Type 1 and 2 diabetes mellitus Flashcards
What is diabetes?
In diabetes, there is a lack of effectiveness of endogenous insulin
How is diabetes diagnosed in general?
DIAGNOSIS
- Symptoms of hyperglycaemia (polyuria/polydipsia/unexplained weight loss/visual blurring/genital thrush/lethargy) AND raised venous glucose detected once (fasting greater than/equal to 7mmol/l or random greater than/equal to 11.1mmol/l) OR
- Raised venous glucose on 2 separate occasions (fasting greater than/equal to 7mmol/l or random greater than/equal to 11.1mmol/l or OGTT 2h value greater than/equal to 11.1mmol/l)
- HbA1c greater than/equal to 48mmol/l but below this does not exclude DM
What are the different types of diabetes
Type 1:
- Immune destruction of the pancreas
- Insulin dependent diabetes
- usually young pts (12-16)
- DKA (ketoacidosis)
- Quite high glucose
- acute onset
Type 2:
- Resistance to the action of insulin
- Non-insulin dependent diabetes
- Maturity onset diabetes (30-70)
- Often overweight
- not prone to ketoacidosis
- Very high glucose
- insidious onset
Monogenic diabetes:
- (e.g. MODY “maturity onset diabetes of the young”, mitochondrial diabetes)
- Autosomal dominant inheritance. Family history of early onset diabetes is often present.
How is glucose control monitored?
- Fingerprick glucose if T1DM, and T2DM if on insulin
- Glycated haemoglobin (Hba1c) relates to mean glucose level over previous 8 weeks
- Ask about hypoglycaemic attacks and symptoms
What is Type 1 diabetes mellitus?
Autoimmune response that triggers the destruction of insulin-producing beta cells in the pancreas leading to an absolute insulin deficiency (⇒ lipolysis and ketogenesis). Commonly manifests in childhood. Associated with HLA DR3/4. May be FH of autoimmune disease.
Explain the cause/ risk factors of type 1 diabetes mellitus
- Caused by destruction of pancreatic insulin-producing beta cells (autoimmune process)
- Associated with other autoimmune conditions
- Genetic: >90% carry HLADR3 +/- DR4
- with an environmental trigger (Enteroviral infections, Cow’s milk protein exposure, Seasonal variation & Changes in microbiota)
- LADA (latent autoimmune diabetes of adults) is a form of T1DM with slower progression to insulin dependence
- Autoantigens associated with T1DM:
*Glutamic acid decarboxylase (GAD)
*Insulin
*Insulinoma-associated protein 2
*Cation efflux zinc transporter
Summarise the epidemiology of type 1 diabetes mellitus
0.25% prevalence in the UK
What presenting symptoms of Type 1 DM can be found in the history?
- Excessive urination (polyuria)
- Nocturian (getting up in the night to pee)
- Excessive thirst (polydipsia)
- Blurring of vision
- Recurrent infections eg thrush
- Unexplained weight loss
- Fatigue
- Polyphagia (Excessive Appetite)
What signs of Type 1 DM can be found on physical examination?
- dehydration
- cachexia
- hyperventilation
- DKA Symptoms (can be triggered by surgery, UTI, MI, pancreatitis, chemotherapy, psychotics, wrong insulin dose/non-compliance):
*Nausea and vomiting
*Abdominal pain
*Polyuria, polydipsia
*Drowsiness
*Confusion
*Coma
*Kussmaul breathing (rapid, deep breathing at a consistent pace)
*Ketotic (sweet smelling) breath
*Signs of dehydration - glycosuria
- ketonuria
What investigations are used to diagnose/ monitor type 1 DM?
Investigations to do in order: Urinanalysis 🡪 random glucose 🡪 fasting glucose 🡪 OGTT 🡪 HBA1c
1. Blood Glucose - fasting blood glucose > 7 mmol/L or random blood glucose > 11.1 mmol/L
2. FBC - MCV, reticulocytes
3. U&Es - monitor for nephropathy and hyperkalaemia
4. Lipid profile
5. Urine albumin creatinine ratio - used to detect microalbuminuria
6. Urine - glycosuria, ketonuria, MSU (check for infection)
7. Investigations for DKA:
- Capillary blood glucose 🡪 urine dipstick (check for glycosuria and ketonuria) 🡪 ABG (check for metabolic acidosis) 🡪 plasma osmolality
- FBC (raised WCC without infection in DKA)
What effect does insulin deficiency have on the organs of the body?
- Increased proteinolysis (breakdown of muscle) to gain amino acids- used for fuel
- Increased hepatic glucose output (HGO)- Counterintuitive- blood glucose is high but it is not being used, so the body gets confused and increases production
- Increased lipolysis (breakdown of fat/ adipose tissue) to gain non-esterified fatty acids/ NEFA’s for fuel
= Formation of ketone bodies
Why are ketone bodies formed as a result of insulin definicency?
- Breakdown of fat:
- Fatty Acyl-Co A into the ketone bodies
- Used as fuel during starvation
- Acidic: accumulation= acidosis
How is Type 1 DM managed?
- Glycaemic Control:
- Advice and patient education – vital to educate to self-adjust doses in the light of exercise, fingerprick glucose and calorie intake
–Basal-Bolus Insulin ⇒ long acting (eg. insulin glargine, subcutaneous injection OD) + short acting (eg. insulin lispro or aspart, before meals) note: insulin is given subcutaneously
a. Short-acting insulin (three times daily before meals):
- Lispro
- Aspart
- Glulisine
b. Long-acting insulin (once daily):
- Isophane
- Glargine
- Detemir - Insulin pumps/ disposable pens
- DAFNE courses (dose adjustment for normal eating)
- Monitor (Regular capillary blood glucose tests, HbA1c every 3-6 months)
- Treatment of hypoglycaemia:
- If reduced consciousness: 50 ml of 50% glucose IV, intravenous dextrose OR 1 mg glucagon IM
- If consciousness and cooperative: 50 g oral glucose + starchy snack - DKA Management
- Management of cardiovascular risk factors
- Management of complications: Thyroid disease is most commonly associated with type 1 diabetes, as both are autoimmune conditions. This can be easily screened for with routine thyroid function tests.
Identify possible complications of type 1 diabetes mellitus
- Diabetic ketoacidosis
- Can be precipitated by infection, errors in management of diabetes, newly diagnosed diabetes, idiopathic - Microvascular complications:
- Retinopathy
- Nephropathy
- Neuropathy - Macrovascular complications:
- Peripheral vascular disease
- Ischaemic heart disease
- Stroke/TIA - Increased risk of infection
- Complications of treatment:
- Weight gain
- Fat hypertrophy at insulin injection sites
- Hypoglycaemia:
*Personality changes
*Fits
*Confusion
*Coma
*Pallor
*Sweating
*Tremor
*Tachycardia
*Palpitations
*Dizziness
*Hunger
*Focal neurological symptoms
Summarise the prognosis for patients with type 1 diabetes mellitus
- Depends on early diagnosis, good glycaemic control and compliance with treatment and screening
- Vascular disease and renal failure are the main causes of increased morbidity and mortality
What is Type 2 DM?
“A condition in which the combination of insulin resistance and beta-cell failure result in hyperglycaemia”
- Body makes insulin but tissues don’t respond to it (reason not fully understood)
- INSULIN RESISTNACE
- obesity and genetic risk factors of T2DM
- Body makes excess insulin to try to move the glucose out of blood
- Eventually puts strain on beta cells (overworked)- beta cell damage
- Insulin starts to go down (depending on time of diagnosis, insulin levels will vary)
Explain the aetiology of type 2 DM
Genetic & environmental:
- Obesity: possible increases rate of release of NEFAs causing post-receptor defects in insulin’s actions
- Genetics: mutations in genes encoding insulin receptors. There are a few monogenic causes e.g. MODY, mitochondrial diabetes
- Pancreatic disease (e.g. chronic pancreatitis)
- Endocrine disease (e.g. Cushing’s syndrome, acromegaly, phaeochromocytoma, glucagonoma)
- Drugs (e.g. corticosteroids, atypical antipsychotics, protease inhibitors)
- Circulating autoantibodies to the extracellular domain of the insulin receptor
What are the risk factors for insulin reistance?
- Metabolic syndrome
- Obesity
- Asian ethnicity
- TB drugs
- SSRIs (Selective serotonin reuptake inhibitors)
- Pregnancy
- Acromegaly
- Renal failure
- Cystic fibrosis
- PCOS
- Werner’s syndrome
- Age
- high BMI
- Family History
- Inactivity
Summarise the epidemiology of type 2 diabetes mellitus
- UK Prevalence: 5-10%
- Asian, African and Hispanic people are at greater risk
- Incidence has increased over the past 20 yrs
- This is linked to an increasing prevalence of obesity
What presenting symptoms of type 2 diabetes mellitus can be found in the history?
May be an incidental finding/ many patients are asymptomatic.
- Some may present with hyperosmolar hyperglycaemic state (HHS)
- Polyuria
- Polydipsia
- Tiredness
- Infections (e.g. infected foot ulcers, candidiasis, balanitis)
- Assess cardiovascular risk factors: hypertension, hyperlipidaemia and smoking
How does the liver react to the reduced insulin levels seen after T2DM?
Hepatic glucose production is increased due to both a reduction in insulin action and increase in glucagon action
“excessive glucagon-mediated glucose output” (but reduced clearance of glucose- still not being removed from circulation)
What consequences do other body tissues face from T2DM?
Skeletal muscle:
- Reduced glucose uptake
- Impaired glycogen synthesis
Adipocytes:
- Reduced glucose uptake
- Increased lipolysis
- Reduced lipogenesis
Liver:
- Increase in hepatic glucose production
- Increased lipogenesis
What signs of type 2 DM can be found on physical examination?
- Calculate BMI (overweight: 25.0-29.9 kg/m2, obese: 30 - 39.9 kg / m2)
- Increased waist circumference
- High blood pressure
- Diabetic foot (ischaemic and neuropathic signs):
*Dry skin
*Reduced subcutaneous tissue
*Ulceration
*Gangrene
*Charcot’s arthropathy (chronic/ destructive disease of the bone structure and joints in patients with neuropathy)
*Weak foot pulses - Skin changes (RARE):
*Necrobiosis lipoidica diabeticorum (well-demarcated plaques on shins or arms with shiny atrophic surface and red-brown edges)
*Granuloma annulare (flesh-coloured papules coalescing in rings on the back of hands and fingers)
*Diabetic dermopathy (depressed pigmented scars on shins)
What investigations are used to diagnose/ monitor type 2 DM?
Investigations in order: Urinanalysis 🡪 random glucose 🡪 fasting glucose 🡪 OGTT 🡪 HBA1c
1. T2DM is diagnosed if one or more of the following are present:
- Symptoms of diabetes and a random plasma glucose ≥ 11.1 mmol/L
- Fasting plasma glucose ≥ 7 mmol/L
- Two-hour plasma glucose ≥ 11.1 mmol/L after 75 g oral glucose tolerance test
2. Monitor:
- HbA1c
- U&Es
- Lipid profile
- eGFR
- Urine albumin: creatinine ration (look out for microalbuminuria)
How is type 2 DM managed?
Glycaemic control - there is a step-wise approach to the management of T2DM:
(Initial:)
1. Lifestyle advice: smoking cessation, diet, exercise
2. METFORMIN – a biguanide, increases insulin sensitivity and helps weight
- If HbA1C >53mmol/l after 16 weeks, add SULPHONYLUREA e.g. gliclazide – increases insulin sensitivity
- If HbA1c >57mmol/l at 6 months, consider
2. INSULIN – first basal, then premeal rapid-acting insulin
3. GLITAZONE (thiazolidinedione) e.g. pioglitazone
4. SULPHONYLUREA RECEPTOR BINDERS
5. GLP ANALOGUES and DPP4 INHIBTORS
6. A-GLUCOSIDASE INHIBITORS e.g. acarbose
- NOTE: sulphonylurea may be given as a monotherapy if patients cannot tolerate metformin
- NOTE: pioglitazone (thiazolidinedione) may also be given alongside metformin and a sulphonylurea
7. Screening for complications:
- Retinopathy
- Nephropathy
- Vascular disease
- Diabetic foot
- Cardiovascular risk factors (e.g. blood pressure, cholesterol)
8. Pregnancy - requires strict glycaemic control and planning of conception
9. Hyperosmolar Hyperglycaemic State - management is similar DKA
- Except use 0.45% saline if serum Na+ > 170 mmol/L
Identify possible complications of type 2 diabetes mellitus
- Hyperosmolar hyperglycaemic state
- Due to insulin deficiency
- Marked dehydration
- High Na+
- High glucose
- High osmolality
- No acidosis - Neuropathy:
- Distal symmetrical sensory neuropathy
- Painful neuropathy
- Carpel tunnel syndrome
- Diabetic amyotrophy
- Mononeuritis
- Autonomic neuropathy
- Gastroparesis (abdominal pain, nausea, vomiting)
- Impotence
- Urinary retention - Nephropathy:
- Microabuminuria
- Proteinuria
- Renal failure
- Prone to UTI
- Renal papillary necrosis - Retinopathy:
- Background
- Pre-proliferative
- Proliferative
- Maculopathy
- Prone to glaucoma, cataracts and transient visual loss - Macrovascular complications:
- Ischaemic heart disease
- Stroke
- Peripheral vascular disease
Summarise the prognosis for patients with type 2 diabetes mellitus
- Good prognosis with good control
- Pre-diabetes can be diagnosed based on fasting blood glucose and oral glucose tolerance test:
*Impaired Fasting Glucose (IFG) = fasting blood glucose 5.6-6.9 mmol/L
*Impaired Glucose Tolerance (IGT) = plasma glucose level of 7.8-11.0 mmol/L measured 2 hrs after a 75 g oral glucose tolerance test - People with IFG or IGT are at high risk of developing type 2 diabetes
What is hyperosmolar hyperglycaemic state?
EXTREME DEHYDRATION
Osmotic diuresis leads to severe fluid loss “Hypovolaemic shock” insulin for suppression of lipolysis and ketogenesis.
Symptoms:
- Polyuria
- Dehydration
- (if left untreated): lethargy, seizures, coma, death
treat with intravenous fluids immediately
(CAUTION: rectifying fluids too quickly can cause Central pontine myelinolysis (brain depletion) rapid rise in Na+ conc
What are the drug treatments for T2DM? What do each drug tackle?
- Metformin (Reduces hepatic glucose production + Improves insulin sensitivity + Increases peripheral glucose disposal)
- Thiozolidinediones
- Pioglitazone (2/3 Improves insulin sensitivity)
- Sulphonylureas
- DPP4-inhibitors
- GLP-1 Agonists (4-6 boost insulin secretion)
- Alpha glucosidase inhibitor
- SGLT-2 inhibitor (7/8 Inhibit carbohydrate gut absorption + Inhibit renal glucose reabsorption)
Weight loss help to achieve all of these solutions
What are some cons of taking metformin?
- GI side effects
- Contraindicated in severe liver, severe cardiac or moderate renal failure
How does Sulphonyleuras work?
“Boosts insulin secretion”
Normal insulin release requires closure of the
ATP-sensitive potassium channel
- Sulphonylureas binds to the ATP-sensitive potasssium channels and closes them (independent of glucose/ ATP)
How does Pioglitazone work?
“Improves insulin sensitivity”
- Adipocyte differentiation modified
- weight gain but peripheral not central
- Improvement in glycaemia and lipids
- Evidence base on vascular outcomes
- Side effects of older types hepatitis, heart failure
What is the role of Glucagon like peptide-1 (GLP-1)
- Gut hormone
- Secreted in response to nutrients in gut
- Transcription product of pro-glucagon gene, mostly from L-cell
- Stimulates insulin, suppresses glucagon
- ↑ satiety (feeling of ‘fullness’)
- Short half life due to rapid degradation from enzyme dipeptidyl peptidase-4 (DPP4 inhibitor)
- Used in treatment of diabetes mellitus
How do GLP-1 Agonists work?
“Boost insulin secretion”
- Injectable –daily, weekly
- Decrease [glucagon]
- Decrease [glucose]
- Weight loss
e.g: Liraglutide, Semaglutide
How do DPP4-inhibitors work?
- Increase half life of exogenous GLP-1
- Increase [GLP-1]
- Decrease [glucagon]
- Decrease [glucose]
- Neutral on weight
e.g: Gliptins
How do SGLT-2 inhibitors work?
“Inhibit carbohydrate gut absorption + Inhibit renal glucose reabsorption”
- Inhibits Na-Glu transporter, increases glycosuria
- HbA1c lower
- 32% lower all cause mortality
- 35% lower risk heart failure
- Improve CKD (chronic kidney disease)
E.g: Empagliflozin, dapagliflozin, canagliflozin
What are the adverse drug effects of anti-diabetic drugs?
- Metformin (Activation of AMPK)=
Lactic acidosis - Sulfonylureas (Inhibits the VGKCs of the pancreatic beta cells)
= Hypoglycaemia, Weight gain - SGLT-2 inhibitors (Prevents reabsorbtion of glucose in PCT)=
UTIs
