Case 17 Flashcards
First line drugs for T2DM
Metformin
Gliclazide
Effect of Metformin
Increases insulin-dependent glucose uptake into tissues.
Inhibits gluconeogenesis in liver.
Inhibits GI absorption of CHOs
Route of Administration of metformin
Oral
MOA of Metformin
Activates AMP-dependent protein kinase in liver.
Potentiates effects of endogenous insulin.
What class of drug is Metformin?
Biguanide class hypoglycaemic drug
ADRs of metformin
Abdominal pain
Anorexia
Diarrhoea
Contraindications of Metformin
Renal, liver or heart failure
Hypoxaemia
Route of administration of Gliclazide
Oral
Effect of gliclazide
Enhances insulin secretion
MOA of Gliclazide
Blocks K+ efflux from beta cells of pancreas.
Beta cells become depolarised.
Depolarisation causes Ca2+ influx.
Results in IP3 mediated enhanced secretion of insulin.
What class of drug is Gliclazide?
Sulfonylurea class hypoglycaemic drug
ADRs of Gliclazide
Haematological disorders
Hypoglycaemia in overdose
Contraindications of Gliclazide
Severe hepatic impairment
Route of administration of Saxagliptin
Oral
Effect of Saxagliptin
Enhanced insulin secretion
MOA of Saxagliptin
Inhibits dipeptidyl peptidase-IV
Enzyme which breaks down incretins
Effect of incretins
Enhance insulin secretion
Effect of DPP-IV
Rapidly breaks down incretins
ADRs of Saxagliptin
Dizziness Dyspepsia Fatigue Gastritis Gastroenteritis Headache Hypoglycaemia
Contraindications of Saxagliptin
Severe hepatic impairment
Sensitive to DPP-IV inhibitors
Route of administration of Exenatide
Subcutaneous injection
Effect of Exenatide
Increased insulin secretion
Suppresses glucagon secretion
Slows gastric emptying
MOA of Exenatide
Mimics incretins.
Acts on GLP-1 receptors causing enhanced insulin secretion.
ADRs of Exenatide
Hypoglycaemia
Injection-site reactions
Abdominal pain
Weight loss
Contraindications of Exenatide
Ketoacidotic
Severe GI pathologies
Drugs which can be coprescribed with metformin
Saxagliptin
Exenatide
Drugs which can be coprescribed with Gliclazide
Saxagliptin
Exenatide
The ‘thrifty’ genotype
Less active
Storing more energy
Heritability
Proportion of observed differences between members of a population that are due to genetic factors
Onset of MODY
<25yrs
Inheritance pattern of MODY
Autosomal Dominant
Distinguishing clinical features of MODY
No obesity
No ketosis
No beta-cell autoimmunity
Onset < 25yrs
Mutation which causes MODY 2
Mutation in Glucokinase (GCK)
Function of glucokinase
An enzyme which catalyses phosphorylation of glucose.
Controls rate limiting step of glycolysis.
Treatment of MODY
Diet management only
Have a mild, stable fasting hyperglycaemia without complications.
Mutation responsible for MODY3
HNF1A
Mutation responsible for MODY12
ATP-Binding Cassette (ABCC8)
Mutation responsible for MODY13
Potassium channel KCNJ11
MODY12 and MODY13 are associated with…
Neonatal diabetes
Features of Permanent Neonatal Diabetes
IUGR Symptomatic hyperglycaemia Onset < 6 months With ketoacidosis Lack of insulin throughout life (requires insulin treatment)
Features of transient neonatal diabetes
Severe IUGR
Symptomatic hyperglycaemia
Onset < 1 month
Lack on insulin which resolves by 18 months
Intermittent childhood hyperglycaemia during illnesses
~50% risk of T2D as adult
Potassium channel structure in beta cells of pancreas
4 Kir6.2 subunits forming the channel pore.
Surrounded by 4 sulphonylurea receptors (SURs) that regulate pore activity.
How do potassium channels affect insulin release?
Glucose enters pancreatic beta cell. Causes ATP to increase in cells. ATP binds to and closes K+ channel Cell depolarises due to build up of K+ Depolarisation causes insulin.
MELAS
Mitochondrial Myopathy
Encephalopathy
Lactic Acidosis
Stroke-like episodes
Common presenting features of MELAS
Diabetes Deafness Exercise Tolerance Muscle weakness Seizures
Donahue Syndrome
Mutation in insulin receptor causing profound insulin resistance
Inheritance pattern of Donahue Syndrome
Autosomal recessive
Distinctive features of Donahue Syndrome
Pre and postnatal growth failure Low subcut adipose Aged face Thick lips Low set ears Acanthosis Nigricans Hyperandrogenism (Hirtsutism, enlarged male genitalia, cystic ovaries) Early mortality
Epigenetics
Stable, heritable modification of chromosomes, without alterations in DNA sequence
Transient neonatal diabetes inherited due to…
Overexpression of imprinted genes at 6q24 e.g. PLAG1
Usually due to paternal UPD or duplication of paternal chromosome
T2DM is more likely to be inherited from (mother/father)
Mother
Intergenerational Effects
Both the foetus and her offspring can be affected by poor nutrition/toxic exposure of mother
Transgenerational Effects
Epigenetic changes that persist for multiple generations.
Tolbutamide is recommended for…
Elderly
Gliclazide is recommended for…
Renal impairment
MOA of Meglitinides
Insulin secretogogues
Closure of K+ ATP channels in beta cells
Incretins
GIP and GLP-1
Enhance secretion of insulin
MOA of statins
Inhibition of HMG-CoA reductase
Who is prescribed statins?
Secondary prevention - those at risk of MI and stroke due to atherosclerotic disease (post MI/Stroke, Angina)
Primary prevention - those at high risk of arterial disease due to elevated serum cholesterol.
Common ADRs of statins
Myalgia GI disturbance Raised liver enzymes Insomnia Rash
Severe ADRs of statins
Myositis
Angioedema
Contraindications for statins
Pregnancy
Treatment of Familial Hypercholesterolaemia
Atorvastatin
Sensitivity
No. of True positives/No. of people with the condition
Specificity
No. of true negatives/No. of people without the condition
Borders of the femoral triangle
Inguinal ligament
Sartorius
Adductor Longus
Contents of femoral triangle
Femoral nerve
Femoral artery
Femoral vein
Where can the femoral artery be palpated?
Midway between ASIS and pubic tubercle
Femoral nerve lies within a fascial compartment along with…
Iliopsoas
Femoral sheath
Fascial extension of abdomen, within which the femoral nerve and artery are contained
Contents of Femoral canal
Lymphatic vessels
Deep lymph node
Empty space
Loose connective tissue
What is the function of the empty space in the femoral canal?
Allows for distension of the femoral vein so that is can cope with increased venous return.
What is the femoral canal?
A rectangular shaped compartment within the femoral triangle.
How can you distinguish between a femoral and direct inguinal hernia?
Femoral = lateral to pubic tubercle
Direct inguinal = medial to pubic tubercle
Meralgia Paraesthetica
Compression of lateral cutaneous nerve as it passes through the inguinal ligament. Causing altered sensation in lateral thigh.
Cutaneous innervation of medial thigh
Obturator nerve
Cutaneous innervation of lateral thigh
Lateral cutaneous nerve of thigh
Cutaneous innervation of posterior thigh
Posterior cutaneous nerve of thigh
Cutaneous innervation of anterior thigh
Femoral nerve
Cutaneous innervation of anteromedial lower leg
Saphenous nerve
Cutaneous innervation of anterolateral lower leg and dorsum of the foot
Superficial branch of common fibular nerve
Motor component of common fibular nerve
Biceps femoris
Lateral and anterior compartments of lower leg
Cutaneous innervation of heel
Tibial nerve
Cutaneous innervation of posterolateral lower leg
Sural nerve (tibial)
Saphenous nerve branches from..
Femoral nerve
Motor component of femoral nerve
Hip flexors - pectineus, iliacus, sartorius
Knee extensors - quadriceps femoris
Sensory component of femoral nerve
Anteromedial thigh
Medial lower leg and foot
Motor component of obturator nerve
Medial compartment of thigh - adductor
Sensory component of obturator nerve
Skin of medial thigh
Motor component of sciatic nerve
Posterior thigh muscles
Motor component of tibial nerve
Posterior compartment of lower leg
Sensory component of tibial nerve
Posterolateral side of the lower leg.
Lateral side of foot
Sole of foot
Motor component of common fibular nerve
Short head of biceps femoris
Anterior and lateral compartments of leg
Sensory component of common fibular nerve
Skin over upper lateral and lower posterolateral leg.
Skin of anterolateral leg and dorsum of foot
Sensory component of superficial fibular nerve
Skin over dorsum of foot
Anterior and lateral aspect of inferior third of lower leg
Motor component of superficial fibular nerve
Lateral compartment of lower leg
Sensory component of deep fibular nerve
Triangular region of skin between 1st and 2nd toes
Motor component of deep fibular nerve
Anterior compartment of lower leg
Some intrinsic muscles of the foot
Blood supply to anterior compartment of leg
Anterior tibial
Nerve supply of anterior compartment of leg
Deep fibular
Blood supply of lateral compartment of leg
Common fibular
Nerve supply of lateral compartment of leg
Superficial fibular
Blood supply of posterior compartment of leg
Posterior tibial
Nerve supply of posterior compartment of leg
Tibial nerve
Nerve supply of posterior compartment of thigh
Sciatic nerve
Nerve supply of anterior compartment of thigh
Femoral nerve
Nerve supply of medial compartment of thigh
Obturator nerve
Surgical intervention for compartment syndrome
Fasciotomy
Compartment syndrome
Bleeding into one of the osteofascial compartments of limb .
Causes an increase in pressure which risks ischaemia of the structures in the compartment
Muscles of lateral compartment of the foot
Fibularis longus and brevis
Action of fibularis longus and brevis
Evert foot and weakly plantar flex ankle
Superficial muscles of posterior compartment of leg
Gastrocnemius
Soleus
Plantaris
Deep muscles of posterior compartment of leg
Popliteus
Flexor digitorum longus
Flexor hallucis longus
Tibialis posterior
Action of superficial posterior muscles of leg
Plantar flexion (weakly) Support longitudinal arch of foot
Effect of rupture of achilles tendon
Unable to plantar flex foot against resistance
Osteofascial Tunnel Posterior to Malleolus
Tom Dick And Very Nervous Harry
Tibialis Posterior Flexor Digitorum Artery Vein Nerve Flexor Hallucis Longus
Lateral and medial plantar arteries arise from…
Posterior tibial artery
Vein most commonly affected by varicosities
Great Saphenous Vein
Venous supply which is most at risk in a fracture of proximal femur
Medial and lateral circumflex veins which arise from profunda femoris
Ankle-Brachial Index
Ratio of systolic blood pressure in ankle compared to that of the brachial artery
Used to diagnose peripheral artery disease
Borders of popliteal fossa
Superomedial: Semimembranosus
Superolateral: Biceps femoris
Inferomedial: Medial head of gastrocnemius
Inferolateral: Lateral head of gastrocnemius and plantaris
Contents of popliteal fossa
Popliteal artery
Popliteal vein
Tibial nerve
Common fibular nerve
Where can the posterior tibial artery pulse be palpated?
Posterior to medial malleolus
Where can the dorsalis pedis pulse be palpated?
Lateral to extensor hallucis longus tendon
Endocrine pancreatic secretions
Insulin
Glucagon
Somatostatin
Pancreatic polypeptide
Exocrine secretions
Digestive enzymes
Bicarbonate
Fasting plasma glucose
4-6mmol/L
Plasma glucose 2hrs after eating
7.8mmol/L
GLUT2
Low affinity transport of glucose into cells
Secretion of Insulin
Glucose enters cells via GLUT2 Glucokinase acts on Glc to produce ATP ATP inhibits K+ efflux via SUR1/Kir6.2 channels Depolarisation causes Ca2+ influx High Ca2+ causes insulin release
Insulin Receptor
Transmembrane Tyrosine-Kinase-Linked Receptor
When insulin binds to its receptor….
The receptor is autophosphorylated by tyrosine kinase.
Results in autophosphorylation of insulin receptor substrates which act globally to reduce plasma glucose.
Insulin activates:
Protein synthesis K+ uptake Glycogen synthesis Glucose uptake Glycolysis
Insulin inhibits:
Lipolysis Gluconeogenesis Glycogenolysis Proteolysis Ketogenesis
Advanced Glycation End-Products
Produced by Hb glycation
Cause oxidative damage and impaired macromolecular function
HbA1c is a measure of
Glycated Hb
Normal HbA1c
<42mmol/mol OR <6%
Values of hypoglycaemia
<4mmol/L
Values of hyperglycaemia
> 6.9mmol/L
Lifestyle factors which increase risk of T2DM
Poor diet
Low levels of exercise
Stress
Genes associated with T2DM
FTO
KCNJ11
FTO
encodes alpha-ketoglutarate-dependent dioxygenase
KCNJ11
encodes the islet ATP-sensitive K+ channel Kir6.2
GLUT2 is found in
Pancreatic cells
Liver cells
GLUT4 is found in
Adipocytes
Muscle cells
MOA of Pioglitazon
Thiazolidinedione
Forms a complex with PPAR-gamma. Complex is an adipocyte gene transcriptional regulator resulting in increased glucose uptake
Effects of Pioglitazon
Adipocyte differentiation
Increased lipogenesis
Increased fatty acid uptake
Increased glucose uptake
ADRs of Pioglitazon
GI disturbance Weight gain Oedema Anaemia Headache Visual disturbance Impotence Haematuria
Contraindications of Pioglitazon
Hx of Heart failure
Haematuria
Previous or active bladder cancer
Disease of exocrine pancreas associated with diabetes mellitus
Pancreatitis
CF
Haemochromotosis
Endocrinopathies associated with Diabetes Mellitus
Cushing’s Syndrome
Acromegaly
Hyperthyroidism
Drugs which may induce DM
Glucocorticoids
Thiazides
Beta blockers
Atypical Antipsychotics
Genetic Syndromes associated with DM
Down’s Syndrome
Klinefelter Syndrome
Wolframs Syndrome
Autonomic symptoms of hypoglycaemia
Sweating
Palpitations
Shaking
Hunger
Neuroglycopenic symptoms of hypoglycaemia
Confusion
Drowsiness Odd behaviour
Speech Difficulty
Incoordination
Symptoms of hypoglycaemia
Sweating, Palpitations
Odd behaviour, incoordination and speech difficulty
General malaise - headache, nausea
Diagnostic criteria for DKA
BG >11mmol/L or known diabetes
HCO3- < 15mmol/L +/- venous pH less than 7.3
Ketonaemia >3mmol/L or significant ketonuria (> 2+)
Causes of DKA
Poor compliance with tx
Infection or intercurrent illness
Medical/Surgical/Emotional Stress
MI
DKA normally occurs in
T1DM
Hyperosmolar Hyperglycaemic State normally occurs in
T2DM
Diagnostic criteria for HHS
BG > 30mmol/L without hyperketonaemia and acidosis
DR: Microaneurysms
Small red spots, caused by swelling of small capillary vessels
DR: Haemorrhages
Red spots caused by small bleeds within retina
DR: Cotton Wool Spots
White and fluffy patches caused by scarred nerve fibres near surface of retina
DR: Hard exudates
Small, shiny, pale, white or yellow spots
Sharp edged
Caused by fatty deposits (due to leaking fluid)
DR: Venous loop
Loop in blood vessel due to poor blood flow
Definition of Diabetic Nephropathy
Proteinuria >0.5g/24hrs
Risk factors for diabetic nephropathy
Genetic and familial predisposition Elevated blood pressure Poor glycaemic control Smoking Hyperlipidaemia Microalbuminuria
Stage I Diabetic Nephropathy
GFR>90
Hyperfiltration
Increased blood flow through kidney
Early renal hypertrophy
Normal renal function
Stage II Diabetic Nephropathy
GFR>60-89
Glomerular lesions
Mild reduction of renal function
Stage III Diabetic Nephropathy
GFR 30-59 (moderately reduced)
Microalbuminuria
Albumin:Creatinine Ratio 30-300mcg/mg/day
Stage IV Diabetic Nephropathy
GFR 15-29 (severely reduced)
Proteinuria > 500mg/24hrs
Creatinine clearance <70ml/min
Stage V Diabetic Nephropathy
End Stage Renal Disease
GFR<15
Creatinine Clearance <15ml/min
Pathophysiology of Diabetic Nephropathy
Renal hypertrophy associated with increased GFR.
Vasodilation of afferent arteriole - raised glomerular pressure.
Damage to glomerulus = mesangial cell hypertrophy and secretion of mesangial matrix.
Eventual glomerulas sclerosis - thickening of basement membrane, no longer acts as an effective filter.
Leakage of large proteins.
Symmetric Polyneuropathy
Pain, paraesthesia, loss of vibration sense in lower extremities (can eventually affect hands).
Can cause unrecognised trauma.
Most common form of neuropathy
Symmetric polyneuropathy
Acute Painful neuropathy
Burning, crawling pains in feet, shins and anterior thighs
Mononeuropathy
Isolated nerve palsies.
Commonly affects CNIII and CNVI which supply external eye muscles.
Diabetic Amyotrophy
Painful wasting of quadriceps.
Knee reflexes absent or diminished.
Usually in older men.
Autonomic Neuropathy
Often Asymptomatic.
CV System - tachy at rest, arrhythmia, postural hypotension, warm foot with bounding pulse (peripheral vasodilation)
GI Tract - gastroparesis (D+V)
Bladder - loss of tone , incomplete emptying
Male erectile dysfunction
Pathophysiology of Diabetic Retinopathy
Hyperglycaemia damaged retinal pericytes.
Weak capillary walls - microaneurysms.
More permeable capillary walls - exudates and macular oedema.
Ischaemia - cotton wool spots and new vessels (VEGF)
Thin walled new vessels prone to bleeding - vitreous haemorrhage.
Fibrotic bands of collagen along margins of new vessels can contract - retinal detachment
Pathophysiology of Neuropathy
Hyperglycaemia causes formation of sorbitol and fructose in schwann cells. Loss of structure and function of schwann cells.
Segmental demyelinisation (reversible but becomes irreversible)
Major risk factor for diabetic foot ulcers
Distal Symmetric Neuropathy
Symptoms of ischaemic in diabetic foot
Claudication
Rest pain
Symptoms of neuropathy in diabetic foot
USUALLY painless - unrecognised trauma
Some forms of neuropathy are painful
Examination of ischaemia in diabetic foot
Dependent rubor - dusky red colouration except when elevated above heart
Trophic changes - soft tissue changes
Cold
Pulseless
Examination
High arch Clawing of toes No trophic (soft tissue) changes) Warm Bounding pulse
Ischaemic ulceration in diabetic foot is usually…
Painful
In heels and toes
Neuropathic ulceration in diabetic foot is usually…
Painless
Plantar
Why is the response to infection less efficient in patients with diabetes?
Vascular disease and neuropathies
Hyperglycaemia
Depression of adherence, chemotaxis and phagocytosis of neutrophils.
Why does poor control of diabetes increase susceptibility to infection?
Depression of adherence, chemotaxis and phagocytosis of neutrophils.
Usual test for diagnosis of microalbuminuria
Albumin:Creatinine Ratio (Spot collection)
Criteria for diagnosis of microalbuminuria
ACR >30mg/min on 2 out of 3 occasions in a 3-6 month period
Causes of false positive test for microalbuminuria
Short term hyperglycaemia Exercise UTI Marked hypertension Heart failure Acute febrile illness
Urine sample for Albumin:Creatinine Ratio must not be….
First void of the day due to diurnal variation in albumin secretion
Screening for diabetic eye disease
Annual DR screening service
+ Visual acuity
First line treatment of T2DM
Metformin
Treatment for Diabetes when Metformin is contraindicated/not tolerated
DPP-4 inhibitor e.g. Saxagliptin OR
Pioglitazone OR
Sulphonylurea e.g. Gliclazide
Why is wound healing impaired in T2DM
Impaired migration, proliferation and differentiation of keratinocytes.
Impaired eNOS activation causing impaired EPC synthesis.
Limited SDF-1alpha expression therefore EPCs not recruited to site.
Fewer EPCs at wound site, reduced neovascularisation (ischaemic wound)