Diabetes Flashcards
pathophysiology of T1 diabetes
Autoimmune disorder where the insulin-producing beta cells are destroyed by the immune system
This results in an absolute deficiency of insulin resulting in raised glucose levels
where is insulin secreted?
beta cells in the islets of Langerhans in the pancreas
common presentation of T1DM
Patients tend to develop T1DM in childhood/early adult life and typically present unwell, possibly in diabetic ketoacidosis
- weight loss, polyuria, polydipsia, fatigue, nausea
prediabetes
fasting glucose 6.1-6.9mmol/L
HbA1c 42-47
require closer monitoring and lifestyle interventions such as weight loss
alpha cell in pancreas secretes
glucagon
beta cell in pancreas secretes
insulin
delta cell in pancreas secretes
somatostatin
F cell in pancreas secretes
pancreatic polypeptide
structure of insulin
alpha & betachains linked via disulphide bonds by C peptide
which is cleaved by B cell peptidase→ activated insulin
insulin secretion from beta cells in directly couple to glucose influx
GLUT2 allows glucose to enter from the interstitium into the cell which then increases the intracellular ATP:ADP ratio.
Closes ATP-sensitive potassium channels (SUR1), depolarising the cell.
This opens voltage-gated calcium channels, increasing intracellular calcium flux
and leading to increased exocytosis of stored insulin.
most common secondary causes of diabetes?
Long-term steroids, other endocrine conditions such as acromegaly and Cushing’s syndrome, and pancreatic damage e.g. cystic fibrosis.
Sulfonylurea cellular mechanism
bind to SUR1 channel and close it which depolarises the cell- endogenous production of insulin
what is a measure of endogenous insulin?
C peptide as exogenous insulin treatment has no C peptide
Pro-insulin is converted to insulin and C- peptide in equimolar amounts
biphasic response of insulin secretion
1st= in response to ingestion of food, stored insulin released 2nd= release of synthesised insulin
route of insulin from the pancreas
- Secreted into portal vein (much higher concentration here than in systemic)
- Acts first on LIVER
- Passes through liver into systemic circulation via hepatic vein
- Acts on MUSCLE and FAT
principle actions of insulin
increased glucose uptake in fat and muscle + glycogen storage in liver and muscle
increased amino acid uptake, protein synthesis and lipogenesis
decreased gluconeogenesis and ketogenesis
insulin causes translation of – to cell membranes
GLUT4 in adipose and muscle tissue
This allows insulin dependant glucose uptake into cells.
does brain tissue have GLUT2 transporters?
no, brain has GLUT3 (not insulin dependant)
glucagon favours
glycogenolysis and gluconeogenesis
stimulatory factors in gluconeogenesis
adrenaline, noradrenaline, Ach
_ obesity leads to insulin resistance
central
glucocorticoids antagonise
insulin
fasting plasma glucose in diabetes
> 7
2hr plasma glucose in OGTT
> 11.1
random plasma glucose in diabetes
> 11.1
HbA1c in diabetes
> 48
is 1 test sufficient for a diagnosis of diabetes if a patient is asymptomatic?
no, the same test should be repeated to confirm diagnosis of diabetes
what does HbA1c reflect?
glycated haemoglobin
• Reflects integrated blood glucose (BG) concentrations during lifespan of erythrocyte (120 days)
when should HbA1c not be used as a diagnostic test?
rapid onset of diabetes- T1DM, children, drugs- steroids
pregnancy- hBA1c is lower and glucose levels can raise rapidly
conditions where RBC survival may be reduced/ increased eg. haemoglobinopathy/ splenectomy
renal dialysis
iron and Vit B12 deficiency
oral glucose tolerance test
a fasting blood glucose is taken after which a 75g glucose load is taken. After 2 hours a second blood glucose reading is then taken
impaired glucose tolerance
Fasting plasma glucose: <7.0 mmol/l
2 hours after 75g oral glucose load: 7.8-11.0 mmol/l
impaired fasting glucose (fasting hyperglcyemia)
Fasting plasma glucose: 6.0 – 6.9 mmol/l
• Intermediate state between normal glucose metabolism and diabetes
prevalence increases with age and increased risk of vascular complication
why does T2DM prevalence increase with age
Beta cell function and number reduces with age
• Obesity increases with age
main driver of progression of T2DM
weight
what can delay progression of glucose intolerance?
lifestyle changes with dietary modification
modifiable risk factors for T2DM
Obesity
Sedentary lifestyles
High carbohydrate (particularly refined carbohydrate) diet
why can T2DM patients present with blurred vison?
lens in eyes coated with glucose and drags interstitial fluid into eyes- refractive error
classical presentations of T2DM
Asymptomatic – found on routine screening
• Thirst, polyuria (osmotic symptoms)
• Malaise, chronic fatigue
• Infections, e.g. thrush (candidiasis); boils
• Blurred vision
• Complication as presenting problem (e.g. retinopathy, neuropathy)
medical disorders associated with T2DM
Obstructive Sleep Apnoea
Polycystic Ovarian Disease
Hypogonadotrophic Hypogonadism in men- reduced testosterone
Non-Alcoholic Fatty Liver Disease
risk alleles for T1DM
HLA haplotypes (HLA-DR and HLA-DQ) as risk alleles- genetic tendency for autoimmune disorders
markers of autoimmune destruction
GAD, IA2 and/or ZnT8
Destruction of pancreatic beta cells carried out by which cell?
cytotoxic lymphocytes
autoimmune disorders associated with T1DM
Thyroid disease • Pernicious anaemia • Coeliac disease • Addison’s disease • Vitiligo
secondary diabetes- exocrine pancreas disorders
Pancreatectomy • Trauma • Tumours CF chronic pancreatitis- alcohol
Maturity Onset Diabetes of the Young - MODY
A group of autosomal dominant inherited genetic disorders affecting the production of insulin. Results in younger patients developing symptoms similar to those with T2DM, i.e. asymptomatic hyperglycaemia with progression to more severe complications such as diabetic ketoacidosis
glycemic control monitoring devices
Home Blood Glucose Monitoring
CGMS – Continuous Glucose Monitoring System
Freestyle Libre Flash Glucose Monitoring System
HbA1c
Blood Ketone Monitoring
Severe insulin deficiency results in
life-threatening metabolic decompensation (diabetic ketoacidosis)
incretins-
gut hormones released post prandially that stimulate insulin release and inhibit glucagon release
HbA1c targets in patients treated with lifestyle/metformin
48mol/mol
HbA1c targets in patients in treatment including any drug which may cause hypoglycaemia (e.g. lifestyle + sulfonylurea)
53 mmol/mol
glycemic index
measure of change in blood glucose following ingestion of a particular food
low GI food
produce a slow, gradual rise in blood glucose after ingestion
• starchy foods (rice, spaghetti, granary bread, porridge) and pulses like beans and lentils
oral hypoglycaemic drugs are indicated for
T2DM
oral hypoglycaemic drug in T1DM
Insulin sensitisers in combination with insulin in Type 1 diabetes
sulfonylurea indication and use (glipizide)
used in non-obese patients (may be insulin-deficient)
• used as monotherapy or in combination with metformin, glitazone or insulin
sulfonylurea SE
Weight gain
Hypoglycaemia
Increased risk of cardiovascular disease and myocardial infarction when used as monotherapy
Metformin (biguanide) mechanism
decreases hepatic gluconeogenesis
• increases insulin sensitivity in muscle
weight neutral
thiazolidinediones (pioglitazone) mechanism
increases insulin sensitivity and decreases liver gluconeogenesis
GLP-1 is rapidly degraded in plasma by
enzyme Dipeptidyl Peptidase 4 (DPP- 4)
Plasma GLP-1 is lower in people with
impaired glucose tolerance (IGT) and type 2 diabetes
GLP-1 Physiological Effects
- Stimulates glucose- dependent insulin secretion
- Suppresses glucagon secretion
- Slows gastric emptying
- Reduces food intake
- Improves insulin sensitivity
GLP1 is secreted from
L cells in the intestine
GLP-1 mimetic eg. Exenatide route and combo
given as a subcutaneous injection
given in combo with either metformin or sulfonylurea
GLP-1 mimetic SE
GI tract upset
Weight loss
Dizziness
Low risk of hypoglycaemia
Gliptins mechanism, route, combo
DDP-4 inhibitors- inhibit degradation of incretin hormones and enhance their actions
• Oral route of administration
• Taken in combination with metformin
• Produce modest reduction in HbA1c
SE of gliptins
GI tract upset
Symptoms of upper respiratory tract infection
Pancreatitis
SGLT-2 Inhibitors eg. empagliflozin mechanism
glucuretic to remove glucose that would otherwise be reabsorbed- increase urinary excretion of glucose
SE of SGLT-2 Inhibitors
Glucoseuria (glucose in the urine)
Increased rate of urinary tract infections
Weight loss
Diabetic ketoacidosis, notably with only moderately raised glucose- rare
indications of insulin therapy
T1DM (ketosis-prone)
T2DM- severe hyperglycemia
Secondary failure to anti-diabetes drugs
Severe intercurrent illness
Metabolic complications (hyperosmolar states)
short acting insulin
working in around 30 minutes and last around 8 hours
soluble- actrapid, humulin-S
intermediate acting insulin
start working in around 1 hour and last around 16 hours
Isophane (NPH)- Insulatard; Humulin-I
basal bolus insulin regimen (T1)
Short-acting or fast- acting insulin before meals; intermediate-acting or long- acting insulin once daily
when is twice or once daily insulin regimens used?
T2 diabetes
once daily with oral tablet
routes of administration of insulin
SUBCUTANEOUS - syringes, pens, pumps
• intrapulmonary - inhaler (historical)
• intravenous, intramuscular - injection (emergency use)
• intraperitoneal - dialysate (renal failure)
• transplanted islets - pancreatic islets
lipohypertrophy at insulin injection sites
slows insulin absorption but resolves if site avoided
Side-Effects of Insulin Therapy
HYPOGLYCAEMIA
• WEIGHT GAIN
• lipodystrophy at injection sites
• peripheral oedema (salt & water retention)
• insulin antibody formation (animal insulins)
• local allergy (rare)
why does alcohol without food cause insulin induced hypoglycemia?
turns off hepatic gluconeogeeneis so mismatch between plasma insulin and glucose concentrations
treatment of mild hypoglycaemia
SELF- Oral fast-acting carbohydrate (10-15g)
- glucose drink
- glucose tablets, confectionery
Oral supplementary snack (starch)
treatment of severe hypoglycaemia
EXTERNAL HELP- Parenteral therapy - i.v. 20% dextrose (25-50g)- not alert - i.m. glucagon (1mg)- can't get IV access Oral therapy - buccal glucose gel; jam, honey
microvascular complications of diabetes
retinopathy, nephropathy, neuropathy, skin and connective tissue changes
macro-vascular complications of diabetes
atherosclerosis, peripheral vascular disease, ischaemic heart disease, cerebrovascular disease & stroke
risk factors for microangiopathy (capillary wall thickening)
diabetes duration, hyperglycaemia, hypertension, smoking
what causes pear scented breath?
fat breakdown to fatty acids causing Acetyl CoA production -> ketones
why is there a risk of hypoglycaemia with sulfonylureas?
endogenous insulin release even if there isn’t any glucose present
conditions associated with T1DM that can cause hypoglycemia
Coeliac disease- mismatch of carbs and insulin
– Addison’s disease (cortisol important in counterregulation)
– Hypothyroidism
– (Hypopituitarism)
autonomic symptoms of hypoglycemia
Sweating
Shaking
Pounding heart (palpitations)
Hunger
neuroglycopenic symptoms of hypoglycemia
Confusion Drowsiness Difficulty speaking Odd behaviour Incoordination
hypoglycemia in children can manifest as
behavioural change- stroppy
mimic stroke in the elderly can be a symptom of
hypoglycaemia
1st defence and prolonged defence hormones in hypoglycemia
adrenaline and glucagon in 1st defence
GH and cortisol in prolonged hypoglycemia
Whipples Triad:
Symptoms result from hypoglycaemia can be confirmed by 2 out of 3 of:
Typical symptoms
Biochemical confirmation (no agreed cut-off)- generally 4
Symptoms resolve with carbohydrate
when treating hypo, what should rapid acting carbs be followed by?
slow release carbs- stops patient from going into rebound hypo
when can someone drive after hypo?
45 minutes later
one severe hypo increases the risk of
further severe hypos
Pathophysiology of diabetic ketoacidosis
DKA is caused by uncontrolled lipolysis and ketogenesis which results in an excess of free fatty acids that are ultimately converted to ketone bodies
hyperglycaemia and hyperketonaemia cause diuresis and dehydration
most common precipitating factors of DKA
infection, missed insulin doses and myocardial infarction
Features of DKA
abdominal pain
polyuria, polydipsia, dehydration
Kussmaul respiration (deep hyperventilation)
Acetone-smelling breath (‘pear drops’ smell)
3 main principles of DKA management
– Fluids: initially fast then slower, to rehydrate
– iv insulin: switch off ketone body production
– Monitor potassium: metabolic acidosis shifts K+ to extracellular
space. As you give insulin, K+ moves into the cells and K+ falls- risk of arrhythmia
insulin after DKA
Swap to s/c insulin once patient eating and drinking- IV insulin has v short half life
• Ensure basal insulin given ≥ 1h before iv insulin stops
hyperosmolar hyperglycaemic state typically presents in
the elderly with T2DM
HHS onset
HHS comes on over many days, and consequently the dehydration and metabolic disturbances are more extreme than DKA
Pathophysiology of HHS
Hyperglycaemia results in osmotic diuresis with associated loss of sodium and potassium
Severe volume depletion results in a significant raised serum osmolarity (typically >320 mosmol/kg), resulting in hyperviscosity of blood.
why may HHS patients not look as dehydrated as they are?
Despite these severe electrolyte losses and total body volume depletion, the typical patient with HHS, may not look as dehydrated as they are, because hypertonicity leads to preservation of intravascular volume.
Clinical features of HHS
General: fatigue, lethargy, nausea and vomiting
Neurological: altered level of consciousness, headaches, papilloedema, weakness
Haematological: hyperviscosity (may result in MI, stroke and peripheral arterial thrombosis)
Cardiovascular: dehydration, hypotension, tachycardia
Diagnosis of HHS
- Hypovolaemia
- Marked Hyperglycaemia (>30 mmol/L) without significant ketonaemia or acidosis
- Significantly raised serum osmolarity (> 320 mosmol/kg)
Management of HHS
- Normalise the osmolality (gradually)- elderly patients so can’t risk flooding lungs
- Replace fluid and electrolyte losses- reduced in Na+
- Normalise blood glucose (gradually)
Prophylactic anticoagulation- heparin
when should metformin be stopped?
- eGFR <30
- during tissue hypoxia: shock, MI, sepsis, dehydration
- after iodine containing contrast
- 2 days before general anaesthetic
triggers for lactic acidosis
advanced kidney failure
tissue hypoxia
why should insulin be started as soon as possible after diagnosis?
Children can develop dehydration + acidosis within 24 hours of first presentation. Children < 2years old are most at risk.
avoid metabolic decompensation and DKA
in child with diabetes vomiting is sign of
insulin deficiency until proved otherwise
T1DM in children HbA1c target
48 or lower
TIR target
time in range of target glucose range
70% target
types of diabetes in pregnancy
gestational diabetes
pre-existing diabetes- T1, T2, CF relates, MODY, steroid induced
Risk factors for gestational diabetes
BMI of > 30 kg/m²
previous macrosomic baby weighing 4.5 kg or above
previous gestational diabetes
first-degree relative with diabetes
family origin with a high prevalence of diabetes (South Asian, black Caribbean and Middle Eastern)
Screening for women who’ve previously had GDM
OGTT should be performed as soon as possible after booking and at 24-28 weeks if the first test is normal. NICE also recommend that early self-monitoring of blood glucose is an alternative to the OGTTs
screening for women with risk factors for GDM
women with any of the other risk factors should be offered an OGTT at 24-28 weeks
gestational diabetes is diagnosed if either:
fasting glucose is >= 5.6 mmol/l
2-hour glucose is >= 7.8 mmol/l
main hormone that causes GDM
hPL- from 2nd trimester, increasing insulin requirements
gestational diabetes increases the risk of
T2DM- 50% 5 year risk
fetal risks of diabetes in pregnancy
- macrosomia (>4.5kg) - hyperglycaemia
- stuck in birth canal (shoulder dystocia)
- premature/ intrauterine growth retardation- placental problems bc preexisting diabetes
- anencephaly
target HbA1c in GDM
53
maternal risks of diabetes in pregnancy
• Miscarriage
• Pre-eclampsia
• Preterm labour
• Intrapartum complications
• Progression of microvascular complications
Severe hypoglycaemia- 1st trim
• Ketoacidosis- inc risk of neonatal death
pre-pregnancy screening in diabetes
background retinopathy
microalbuminuria
what diabetic complication can progress in pregnancy?
retinopathy
GDM includes
women with undiagnosed type 1, type 2 or monogenic (MODY) DM
after birth if fetal insulin is still high, there is a risk of
hypoglycaemia
Management of GDM
home blood glucose monitoring
metformin/insulin
induced at term
insulin stopped once delivered
targets for self monitoring of pregnant women (pre-existing and gestational diabetes)
Fasting 5.3 mmol/l
1 hour after meals 7.8 mmol/l, or:
2 hour after meals 6.4 mmol/l
what type of insulin used in GDM?
short acting
aspirin in pregnancy
Aspirin 75mg from 12-36 weeks (reduces pre- eclampsia risk)
Induced labour in GDM
Labour induced before 40 weeks
– Because of increased risk of IUD and other maternal/fetal complications
– Increased risk of instrumental delivery and C Section
Neonatal immediate postnatal care checks for
hypoglycaemia, macrosomia, jaundice, resp distress syndrome
SE of metformin
Diarrhoea and abdominal pain- dose dependent
Lactic acidosis
Does NOT typically cause hypoglycaemia
SE of Pioglitazone
Weight gain Fluid retention Anaemia Heart failure Extended use may increase the risk of bladder cancer Does NOT typically cause hypoglycaemia
