principles Flashcards
define diabetes
hyperglycasemia above a fasting glucose of 7mmol/L
-> a threshold set in relation to risk of diabetic retinopathy
main mechanism of metformin
inhibits complex 1 in respiratory chain causing a fall in cellular ATP, results in -
- reduction in hepatic gluconeogenesis
- activation of AMP-activated protein kinase (AMPK)
- increases gut glucose utilisation + metabolism
what organs does metformin highly concentrate in?
intestine, liver, kidney
Organic Cation Transporters (OCTs) are found here which metformin needs to get into cells as its hydrophillic
benefits of metformin
- weight neutral / negative
- v cheap
- potent glucose monitoring
- generally well tolerated
- CV benefit ish
metformin side effects
GI upset - diarrhoea, nausea, abdo pain (20%)
lactic acidosis - in liver disease / renal failure, metformin increase lactate
reduced B12 absorption
*modified release formula available (better tolerated)
how can metformin side effect be reduced?
starting - should be titrated up slowly to reduce incidence of GI side effects
sulphonylureas MoA
act directly on pancreatic beta-cells to increase insulin secretion
glucose independent = insulin secretion even when not needed (glucose low/norma) –> results in HYPOglycaemia
suphonylurea side effects
hypoglycaemia risk
weight gain
cheap but lack of CV benefit (compared to metformin)
thiazolidinediones side effects
weigh gain
fluid retention - peripheral oedeam
fracture risk - increase fat in bones + decrease bone density
thiazolidinediones (TZDs) MoA
TZD = pioglitazone
PPAR-gamma rceptor agonist
reduces peripheral insulin resistance (insulin sensitiser)
increase fat mass - “suck out” fat from liver, pancreas + muscle
increases adiponectin + reduced inflam cytokines
Dipeptidyl peptidase-4 (DDP-4) inhibitors
increases levels of incretins (GLP-1 + GIP) by decreasing their peripheral breakdown
–> increase insulin secretion but only when needed (unlike sulphonylureas)
well tolerated - minimal SE
moderate cost
weight neutral
weak glucose lowering
GLP-1 like molecules
promote insulin secretion when needed (glucose dependent)
lowers glucagon
reduces appetite (weight loss) + gastric emptying + BP
potent at glucose lowering
expensive
SE - N+V, gallstones
(subcutaneous)
SGLT-2 inhibitors MoA
inhibits reabsorption of glucose in the kidney
–> makes you pee sugar - increase thrush risk
(oral)
describe the structure of insulin
polypeptide composed of an A chain + B chain linked by disulfide bonds
how is insulin synthesised?
in the rough endoplasmic reticulum of beta-cells
preproinsulin -> proinsulin + single peptide -> C-peptide + insulin
C-peptide = no function preproinsulin = single chain preprohotmone
what do alpha-cells of the pancreatic islets secrete?
glucagon
what do delta-cells of the pancreatic islets secrete?
secrete somatostatin
comment on insulins physiological window
NARROW
death by causing hypoglycaemic coma
how does glucose enter pancreatic beta-cells?
via GLUT2 glucose transporter
what is glucose phosphorylated by in the pancreatic beta cell?
glucokinase
list the steps of insulin release from an increase in glucose metabolism
- increase in glucose metabolism in beta cell leads to increase in intracellular ATP
- ATP inhibits ATP-sensitive channel K channel leading to depolaristaion of beta cell membrane
- depolarisation causes opening of voltage-gated Ca2+ channels allowing Ca2+ to enter
- increase in Ca2+ leads to fusion of secretory vesicles with the cell membrane –> release of insulin
what can be said about the amount of glucose that enters the beta-cell compared to the amount of insulin released?
directly proportional
glucokinase activity in patients with type 2 diabetes
glucokinase is maximally active at all times
- > post meal (increase glucose) won’t stimulate more insulin = glucose insensitive
- > chronically secreting insulin (high levels) = mitochondrial exhaustion = reduced ATP production
the release of insulin is biphasic, what are the differences between the 2 wves?
1st = short, sharp peak = prevents sharp increase in glucose (hypo)
2nd = broader, shorter = more tuned to insulin requirement, related to glucose intake (amount, duration)
3 key healthy lifestyle behaviours to prevent obesity
limiting energy dense food
reducing sedentary time
increase physical activity
why is prevention difficult in the NHS?
not easy
not cheap
requires constant reinforcement by education
what is the evidence that T2DM can be prevented?
weight reduction - calorie reduction + improved exercise
what are the barriers to prevention of T2DM + how can they be overcome?
identify + engage people at risk - screen for impaired glucose tolerance (HbA1C)
political - sugar tax
low income at highest risk but poorest engagement
evaluate if programme working - high quality data collection
is it posiible to reverse hyperglycaemia?
yes - weight reduction
**less need for medication
how do you measure insulin resistance?
gold standard = hyperinsulinemic-euglycemic clamp
sample taken from artery
insulin constantly effused, glucose variably depending on levles in sample, RBCs effused to replace
alpha cells + glucagon
secrete glucagon inversly proportional to blood glucose
glucagon acts on liver to promot hepatic glucose production - raising blood glucose
glucagon secretion during fed state in T2DM
glucagon secretion is elevated in the fed state in T2D + contributes to hyperglycaemia
how do alpha cells respond to low glucose
K-ATP channels open
voltage-gated sodium channels contribute to action potentials
P/Q type volgated gated calcium channels enable calcium influx
glucagon exocytosis is triggered
how do alpha cells respond to high glucose?
K-ATP channels closed, cell depolarised
presence of SGLT 2 glucose transporter contributes to non-voltage regulated sodium ion influx
NaV + CaV channels closed, glucagon not exocytosed
current guidlines recommend prioritising what percentage weight loss in individual living with type 2 diabetes who are overweight or obese?
> 5%
name 2 benefits of physical activity for individual with type 2 diabetes?
improved glycaemic control
reduction in cadiovascular risk
where are the thyroid hormone receptors typically found in a cell?
nucleus
Thyroid hormones enter cells by diffusion or by carriers, once inside they bind to a thyroid hormone receptor. These are intracellular DNA-binding proteins found in the nucleus. Once bound they form a complex which then binds to the thyroid hormone responsive element on DNA.
what are the 3 different types of hormone structure?
- steroids e.g. oestrogen
- amine-derived e.g. adrenaline
- proteins e.g. insulin, ADH, oxytocin
effect of insulin on proteolysis, lipolysis + glycogen synthesis?
decreases proteolysis
decreases lipolysis
increases glycogen synthesis
what hormone stimulates ACTH production?
CRH corticotropin-releasing hormone
–> ACTH then stimulates cortisol
what does GnRH stimulate?
stimulates release of LH/FSH which goes on to stimulate estrogen / testosterone depending
what controls prolactin secretion?
dopamine inhibits prolactin secretion
which hormones released by the hypothalamus are stored in the posterior pituitary?
vasopress + oxytocin
what hormones in the hypothalamus + pituitary stimulate production of thyroxine?
TRH –> TSH –> thyroxine
what type of drug is orlistat?
lipase inhibitor
what is the max time orlistat is safe to prescribe?
4yrs - 2yrs recommeded tho
definition of a very low calorie diet
under 800kcal
! under close supervision
never first line + only BMI >30
what is the BMI referral criteria for bariatic surgery?
BMI > 40
or 35-40 if co-morbitidies
have tried everything else
can cope with surgery shiz
which bariatric surgery is viewed as a malabsorptive procedure?
gastric bypass
bilio-pancreatic diversion
why is it difficult to maintain weight loss?
adaptive thermogenesis - weight loss seen as threat to survival
the lower the resting metabolic rate (RMR) - the harder it is to lose weight
