Week 13 - Pancreas Flashcards
The ideal experimental study will be… (5)
Controlled (placebo) Randomized Double blind Large Analysed by 'intention to treat' method
Considerations when testing medical interventions. So what are the implications for your trial?
Patients will tend to get better naturally
Placebo effect
Effect of treatment itself
Can’t conduct study in sick patients
Why is random allocation good? (4)
Best way to ensure intervention / control groups have similar characteristics
Avoids allocation bias
Simplifies interpretation of different between intervention / control
Facilitates blinding
Significance of blinding
Need to keep key people (patient, outcome assessor, statistician) blind to randomization code
Single blind - patient OR assessor
Double blind - Patient AND assessor
Triple blind - Patient + outcome assessor + statistician
Which trial outcomes should be used?
Symptom, clinical sign, biochemical test, development of clinical disease, death
Ideally objective
Should be important for both patient and doctors
Can have several
3 basic designs of randomised control trial
Parallel group - single intervention
Crossover trial - single intervention switched part way through (for rapidly achieved, reversible outcomes)
Factorial design - 2 or more interventions
What is the importance of trial size?
If too small, statistical power is limited
May fail to detect an important intervention effect (TYPE 2 ERROR)
Estimate of trial effect will be imprecise
What is a type 2 error?
May fail to detect an important intervention effect because trial too small
What are the advantages of a large sample size?
Higher statistical power
More precise estimate of effect size
Ability to think about impact of intervention in different sub-groups
BUT this does not automatically make the trial more representative - still need to do good sampling
Discuss the ethics of randomized control trials
Intervention must be LIKELY to benefit rathre than harm
Control group to get usual care - not no care
Informed consent crucial
Monitoring / reporting safety and adverse effects
What is the null hypothesis?
Assumption that there will be no difference between intervention and control groups - important first step of analysis
Steps of trial analysis (3)
- Compare characteristics of intervention and control groups at entry
- Establish whether intervention has been applied, how did it meet endpoints
- Does outcome differ? (Measurement depends on what the outcome is)
& what does this mean in terms of risk, relative risk, absolute risk, etc.
ISSUE with trial anaylsis
No all patients will comply with study
Some will choose to stop, have to stop, etc.
Can be correct with ‘Intention to treat analysis’
LOOK AT THIS xxxx
Cost-benefit vs cost-effectiveness
Benefit - how much does it cost to ‘save a life’ using this treatment?
Effectiveness - Cost of benefit compared with other clinical interventions
What are the acute metabolic complications of diabetes?
DKA and HHS
Outline Type 1 diabetes pathophysiology
Complete lack of insulin
Compensatory hormones are secreted
Ketone bodies produced
Insulin deficiency leads to ketosis (which leads to acidosis) and hyperglycaemia (which leads to osmotic diuresis and dehydration)
What are the compensatory hormones secreted in type 1 diabetes?
Glucagon
Catecholamines
Cortisol
Growth hormones
What do Type 1 diabetes lose through osmotic diuresis?
Water, sodium, total body potassium, chloride, calcium, phsophate, magnesium
Electrolyte imbalance particularly bad for electrical tissues in heart
Diagnosing DKA - 2 signs
Ketones +++
Glucose high
What do you give to someone in DKA?
Insulin
Fluids
Metabolic correction
Investigations for DKA
pH less than 7.3 Capillary and seum glucose - can be normal Ketones ABG ECG - heart attacks can put you in a DKA (and vice versa) CE - cardiac enzymes (troponin) FBC - infection Amylase CXR Blood cultures MSU - infection
How do you diagnose type 1 diabetes?
Random blood sugar of over 11.1 (if they have symptoms)
If no symptoms, need two random readings above 11.1
Ongoing management of diabetic patient with DKA
Hours early warning scores & blood gas
Hourly fluid balance
Electrolytes every 2-4 hours
XXX
Definition of hyperglycaemic hyperosmolar state
Hyperglycaemia (>30mmol/l) without significant ketosis or acidosis
Dehydration with some depression consciousness
Management of hyperglycaemic hyperosmolar state
Fix hypokalaemia
Insulin
Fluids
Chronic complications of diabetes
Microvascular - nephrology, rentinopathy, neuropathy
Macrovascular - CHD, stroke, PVD, blood pressure
What is the pathophysiology of the chronic complications?
Leakage of PAS positive glycated plasma proteins, which increase extracellular matrix, hypertrophy and hyperplasia of endothelium
What is HbA1c?
Average of amount of glucose over the past 90 days
Also called amadori product
This process happens will all proteins
Controllable risk factors for microvascular complications in patients with diabetes
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Risk factors for retinopathy (4)
Poor glycaemic control
Genetic factors
High BP
smoking
Classification of diabetic retinopathy
Proliferative and non-proliferative (with or without maculopathy)
IT will be the first microvascular complication
Markers of nonproliferative DR
xxx
Markers of proliferative diabetic retinopathy
xxx
Treatment for proliferative retinopathy
burn about 1000 holes in retina to decrease the oxygen demand for the retina.
Lose some peripheral vision, but helps to maintain central vision
Nephropathy - risk factors and incidence
xxx
How do we screen for nephropathy?
Microalbuminuria
Albumin : creatinine random sport collection
24h urine collection with creatinine
Timed collection
Treatment and prevention of diabetic nephropathy (4)
Tight BM control
Tight BP control
ACE inhibitor
Low protein diet, lipid control
BP is key
Types of diabetic neuropathy
xxx
Describe autonomic neuropathy
Damage to nerves supplying major organs Rare complication (occurs after 12-20 ts poor control) Feeling dizzy, delayed stomach emptying, diabetic diarrhoea, sweating when eating, bladder and erectile dysfunction)
Describe neuropathic vs ischaemic foot
Neuropathic - Sensory defect, but you still have pulses, foot starts to claw and you are no longer walking on fat pads, ulceration and callus formation where you are walking
Ischaemic foot - not necessarily going to have sensory defect but will lose pulse, foot structure is maintained and ulceration will not necessarily be at pressure points
Cardiovascular disease risk in diabetes
Risk in type 2 diabetes patients same as people who have already had a heart attack
SO need to use secondary prevention methods in diabetes patients xxx ADD EXAMPLES
HbA1c targets XXX
XXX
Outline of general diabetic management
Advice Blood pressure Cholesterol Diabetic control Eye care Foot care Guardian drugs (ACE inhibitors)
What causes obesity? (5)
Metabolism Appetite regulation Energy expenditure Genetics Behavioural and cultural factors
Common findings in obese patients (2)
Lack of feeling of fullness
Night eating habits
Factors that contribute to weight gain (6)
Socio-economic status Smoking cessation Hormonal Inactivity Psychosocial / emotions Medications
Medical complications of obesity
Pulmonary disease Stroke Cataracts CHD Diabetes Cancer (various) ETC
What is insulin resistance syndrome?
Physiologic response inadequate for amount of insulin secreted
What are the clinical manifestations of insulin resistance syndrome?
Central obesity Glucose intolerance Atherosclerosis Hypertension Polycystic ovary syndrome
What is metabolic syndrome?
xxx
What causes NAFLD?
Excessive intake of fat
Reduced hepatic oxidation of FFA
Increased De Novo lipogenesis
Increased delivery of FFA
In what patients would you consider drug therapy?
xxx
Potential pharmacological interventions for obesity?
Orlistat - inhibits pancreatic lipase causing fat malabsorption
GI adverse effects
What are incretins?
GI hormones that are released after meals, stimular insulin secretion
GLP1 signalling system
What is the gold standard treatment in obesity?
Bariatric surgery
Outline insulin analogues - quick overview of types and benefits
xx
Faster
Commonest drug with errors - why?
Insulin - wrong dose, wrong time,
Sick day rules for patients with diabetes
NEver stop insulin
If BM less than 11
If BM 11-17
If BM
xx
Common causes of hypoglycaemia
Missed/delayed meals Overdose / estimation of insulin Weight loss Increased physical activities xxx
Outline the stepwise management of type 2 diabetes
Diete and exercise
oral monotherapy
oral combination
insulin + oral agents
What is metformin?
Insulin sensitiser
xxx
What are sulphoylureas?
Stimulate insulin secretion
Act on beta cells
Risks of hypo
Discuss action of incretin hormones / GLP-1 analogues?
B-cell A-cell Liver Stomach Brain
INJECTION
Work on pancreas
xxxx
Discuss actions of DPP-4 inhibitors
Works on same pathway as GLP-1 analogues, but less effective
ORAL
Work on pancreas
xxxx
Discuss actions of SGLT-2 inhibitors
xxx
Inhibits SGLT2 receptors in PCT, patient will pee out glucose
Can cause UTIs
How would you classify diabetes?
Vascular disease
& this is the biggest risk for mortality (especially macrovascular)
What is the sequence of hormones that come in in response to hypoglycaemia?
xxx
What is the plasma glucose concentration (when constant)?
5 mmol/L
Range is 4-7 mmol/L in healthy people
What is the critical glucose level for the brain?
Less than 2.5 mmol/L
What prevents plasma glucose surging / plummeting?
Hormone control of metabolism to maintain constant levels
Roles of insulin
Stimulates nutrient storage - uptake of glucose, glycogen synthesis, uptake of FA and AA
Inhibits nutrient release - Inhibits release of glucose from liver, inhibits fat and protein breakdown
What are the counter-regulatory hormones and their role?
Stimulate pathways leading to energy release
Glucagon: principal effects in liver
Stimulates hepatic glucose production
Adrenaline (and sympathetic NS)
Stimulates hepatic glucose production
Stimulates lipolysis: release of FA from adipose tissue stores
Cortisol
Stimulates hepatic glucose production
Stimulates proteolysis: release of amino acids from body proteins (skeletal muscle)
Metabolic pathways that prioritise energy STORAGE (3)
Glycogenesis - Synthesis of glycogen from glucose
Lipogenesis - Synthesis of FA from acetyl CoA
Triglyceride synthesis - Esterification of FA for storage as TG
Metabolic pathways that prioritise energy RELEASE (4)
Glycogenolysis - Release of glucose from glycogen stores
Gluconeogenesis - De novo synthesis of glucose from non-carbohydrate substrates
Lipolysis - Release of FA from TG breakdown
Ketogenesis - Production of ketone bodies from Acetyl CoA via beta-oxidation (FA to Acetyl Co A)
Outline the metabolic response to hypoglycemia
Imediate response is glucagon from pancreas, fall in plasma glucose is detected by pancreas (which starts secreting more glucagon) xxxx
Short, medium and long term defences against hypoglycemia
Short - glucagon, epinephrine, sympathetic NS
Medium - Ketogenesis (this protects muscle tissues from proteolysis)
Long - Cortisol stimulate proteolysis to supply AA substrates for gluconeogenesis
Defences against hyperglycemia
Insulin - stimulates glucose uptake by tissues, inhibits liver glucose production
Lack of insulin action leads to hyperglycemia, DM (type 1 and type 2)
What does insulin stimulate in Liver, adipose tissue and muscle?
Insulin stimulates Liver glycogenesis glycolysis lipogenesis Adipose tissue glucose uptake free fatty acid uptake lipogenesis Muscle glucose uptake amino acid uptake glycogenesis
What does insulin inhibit in liver and adipose tissue?
Insulin inhibits
Liver
glycogenolysis
gluconeogenesis
Adipose tissue
Lipolysis
2 vehicles for fat transport
Chylomicrons VLDL particles (carry from liver
How is fat stored?
As triglycerides (transported as free fatty acids)
How do you turn free fatty acid into triglyceride
Esterification
What transporter does adipose tissue do to take up glucose?
GLUT4, insulin dependent
Describe metabolic pathway in adipose tissue
xxx
Describe metabolic pathway in muscle
Muscle has a private store of glycogen (it an’t be shared with the rest of the body) - will only leave cell as lactate, fatty acid, AA
Skeletal muscle is MOST IMPORTANT IN GLUCOSE UPTAKE
What transporter does muscle tissue do to take up glucose?
GLUT4, insulin dependent
What is most important in glucose uptake? Good buffer to prevent spikes
Skeletal muscle
Describe glucose and amino acid metabolism in the liver
xxx
Describe fatty acid metabolism in the liver
FA can be turned into acetyl CoA via B-oxidation (stimulated by glucagon) BUT this process leads to development of keto acids if overloaded
FA can be turned into triglycerides for transport by VLDLs
What is ketogenesis?
synthesis of acetoacetate and hydroxybutyrate (ketone bodies) from Acetyl Co A
Overview of diabetic ketoacidosis
xx
Overview of the metabolic disturbances in DM
xxx
What is a SGLT transporter? Types and characteristics
xxx
Role of somatostatin? Where is it made?
xxx
What can measuring C protein show us?
Whether insulin is being secreted
Factors regulating insulin secretion
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