an introduction to type 2 diabetes: a metabolic disease Flashcards
diabetes mellitus definition
metabolic diseases characterised by hyperglycaemia resulting from defects in insulin secretion, insulin action or both
type 2 diabetes definition
metabolic disorder caused by insulin resistance and insulin deficiency resulting in hyperglycaemia
pre-diabetes definition
borderline diabetes - at high risk of developing type 2 diabetes
how can pre-diabetics be identified?
- impaired glucose tolerance test (IGT) - ingest 75g of carb and measure blood glucose pre and post test
- above normal blood glucose concentration after fasting (impaired fasting glucose = IFG)
- above normal HbA1c
NICE recommends high risk/moderate risk rather than pre-diabetes
what is a normal fasting glucose?
<5.5
what is fasting glucose levels in pre diabetes and diabetes?
pre = 5.5-7
diabetes = 7<
normal oral glucose tolerance test result
<7.8
oral glucose tolerance test results in pre diabetes and diabetes
pre = 7.8-11.1
diabetes = 11.1<
normal HbA1c levels
<42
HbA1c levels in prediabetes and diabetes
pre = 42-47
diabetes = 47<
what does HbA1c look at?
glycated Hb over the last 3 months
t2d accounts for what % of cases?
90%
is diabetes more common in men or women?
men
what age group is most affected by diabetes?
65+
but increasing diagnosing under 40 years and in children
what ethnicities are msot affected?
black Caribbean and Indian
how and why are south asians more predisposed to t2d?
- more abdominal fat
- more insulin resistance and hyperinsulinaemia
- increased inflammatory response
- lower adiponectin
- more dyslipidaemia
why?? underlying genetic factors, lifestyle, cultural practices
what accounts for death in 70% of type 2 diabetics?
cardiovascular disease
link between morbidity + mortality and t2d
- commonest cause of chronic kidney disease
- commonest cause of lower limb amputation
- commonest cause of blindness in working population
- non-alcoholic fatty liver disease (NAFLD) — most common liver disease in world
type 2 diabetes pathophysiology
what are the non-modifiable risk factors of t2d?
- age
- ethnicity
- family history
- low birth weight
- history of GDM
what are modifiable t2d risk factors?
- obesity = approx 80% of the risk for developing t2d
- hypertenison
- dyslipidaemia (low HDL, high triglycerides)
- PCOS
- poor dietary habit (low fibre, high glycaemic index diet)
what type of fat has a much greater association with t2d?
visceral and abdominal fat have a much greater association wit t2d than cutaneous fat
what does an increase fat mass lead to?
insulin resistance and type 2 diabetes
genetics of t2d?
- polygenic
- the risk of developing the condition is as high as 70% if both parents have suffered from the condition
- 1st degree relatives of individuals with t2d are about 3 times more likely to develop the disease
- monozygotic twins, there is a 50-90% concordance for developing the condition
environment — > genetics
what are the key pathological processes in t2d?
- insulin resistance
- insulin secretory defect
- increased production of glucose by the liver
- loss of incretin effect
- other mechanisms eg. insulin feedback/CNS changes
what is insulin used for?
- glucose transport
- survival
- glycogen synthesis
- axon growth
- protein synthesis
- cell growth
- gene expression
- proliferation, differentiation, development
COMPLEX SIGNALLING PATHWAY
what is insulin released into the blood from?
beta cells Islets of langerhans in pancreas
what type of receptor is the insulin receptor?
modified tyrosine kinase receptor
what is an important component of the insulin signalling cascade?
the exocytosis of GLUT4 to the cell membrane and then the facilitated diffusion of glucose into the cell
energy from the glucose is used for what things inside the cell?
- cellular respiration
- protien and lipid synthesis
- inhibit hepatic gluconeogenesis (if in liver)
- promotes hepatic glycogen synthesis
what is insulin resistance?
a problem with the cellular mechanisms which allow a normal insulin signalling cascade
what are the effects of insulin resistance?
- hyperglycaemia
- increased lipolysis
- increased proteolysis
- increased hepatic gluconeogenesis
what are adipocytes innervated by?
autonomic nervous system, particularly the sympathetic nervous system
what is increased in high amounts of adipocytes?
increased lipolysis —> increased fatty acids = damaging molecules
- free fatty acids used as energy for gluconeogenesis —> increased glucose
- fatty acids decrease glucose utilisation and glycogenesis in muscle
- free fatty acids are toxic to beta cells — less insulin released
what inflammatory mediators do adipocytes release? what do they trigger?
TNFa and IL-6 — trigger more lipolysis
how is the sympathetic nervous system altered in obesity?
greater action of the SNS —> leads to more lipolysis and affects muscles (eg. by decreasing muscle blood flow)
what are cellular mechanisms of insulin resistance?
- genetic causes (rare)
- lipotoxicity — direct effect of too many free fatty acids on cells
- inflammation
- oxidative stress/glucotoxicity
- endoplasmic reticulum stress
why do you get impaired insulin secretion?
- as hyperglycaemia develops, beta cells secrete more insulin to deal with the increase in glucose
- as a beta cell mass is depleted, insulin levels fall and there is secretory failure
- the time frame for beta cell dysfunction to absolute insulin deficiency is highly variable
- at time of diagnosis, B cell dysfunction may be reduced by 50% in patients with t2d
in patients with t2d, there is increased deposition of what within islet cells?
amyloid
what are toxic to beta cells?
hyperglycaemia (glucotoxicity) and high lipids (lipotoxicity)
also chronic low level inflammation
what are beta cells damaged by?
- amyloid deposits
- inflammation
- glucotoxicity
- lipotoxicity
what is hepatic gluconeogenesis increased in t2d?
- increased availability of gluconeogenesis substrates eg. fatty acids—> increased gluconeogenesis
- resistance of the liver to the action of insulin —> improper suppression of hepatic gluconeogenesis
- elevated glucagon due to resistance to feedback suppression from insulin and glucose
what are incretins?
gut peptide hormones that are secreted after nutrient intake and whose primary role is to stimulate insulin release
what are the 2 incretins?
- GLP-1 = glucagon-like peptide 1 = secreted by GLP-1 L cells ;coated in ileum and large intestine
- GIP = glucose-dependent insulinotropic polypeptide = secreted by GIP K cells located in the proximal duodenum
what does GLP-1 do?
- inhibits gastric emptying — slows the transit of carbs through the gut and so gives more time for insulin to act and for the body to bring down blood glucose levels
- promotes insulin release
- inhibits glucagon release
- appetite suppressing effects on the brain
what does glucagon do?
promotes glycogen breakdown to release glucose
GLP-1 levels in t2d?
decreased
symptoms and signs of t2d
- asymptomatic
- polyuria and nocturia = osmotic symptoms
- polypdipsia
- lethargy
- weight change (weight loss once severe insulin deficiency occurs)
- thrush/genital itching
- prolonged healing time
- visual disturbance
type 1 vs type 2 diabetes
note cause of death is CVD in both
how is diabetes diagnosed?
diabetes symptoms (eg. polyuria, polypdipsia), plus:
- HbA1c of >48 mmol/mol or
- a random venous plasma glucose conc >_11.1 mmol/l or
- a fasting plasma glucose conc of >_7mmol/l or
- 2 hour plasma glucose concentration >_11.1 mmol/l 2 hours after 75g anhydrous glucose in an oral glucose tolerance test (OGTT)
with NO symptoms:
- 2 separate +ve results from separate days (any 2 of the above but in common practise HbA1c is used)
when would HbA1c not be used?
- rapid onset of diabetes — an increase in HbA1c may not be detected until a few weeks later
- pregnancy — HbA1c is typically lower
- conditions with decreased red cell survival (haemoglobinopathy, haemolytic anaemias severe blood loss, splenomegaly, antiretroviral drugs)
- increased red cell survival may increase HbA1c eg. splenectomy
- renal dialysis reduces HbA1c especially if treated with erythropoietin
- iron and B12 deficiency and their treatment
for the above (except pregnancy) diagnose by fasting glucose >_7 mmol/L twice, or once with symptoms
pregnancy — separate diagnostic criteria
aims of diabetes treatment
- remission — WEIGHT LOSS
- improve glycaemic control
- treat co-existing CV risk factors (dyslipidaemia, hypertension, smoking etc)
how is t2d managed?
- lifestyle modification — NHS diabetes prevention programme (DPP)
- ASSESS cv risk eg. QRISK2/3
- diet and exercise
- weight loss - aim 10% reduction
- smoking cessation
- pharmacology
- bariatric surgery (BMI > 35 and diagnosed with T2D in last 10 years)
- regular review (HbA1c every 3-6 months)
- treatment escalation if HbA1c >58mmol/l
- screening annually for retinopathy, nephropathy, neuropathy
what are the treatment targets in t2d?
- HbA1c <48mmol/mol if not on medication which cause hypoglycaemia (otherwise <53 mmol/mol)
- BP <140/80 (<130/80 if complications present)
- total cholesterol <4mmol/l, LDL <2 mmol/l, HDL >1 (men) >1.2 (women)
how do you test for retinopathy?
retinal photography
how do you test for nephropathy?
urine dipstick, albumin creatinine ratio (ACR), urea and electrolytes
how do you test for neuropathy?
foot inspection, 10g monofilament or 128Hz tuning fork tests and pulses
what are the different pharmalogical treatments in t2d?
dependent on the individual and CV risk. start with metformin
look at treatment algorithm
in lecture
what does metformin do?
- reduces insulin resistance and hepatic glucose output
- reduces weight
- appetite suppressing effects
- exact mechanisms not known — AMPK? (=energy sensing kinase) GDF15? (peripheral cytokines and messengers)
- dosage : 500mg OD, increase stepwise to 1g BD
what are metformin side effects? what is used instead?
- diarrhoea, nausea, anorexia, lactic acidosis
- modified release preparations
what do SGLT2 inhibitors do?
- reduces glucose reabsorption from PCT of nephron (where 80% of glucose is reabsorbed via SLGT2 channels in PCT)
how are SGLT2 inhibitors used?
- combination therapy in most patients
- can be used as mono therapy in specific cases eg. cant tolerate metformin due to heart failure and higher CV risk, poor kidney function
what are the additional effects of SGLT2 inhibitors?
weight loss, BP lowering, CVD protection, renal protection
side effects of SGLT2 inhibitors?
increased risk of UTI, DKA (diabetic ketoacidosis but rare)
what do sulphonylureas do?
- increase insulin secretion
- meglitinides have similar mechansim
- bind to SUR-1 receptor (subunit linked to KATP channel) leading to closure of ATP K+ channel — depolarisation — Ca++ enters — exocytosis of insulin
what are the main side effects of sulphonylureas?
hypoglycaemia and weight gain
what is the dipeptidyl peptidase 4 (DPP4) enzyme?
an enzyme that break down GLP-1
what do DPP4 inhibitors do?
prevent the action of DPP4 enzyme — GLP-1 remains in system for longer
- prevents breakdown of incretins, preserving incretin effect
how are DPP4 inhibitors used?
- usually combination therapy with metformin/metformin + SU
- monotherapy if metformin or SU intolerant
DPP4 inhibitor SEs
GI disturbance (due to GI emptying being slowed down), rash, headache, sore throat
describe thiazolidinediones
not used as much anymore
- act on PPARy nuclear receptor
- PPARy agonist
- inhibits specific gene transcription - insulin-sensitive gene transcription mechanisms — increases glucose uptake into adipocytes so it can be stored and converted into lipids, increase FA transporters to be inserted into adipocyte CM so more lipogenesis)
- also a link with inflammatory mediators and cytokines
activation decreases insulin resistance
SEs = increased fracture risk, fluid retention, HF, small increased risk of bladder cancer
what do GLP-1 analogues do?
when are GLP-1 analogues used?
when should insulin therapy be considered?
if:
- inadequate control despite dual therapy (metformin plus another oral antidiabetic drug)
- oral antidiabetic drugs are contraindicated or not tolerated
what are reasons for not initiating insulin therapy?
- obesity
- physical and mental health - hypoglycaemia
- anxiety about needles
- personal preference
- concerns related to license to drive group 2 vehicles
what is used in insulin therapy?
hypoglycaemia is any blood glucose less than what?
4mmol/L
symptoms of hypoglycaemia
hunger, palpitations, sweating, tremors
what do recurrent hypoglycaemic episodes lead to?
CVD and cognitive impairment
who needs to let the DVLA know about their diabetes?
on insulin treatment for linger than 6 months
