principles Flashcards by Susannah Welch

define diabetes

hyperglycasemia above a fasting glucose of 7mmol/L

-> a threshold set in relation to risk of diabetic retinopathy

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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

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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

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benefits of metformin

weight neutral / negative
v cheap
potent glucose monitoring
generally well tolerated
CV benefit ish

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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)

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how can metformin side effect be reduced?

starting - should be titrated up slowly to reduce incidence of GI side effects

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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

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suphonylurea side effects

hypoglycaemia risk
weight gain

cheap but lack of CV benefit (compared to metformin)

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thiazolidinediones side effects

weigh gain
fluid retention - peripheral oedeam
fracture risk - increase fat in bones + decrease bone density

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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

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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

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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)

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SGLT-2 inhibitors MoA

inhibits reabsorption of glucose in the kidney
–> makes you pee sugar - increase thrush risk

(oral)

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describe the structure of insulin

polypeptide composed of an A chain + B chain linked by disulfide bonds

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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

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what do alpha-cells of the pancreatic islets secrete?

glucagon

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what do delta-cells of the pancreatic islets secrete?

secrete somatostatin

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comment on insulins physiological window

NARROW

death by causing hypoglycaemic coma

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how does glucose enter pancreatic beta-cells?

via GLUT2 glucose transporter

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what is glucose phosphorylated by in the pancreatic beta cell?

glucokinase

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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?

1. steroids e.g. oestrogen 2. amine-derived e.g. adrenaline 3. 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