Case 05 - Diabetes Flashcards
Hormones involved in the regulation of blood glucose levels
- Anabolic hormones: insulin
- Catabolic hormones: glucagon, adrenaline/epinephrine (catecholamines), cortisol, growth hormone (GH)
Alpha cells release
Glucagon
Hyperglycaemia occurs as a result of inadequate insulin action. This can be due to 3 main causes:
- Reduced insulin production
- Reduced insulin target organ sensitivity
- An overwhelming increase in the activity of glucagon, cortisol or GH
Diabetes is defined as
A reduction in insulin action sufficient to cause a level of hyperglycaemia that, over time, will result in diabetes specific microvascular disease, such as retinopathy, nephropathy and neuropathy
Non-diabetic hyperglycaemia is defined as
A reduction in insulin action sufficient to cause hyperglycaemia, but not to a level that will result in microvascular damage
Other names for non-diabetic hyperglycaemia (NDH)
- ‘Pre-diabetes’
- Impaired glucose tolerance (IGT)
- Impaired fasting glucose (IFG)
Having diabetes generally increases one’s relative risk of death, but the risk is higher in:
- Type 1 diabetics
- Those aged under 55
- (Females)
The prevalence of diabetes (both types 1 and 2) has risen consistently over the past 20 years, with a 5% increase in the number of diagnoses every year. What percentage of the English population is currently diagnosed with diabetes?
> 5% (3 million people, estimated 1 million people remain undiagnosed)
Percentage of hospital inpatients with diabetes
15%
Diabetes is a common cause of (1) and the commonest cause of (2) . It also causes >50% of (3).
(1) Blindness in working-age adults
(2) End-stage kidney disease (ESKD)
(3) Major amputations
Diabetes causes >50% of what?
Major amputations
Percentage of the NHS budget spent on diabetes
10%
What percentage of diabetics has
(1) type 1 diabetes?
(2) type 2 diabetes?
(1) 10%
(2) 90%
As for diabetes, the prevalence of non-diabetic hyperglycaemia (NDH) has also been on the rise. What percentage of the English population has NDH?
~10%
Individuals with non-diabetic hyperglycaemia are at an increased risk of
- Progressing to type 2 diabetes
- MACROvascular disease (CHD, CVD, PVD)
- Gestational diabetes (associated with significant foetal morbidity/mortality)
Every year X% of individuals with non-diabetic hyperglycaemia develops type 2 diabetes.
5-10%
Is diabetes more common in men or women?
Men (both type 1 and 2, and in all age groups)
(1) MACROvascular = affecting ?
(2) MICROvascular = affecting ?
(1) Arteries
(2) Capillaries
Normal HbA1C
<42 mmol/mol
HbA1C range for NDH/IGT/IFG/‘pre-diabetes’
42-47 mmol/mol
HbA1C for diabetes
≥48 mmol/mol
Normal fasting glucose
<6.1 mmol/L
Fasting glucose for NDH/IGT/IFG/‘pre-diabetes’
6.1-6.9 mmol/L
Fasting glucose for diabetes
≥7 mmol/L
Normal random blood glucose (RBG)
<7.8 mmol/L
Random blood glucose (RBG) for NDH/IGT/IFG/‘pre-diabetes’
7.8-11 mmol/L
Random blood glucose (RBG) for diabetes
≥11.1 mmol/L
Random blood glucose (RBG) is defined as
Plasma glucose levels 2h post a 75mg glucose load
A raised fasting glucose alone is not enough to diagnose diabetes - what is?
- 2 x raised fasting glucose OR
- 1 x raised fasting glucose with symptoms
Which type of diabetes can’t be diagnosed using HbA1C?
Type 1
The HbA1c test is very useful in monitoring. How does it work?
- Gives an indication of average blood glucose levels over the past 3 months
- Measures how much Hb has been glycosylated
- Over a period of 3 months (life-span of a RBC), the Hb in RBCs is exposed to glucose
- If, on average, blood glucose levels are high, more Hb will be bound by glucose and the HbA1c will be elevated
Why can a single HbA1c <48 mmol/mol not rule out diabetes?
Because it may be a false negative due to increased RBC turnover*, which can occur in haemolytic anaemia, infection, blood loss and haemoglobinopathies (e.g. sickle cell disease)
*Blood glucose levels are high but Hb glycosylation is low because Hb has only been exposed to glucose for a short time
Type 1 diabetes is due to (1), whereas type 2 is a result of (2).
(1) Beta cell destruction (by autoantibodies)
(2) Insulin resistance and beta cell dysfunction
Type 1 diabetes is an autoimmune disease that most commonly presents in childhood. What is thought to be the trigger?
Early viral illness
Percentage of individuals with other types of diabetes
<2%
Why might prevalence of diabetes drop in old age?
Possibly due to higher rates of avoidable and premature deaths in people with diabetes
RFs for T2DM
Unmodifiable:
- Age
- Family history
- Black African Caribbean background
- South Asian background
Modifiable:
- Poor diet
- Being overweight/obese, especially visceral/abdominal obesity (increased intra-abdominal fat)
- Inactivity
Other:
- Socio-economic deprivation
The term ‘African Caribbean’ refers to
People who originate from the Caribbean islands but have an African ancestry
Onset of
(1) T1DM
(2) T2DM
(1) Typically <30
(2) Typically >30
Types of (hypoglycaemic) drugs used in type 2 diabetes
Drugs that increase insulin sensitivity
- Biguanides
- Thiazolidenediones
Drugs that increase beta cell activity / insulin secretion
- Sulfonylureas (SUs)
- Meglitinides
Drugs that increase GLP-1 activity
- GLP-1 receptor agonists
- DPP4 antagonists
Drugs that slow glucose absorption
- Alpha-gluosidase inhibitors
Drugs that promote glucose excretion
- SGLT2 inhibitors
Insulin
Biguanides
(1) Examples
(2) MOA
(1) Metformin
(2) Decrease HGP, increase glucose uptake by skeletal muscle, decrease intestinal glucose absorption
Thiazolidenediones
(1) Examples
(2) MOA
(3) To remember
(1) Pioglitazone
(2) Increase sensitivity of peripheral tissues (esp. fat + skeletal muscle) to insulin
(3) Risk of osteoporosis
Sulfonylureas (SUs)
(1) Examples
(2) MOA
(3) To remember
(1) -GLI ; gliclazide, glipizide, glibenclamide
(2) Increase insulin secretion
(3) Often 2nd line because cheap, weight gain + risk of hypoglycaemia
Meglitinides
(1) Examples
(2) MOA
(3) To remember
(1) -GLINIDE ; nateglinide, repaglinide
(2) Increase insulin secretion
(3) Not popular because short-acting (frequent dosing schedule), weight gain + risk of hypoglycaemia
GLP-1 receptor agonists
(1) Examples
(2) MOA
(3) To remember
(1) -TIDE ; exanatide, liraglutide
(2) Mimic endogenous GLP-1, which increases insulin secretion by beta cells, decreases glucagon secretion by alpha cells, slows gastric emptying + increases satiety
(3) SC injections only, promotes weight loss, GI SEs are common
DPP4 antagonists
(1) Examples
(2) MOA
(1) -GLIPTIN ; sitagliptin, vidagliptin, linagliptin, alogliptin
(2) Increase GLP-1 activity by inhibiting DPP4, the primary enzyme responsible for metabolising GLP-1
SGLT2 inhibitors
(1) Examples
(2) MOA
(3) To remember
(1) -GLIFLOZIN ; dapagliflozin, canagliflozin, empagliflozin
(2) Block sodium glucose 2 co-transporters (SGLT2) in the PCT —> less glucose reabsorbed / more glucose excreted
(3) Risk of thrush + UTIs (because of glucose in urine), promotes weight loss
Alpha-glucosidase inhibitors
(1) Examples
(2) MOA
(3) To remember
(1) Acarbose
(2) Slow intestinal digestion + absorption of carbohydrates by blocking amylases
(3) Not popular because of of unpleasant GI SEs (diarrhoea, flatulence)
Which drugs used in the treatment of diabetes cannot be administered orally (bc they are proteins + would be digested)?
- Insulin (short-acting: SC injections or infusions, IV // long-acting: SC injections only)
- GLP-1 receptor antagonists (SC injections)
Metformin advantages/disadvantages
Disadvantages:
- Transient GI upset is very common (nausea + vomiting, diarrhoea, abdominal discomfort, loss of appetite, taste disturbance - metallic)
- Risk of lactic acidosis (rare but potentially fatal) in alcohol excess and in intercurrent illness that causes metformin accumulation (e.g. renal impairment), increased lactate production (e.g. hypoxia) or decreased lactate metabolism (e.g. liver failure)
- Decreases vitamin B12 absorption, check regularly
- Slow onset (SUs for rapid control)
- Contraindicated in severe renal impairment (eGFR <30) + severe hepatic impairment
Advantages:
- Low risk of hypoglycaemia + weight neutral (because doesn’t increase insulin secretion)
- Cheap
- In use for >50 years
- Can be used in pregnancy
Hypoglycaemic drugs that promote weight loss (in turn prevents worsening of insulin resistance)
- Biguanides (metformin)
- GLP-1 receptor antagonists
- SGLT2 inhibitors
(Similar to the ones that commonly results in GI SEs)
Hypoglycaemic drugs that promote weight gain (because increase insulin secretion)
- Sulfonylureas (SUs)
- Meglitinides
- Insulin
Hypoglycaemic drugs associated with a risk of hypoglycaemia (because increase insulin secretion)
- Sulfonylureas (SUs)
- Meglitinides
- Insulin
Hypoglycaemic drugs for which GI SEs are common
- Biguanides (metformin)
- GLP1- receptor antagonists
- Alpha-glycosides inhibitors (acarbose)
(Similar to the ones that promote weight loss)
GlP-1
1) Stands for
(2) Another name for it
(3) Released in (3a) in response to (3b
(1) Glucagon-like peptide-1
(2) Incretins
(3a) The small intestine
(3b) Ingestion of food
Indications for insulin
- T1DM
- T2DM where oral hypoglycaemic drugs do not suffice
- Diabetic metabolic emergencies (DKA, HHS)
- Hyperkalaemia (with glucose! // insulin drives K+ into cells, reducing serum levels; only works as a short-term measure because as soon as stooped, K+ leaks back into the circulation)
How does insulin reduce glucose levels?
- Increases glucose uptake into tissues (skeletal, muscle, adipose)
- Increases use of glucose as an energy source
- Increases glycogen, lipid and protein synthesis
- Decreases gluconeogenesis and ketogenesis (2nd reason why needed in DKA, aside from to reduce glucose levels)
Insulin
(1) Formulation
(2) Typical dose/frequency
(3) SEs
(1) Self-administered SC injections; IV in diabetic metabolic emergencies and hyperkalaemia
(2) Daily, 1-2 long-acting doses (to meet basal requirements) + short-acting doses with meals (to control post-pyramidal glucose)
(3) Hypoglycaemia, lipohypertrophy at injection site, weight gain
For patients being treated with insulin, when is hypoglycaemia more likely to occur?
- Hepatic or renal impairment (decreased metabolism + clearance of insulin)
- Alcohol excess (inhibits gluconeogenesis + glycogenolysis)
- Pregnancy (reason unknown)
Symptoms of hypoglycaemia
- Sympathetic symptoms precede neuroglycopenic symptoms
- Sympathetic symptoms: hunger, sweating, pallor, tachycardia, tremor
- Neuroglycopenic symptoms: paraesthesiae, blurred vision, confusion, personality changes, seizures, hemiparesis, loss of consciousness, coma
What is hypoglycaemia unawareness?
In some people with long-standing diabetes the early adrenergic symptoms of hypoglycaemia are absent, so hypoglycaemia occurs without warning
When does a patient with diabetes need to inform the DVLA about their condition and stop driving?
If she/he has complete hypoglycaemia unawareness or > 1 severe episode of hypoglycaemia
Treatment of hypoglycaemia
- If conscious and able to cooperate: 15-20g of a quick-acting carbohydrate snack (e.g 50-100 ml lemonade or coke), re-check blood glucose after 10-15 min (repeat snack up to 3 times)
- If conscious but unable to cooperate: glucose gel between teeth and gums
- If unconscious or unresponsive to snack/GlucoGel: IV glucose (venotoxic, avoid) or glucagon* (SC, IM or IV)
- Long-acting carbohydrate snack (e.g. slice of toast) once blood glucose >4.0 mmol/L and patient has recovered (small snack or risk hyperglycaemia)
*Mobilises hepatic glycogen (doesn’t work if fasting or malnourished)
(Oxford Handbook p. 834)
Patients with diabetes have a reduced life expectancy. Commonest causes of premature death in treated patients:
- Cardiovascular disease (70%)
- CKD (10%)
- Infection (6%)
