t2dm

Question 1

symptoms

Answer 1

due to a slowly rising glucose:
• Tiredness, lethargy
• Polyuria and polydipsia = nocturia = poorly sleep = feel tired
• Often drink sugary drinks because of thirsty and tired – cause glucose to rise slowly
• Normal glucose 5.5
• When 10 – reach renal threshold – polyuric and polydipsia
• With other co-morbidities it becomes difficult to drink enough
• Osmotic diuresis causes loss of water and a rise in Na
• Eventually glucose really high, as is the sodium
• Polyuria – takes sugar out, water leaves by osmosis = high Na left = hyperosmolar – insidious

Question 2

osmolatity calculation

Answer 2

osomolarity = cations (Na+K) + anions (Cl + Bicarb) + glucose + urea
cant measure the other ions - but you cant be charged - so just double cations instead:
osmolarity = 2(cations) + glucose + urea
Na + K = 144

Question 3

problem with being really hyperosmolar

Answer 3

at 430mM - start pulling water out of the brain = confused

might present with a stroke - made worse by the really high glucose

Question 4

describe the insidious onset of t2dm

Answer 4

people spend months to years not knowing they have it
have hyperglycaemia but no dm
intermittent polyuria and dipsia – assumed to be prostate trouble or water work infections – don’t come to dr
Hyperglycaemia – slowly damages the endothelium = micro and macrovascular complications
MI in dm – because neuropathy, you don’t feel the pain and then go to HF

Question 5

microvascular complications

Answer 5

glycosylation of bm proteins = leaky cap =
retinopathy
nephropathy
neuropathy

Question 6

macrovascular complications

Answer 6

dyslipidaemia, HTN, hypercholosteraemia =
IHD
CVA
peripheral gangrene

Question 7

summarise retinopathy

Answer 7

Background diabetic retinopathy - Hard exudates (deposits of cholesterol) and blot haemorrhages, microaneurysms (little red dots) . Macular is preserved
Cotton woll spots mean ischemia – means hypoxia in cells in this area. Anywhere else get pain on hypoxia, advice people to walk etc to get collaterals. In eye - bad because new vessels thin and can bleed so if bleed = permenant blind – this is pre-proliferative
proliferative - Tiny new vessels – one cell between vitreous and vessel = blind

Question 8

treatment for retinopathy

Answer 8

Treatment for background diabetic retinopathy – improve blood glucose control to prevent vision changing
Pre-proliferative: need pan retinal photocoagulation (laser treatment) destroy some of the periphery. Deliberately kill off part of the eye in order to maintain central vision – must keep macular. Can lose 1/3 periphery without problem
Little spots in periphery – if anything moving in periphery can see it because it catches part of the periphery that is fine. Preserve the middle bit, eyes not better though

Question 9

is there evidence glycaemic control prevents complications

Answer 9

yes - intensive control from new diagnosis helps outcomes at 15 yrs - but no improvement before then
if stop intensive control - pts control returns to that of non-intervention
but have legacy effect - any end point stay better - benefits they had in the 1st 15yrs are lasting

Question 10

summarise findings of the accordand MI and die – coronary arteries already damaged, cant undo study

Answer 10

Randomised people to either have tight control at this point, using their drug? Said that if you want to prove benefit – need to take people already had MI because they’re likely to have another. This reduced the risk of stroke and MI, but more deaths in the intensively controlled people. Actual death rate went up – people had sudden death, because of previous MI – identify a previously unrecognised harm of intensive… cant take people with ischemic and tighten. Because get more hypo, and hypo in IHD = VF
therefore in elderly give less aggressive treatment

Question 11

drug class of metformin

Answer 11

biguanide

Question 12

DCCT trial

Answer 12

type 1 dm

good control improves outcomes

Question 13

incretins

Answer 13

GLP1 analogues

proteins that stimulate the production of insulin

Question 14

gliptins

Answer 14

dipeptidyl peptidase 4 inhibitors – inhibit thing that breaks down your own GLP1

Question 15

insulin

Answer 15

• Excellent drug even when people are not dependant on it (NIDDM)
• Need a long acting depot insulin eg zinc suspension - Insulatard
• Short acting insulin eg normal soluble insulin just before meal - actrapid

Question 16

problem with insulin

Answer 16

when given subcut - the A and B chains stick to each other = delayed release - therefore need to have half an hour before meal

Question 17

insulin analogues

Answer 17

lispro - switch the 2 aa on end of B chain - proline with lysine = make the insulin act much more rapidly
aspart - swith proline to Aspartate
act much quicker which means the pt can inject when they eat
profile mimics insulin profile of insulin following a meal
expensive

Question 18

long acting insulin analogues

Answer 18

different alterations in the molecule to try and attain a plateau conc over time
o Glargine – A chain – add arginine, make sticky so last longer = less chance of hypoglycaemia
insulin detemir - 14C FA chain attached to B29, delayed onset
gives background concentration of insulin like pancreas
previous pong acting insulins were zn suspension of insulin - efficacy waned over 24hr

Question 19

advantages of insulin

Answer 19

can give best control of Hba1c when compared to diet and exercise
no SE when compared to metfromin (diarrhoea), sulphonylureas (occaisional skin reactions), thiazolidinediones (rare hepatic, ?osteoporosis)

Question 20

disadvantages of insulin

Answer 20

o If you drive HGV – cant work
o Exenatide exempt
o Hypoglycaemia common with good control – less MI but cant drive
o Weight gain because insulin make you hungry
 If glucosuria stops calories saved = increased appetite
o Increased insulin as a consequence
o High doses needed

Question 21

why weight gain with insulin

Answer 21

if glucosuria stops = many calories retained
increased appetite 
improved wellbeing 
set point of body weight (hypothalamic) 
poor control enables weight loss

Question 22

GLP-1 analogues

Answer 22

gut males GLP1, signals panc to make insulin and reduce glucagon
has a direct effect on gastric emptying and appetite = increase hypothalamic satiety

exanatide

Question 23

incretins

Answer 23

extendin 4 from Gila monster venom - similar in structure to GLP-1 but longer t1/2
exenatide - sythetic version - injection
increase hypothalamic satiety
liraglutide (victoza or saxenda) semaglutide

Question 24

gliptins

Answer 24

vildagliptin and sitagliptin

ie DPP4 inhibitors

Question 25

gliptins and incretins effect on weight

Answer 25

both seem effective strategies in weight reduction | but must still do exercise

Question 26

thiazolidinediones

Answer 26

insulin sensitisers eg rosiglitazone (taken off market because responsible for adverse effects) pioglitazone

Question 27

SGLT2 inhibitors

Answer 27

• Blocks the resorption of glucose – continue to pass glucose in urine • Sglt2 and 1 transporters normally resorb glucose • However if block them = glucosuria o Get infection – UTI and thrush o However – prevents death in 6mo o Looked for major adverse cardiac events (MACE) o People already had heart attack o Diuretic so BP falls and weight falls because losing glucose o All the other things improved at the same time o At 4yrs – 14% reduction in MACE o At 6mo – reduction in heart disease, and big difference after 3yr o Beneficuial – especially death from MI o Improvement for HF, people with dm have weak ventricles – diuretic = reduce strain on heart o This study chose people at high risk – used in people with HF o No evidence at start of dm, when no risk of IHD – just get the SE and no benefit o If have renal disease – prevents worsening – prevents time to double creatinine and new onset macroalbuminuria o When give empagliflozin – immediately worsen GFR then maintain steady state (same as ACEi) – maintain renal function o Empagliflozin – increased evidence of dm ketoacidosis in pts with insulin and SGLT2 inhibitors

Question 28

overal hyperglycaemic management

Answer 28

from start all on diet and exercise and metformin then add a second oral agent eg GLP-1 receptor agonist or basal insulin if have long-standing, suboptimally controlled T2dm and established atherosclerotic cardiovascular disease, empaglifloxin or liraglutide should be considered - reduce CVS and all-cause mortality when added to standard care

Question 29

treatment options for hyperglycaemia

Answer 29

``` diet and exercise biguanide sulphonylurea insulin senstitiser insulkin incretin gliptin SGLT2 inhibitors ```

Question 30

canagliflozin (SGLT2 inhib) adverse effects

Answer 30

``` hypo when used in combinatioon of insulin or sulphonylurea vulvovaginal candidiasis constipation, thirst, nausea, polyuria - increased urine vol pollakiuria increased urine freq UTI balanitis or balanoposthitis dyslipidaemia increased haematocrit ```