
ii) GLP release from GI tract causes insulin release
iii) GLP is a hormone and needs to be removed by DPP-IV
