Diabetes Mellitus – Pathogenesis and Metabolic Abnormalities Flashcards
Describe diabetes in the UK
- Affects 5% of total population -Affects 10% of people over 65
- Around 3.2 million people are known to have diabetes -Many people have undiagnosed diabetes
- About 25% require insulin therapy
What is diabetes?
- Diabetes mellitus is a condition associated with an elevated blood glucose.
- This is a consequence of deficiency of INSULIN, or of its reduced action, or of a combination of both
Describe insulin
- Hormone secreted in pancreas (islets)
- Anabolic hormone (actions centred around storage of nutrients and energy sources)
- Mitogenic= growth and proliferation of calls stimulated
- Essential for fuel storage and cell growth
- Promotes uptake of glucose into cells for energy
- Prevents breakdown of fat and protein
Describe the structure of a pancreatic islet
- Clusters of beta cells secreting insulin, central location
- Alpha cell, secreting glucagon, tend to sit peripherally in islets
- Delta cell (secretes somatostatin)
- F cell (secretes pancreatic polypeptide)
- Exocrine acinus surrounds (exocrine go to pancreatic duct, endocrine directly into bloodstream, drain out through portal circulation)
What pancreatic cells make what hormone?
- Alpha cell= glucagon, 11%
- Beta cell= insulin, 85%
- Delta cell= somatostatin, 3% (inhibitory, analogues used therapeutically for excess hormones in acromegaly)
- F cell= pancreatic polypeptide, 1% (excess= diarrhoea)
Describe the structure of insulin
-Protein
-Complex quaternary structure
-Alpha subunit and beta subunit linked by directly by disulphide bonds and indirectly by c peptide (in the middle, proinsulin)
=c peptide cleaved away by B-cell peptidases to form insulin
How is insulin secreted from beta cells?
-Insulin secretion from beta cells directly coupled to glucose influx (interstitial fluid)
-GLUT2 glucose transporter= glucose into cells without insulin
=Amount of beta cells concentration dependent
=metabolised by glycolysis cycle
=ATP generated
=ATP sensitive potassium channel allowing K+ out into cells along concentration closed
=Concentration of K+ increases so depolarisation closing voltage gated calcium channel
=Affect levels of calcium in cells so exocytosis of insulin into blood
What are sulphonyl urea drugs?
-Bind to SUR1 proteins to close potassium channel
=bypass glucose intake
=stimulate insulin production
What are the phases of insulin secretion?
- Pro-insulin is converted to insulin and C-peptide in equimolar amounts
- In response to ingestion of food, stored insulin is released first (in secretory granules), followed by newly synthesised insulin
- This gives a biphasic response of insulin secretion
- C-peptide can be used as a measure of endogenous insulin secretion in people with diabetes (exogenous has no c peptide)
What are the sites of action of insulin?
- Secreted into portal vein
- Acts first on LIVER (much higher concentrations in portal circulation)
- Passes through liver into systemic circulation
- Acts on MUSCLE and FAT
What are the principal actions of insulin?
- Increase Glucose uptake in FAT and MUSCLE
- Increase Glycogen storage in LIVER and MUSCLE
- Increase Amino Acid uptake in MUSCLE
- Increase Protein Synthesis
-Increase Lipogenesis in ADIPOSE TISSUE
- Decrease Gluconeogenesis from 3-Carbon precursors
- Decrease Ketogenesis (in LIVER)
- Increase Cell proliferation
- Decrease Apoptosis
How does insulin affect glucose transport into cells?
- Causes translocation of GLUT4 to cell membranes from cytoplasm to allow insulin-dependent glucose uptake into cells
- Glucose transporter in adipose and muscle cells in cytoplasm
Sources of blood glucose
- Carbohydrates broken down into portal system
- Glycogen in liver hydrolysed (starvation= gluconeogenesis)
- Kidneys also do gluconeogenesis
How does the brain allow glucose uptake?
- GLUT 3 in brain, insulin independent receptor
- Always supply of glucose
What are the 3-carbon precursors used in gluconeogenesis?
- Alanine (from ingested protein)
- Pyruvate (from muscle protein)
- Lactate (from muscle glycogen)
- Glycerol (from fat)
What other hormones are used in glucose homeostasis?
-Adrenaline
-Epinephrine
-Norepinephrine
-Cortisol
=important in times of stress
=high metabolic demand
Why is blood glucose maintained within a narrow range by homeostatic mechanisms?
- Optimal functioning of brain (can’t switch to ketones as quickly)
- Maintenance of energy source for most tissues
- Integrity and health of blood vessels
How might insulin deficiency occur?
-Destruction of islets (type 1 autoimmune)
=infiltration of inflammatory cytotoxic lymphocytes
=insulitis
-Toxins
=alcohol can cause acute and chronic pancreatitis where islets can get damaged
How might insulin resistance occur?
-Problem in insulin signalling pathway (can be multiple blockages/ suboptimal function occurs)
What are the severe insulin resistance syndromes?
-Mostly very rare, problems with insulin receptors
=Leprechaunism
=Rabson-Mendenhall syndrome
=Type A insulin resistance
What are other causes of insulin resistance?
- Acromegaly (GH excess)
- Pheochromocytoma
- Cushing’s
What is dysglycaemia?
-Spectrum of impaired fasting glycaemia =Normal= up to 6.0 mmol/l =Impaired fasting glycaemia= 6.0-7.0 mmol/l =diabetes above 7.0 mmol/l *Risk of diabetic retinopathy
What are the 4 ways to be diagnosed with diabetes?
- Fasting plasma glucose > 7.0 mmol/l
- 2hr plasma glucose in OGTT> 11.1 mmol/l
- Random plasma glucose > 11.1 mmol/l
- HbA1c > 48 mmol/mol
- If the patient is asymptomatic, the same test should be repeated to confirm the diagnosis of diabetes
- Do not delay urgent care waiting for a second test
What is glycated haemoglobin (HbA1c)?
- Rate of formation of glycated haemoglobin is directly proportional to ambient blood glucose concentration
- Reflects integrated blood glucose (BG) concentrations during lifespan of erythrocyte (120 days)
- Blood sample can be taken at any time of day, irrespective of food consumption
What are the reference ranges for HbA1c?
- Normal ≤41 mmol/mol
- Pre-diabetes 42-47 mmol/mol
- Diabetes ≥ 48mmol/mol
What are the situations where HbA1c should not be used as a diagnostic test?
-Rapid onset of diabetes =Suspected Type 1 Diabetes =Children =Drugs – steroids; antipsychotics -Pregnancy =Glucose levels can rise rapidly =HbA1c is lower -Conditions where red cell survival may be reduced =Haemoglobinopathy =Haemolytic anaemia =Severe blood loss =Splenomegaly =Antiretroviral drugs -Increased red cell survival =Splenectomy -Renal dialysis =Reduced HbA1c, especially if treated with erythropoietin -Iron and vitamin B12 deficiency =Small effects on HbA1c
Describe the Oral Glucose Tolerance Test (OGTT)
- Used to assess state of glucose tolerance
- 75g oral glucose load
- No restriction or modification of carbohydrate intake for preceding three days
- Fast overnight
- Test is performed in morning – seated; no smoking
- Blood samples for plasma glucose taken at 0hrs and 2 hrs
Describe Impaired Glucose Tolerance
- Fasting plasma glucose: <7.0 mmol/l
- 2 hours after 75g oral glucose load: 7.8-11.0 mmol/l
- Affects 20% of population aged 40-65 years (UK)
- Increased mortality from cardiovascular disease (doubled)
- Natural history - 15% develop diabetes in 5 years, 15% return to normal
- Check fasting plasma glucose annually
Describe Impaired Fasting Glucose
- Fasting hyperglycaemia
- Fasting plasma glucose: 6.0 – 6.9 mmol/l
- Intermediate state between normal glucose metabolism and diabetes
- Impaired glucose tolerance often present also (but not always)
- Found in 5% of population and prevalence increases with age
- Increased risk of vascular complications
Describe Pre-Diabetic states
- Fasting blood glucose 6.0-6.9 mmol/l
- 2 hr OGTT blood glucose 7.8-11.0 mmol/l
- HbA1c 42-47 mmol/mol
-Fasting hyperglycaemia and Impaired Glucose Tolerance often co-exist
