Diabetes lecture 1 Flashcards
Aetiological classification of type 1 diabetes
B cell destruction, usually leading to absolute insulin deficiency, autoimmune, idiopathic
Aetiological classification of type 2 diabetes
May range from relative insulin deficiency to a predominantly secretory defect with or without insulin resistance
Aetiological classification of other types of diabetes
Genetic defects of B cell function Genetic defects in insulin action Diseases of the exocrine pancreas Endocrineopathies Drug or chemical induced e.g. nicotinic acid, glucocorticoids, high dose thiazides etc. Infections Uncommon forms of immune-mediated diabetes Gestation diabetes
Characteristics of type 1 diabetes
B cell destruction Islet cell antibodies Strong genetic link Age of onset usually below 30 Faster onset of symptoms Insulin must be administered Patient not usually overweight Extreme hyperglycaemia causes diabetic ketoacidosis
Characteristics of type 2 diabetes
No B cell destruction No islet cell antibodies Very strong genetic link Age of onset usually above 40 Slower onset of symptoms Diet control and oral hypoglycaemic agents often sufficient control Patients usually overweight Extreme hyperglycaemia causes hyperosmolar hyperglycaemic state
Effects on the liver of high blood glucose
High blood glucose: Increases glycogen storage Decreases gluconeogenesis Decreases glycogenolysis Leads to glucose uptake/storage
Effects on the liver of low blood glucose
Low blood glucose: Increases glycogenolysis Increases gluconeogenesis Decreases glycogen storage Leads to glucose production
Features of the endocrine pancreas
Endocrine pancreas consists of around 1 million islets of Langerhans cells
They are interspersed throughout the pancreatic gland
Within the islets there are at least five hormone-producing cells
Cell types within the pancreas
Alpha cells: 20% of islet mass, secrete glucagon and proglucagon
Beta cells: 75% of islet mass, secrete insulin, C-peptide, proinsulin, amylin
Delta cells: 3-5% of islet mass, secrete somatostatin
Epsilon cells: <1%of islet mass, secrete ghrelin
Insulin structure
Insulin is a small protein with a molecular weight of 5808
Consists of 51 amino acids arranged in two chains and linked by a disulphide bridge
Proinsulin is processed in the golgi of beta cells and packaged into granules where it is hydrolysed into insulin by removal of four amino acids
Insulin release
In the resting cell, ATP levels are low
Potassium diffuses down its concentration gradient through ATP-gated potassium channels so the cell is fully polarised (-ve)
Insulin release is minimal
As glucose concentration increases, ATP production increases which closes the potassium gate and the cell depolarises
Voltage-gated calcium channels open in response to depolarisation, allowing more calcium to enter the cell
The increased calcium leads to insulin release
Rate of insulin release
The human pancreas contains around 8mg of insulin = approx 200 units
The response t glucose is biphasic- the initial response releases stored insulin- this occurs over the course of two minutes
The second phase (after 5-10 mins) is sustained over an hour and represents the release of newly synthesised insulin
The basal rate of release is ~1 unit/hour, on food intake release is 5-10 fold higher
Total daily secretion is approximately 40 units
The insulin receptor
Insulin diffuses into tissues and then binds specialised receptors
The receptors comprise two covalently linked heterodimers each containing an A subunit and a B subunit
The B subunit contains a tyrosine kinase
When insulin binds to the A subunit a conformational change brings the catalytic loops of the B subunits together
Phosphorylation of the tyrosine residues facilitates tyrosine kinase activation
The insulin receptor 2
The first proteins to be phosphorylated by the tyrosine kinase are the insulin receptor substrates (IRS)
The IRS then activates other kinases related to energy metabolism PIP-3
Alternatively IRS may stimulate a mitogenic pathway hat activates the mitogen activated protein kinase (MAPK) system
Insulin’s second message
Pathway activations result in a variety of effects:
Translocation of glucose transporters to the cell membrane
Increased glycogen synthase activity
Increased glycogen formation
Effects n protein synthesis
Lipolysis and lipogenesis
Activation of transcription factors that enhance DNA synthesis, cell growth and division
Effects of insulin on its tissue targets
Essentially, insulin promotes storage of glucose and fat within target cells Primarily this occurs in: Muscle- myocytes Fat- adipocytes Liver- hepatocytes
Effects of insulin- reversal of catabolic effects in the liver
Inhibits glycogenolysis
Inhibits conversion of fatty acids and amino acids to keto acids
Inhibits conversion of amino acids to glucose
Effects of insulin- anabolic effects in the liver
Promotes storage of glycogen
Increases triglyceride synthesis and VLD lipoprotein formation
Effects of insulin- increased protein synthesis in muscle
Increased amino acid transport
Increased ribosomal protein synthesis
Effects of insulin- increased glycogen synthesis
Increased glucose transport
Increased glycogen synthase and inhibits phosphorylase
Effects of insulin- effects on adipose tissue
Increased triglyceride storage
Lipoprotein lipase is induced and activated by insulin to hydrolyze triglycerides from lipoproteins
Glucose transport into cell provides glycerol phosphate to permit esterification of fatty acids supplied by lipoprotein transport
Intracellular lipase is inhibited by insulin
Pathophysiology of type 1 diabetes
Acute insulin deficiency
Unrestrained hepatic glycogenolysis and gluconeogenesis output
Decreased glucose uptake in insulin sensitive tissues i.e. adipose and muscle
Hyperglycaemia
Pathophysiology of type 2 diabetes
Gradual decrease in insulin
Unrestrained hepatic glycogenolysis and gluconeogenesis output
Decreased glucose uptake in insulin sensitive tissues i.e. adipose and muscle
Hyperglycaemia
Insulin resistance
Abdominal fat has different properties cf. subcutaneous fat and can cause lipotoxicity
Abdominal fat is resistant to the antilipolytic effects of insulin leading to the release of excessive free fatty acids
These free fatty acids result in insulin resistance in the liver and muscles
Results in increased gluconeogenesis in the liver and inhibition of insulin mediated glucose uptake in the muscle
Excess fat may also contribute to insulin resistance because adipocytes become too large to store additional fat, fat then gets stored in muscles, liver and pancreas
Clinical manifestations
Osmotic effects of glucose and abnormalities in energy partitioning
Polyuria- increased urine production, particularly at night
Polydipsia- increased thirst
Fatigue- due to the inability to utilise glucose
Weight loss- if the body can’t utilise glucose it will use protein and fat
Blurred vision- changes in lens refraction
Higher infection rate
WHO criteria for diagnosis
Diabetes symptoms plus: a random venous plasma glucose concentration >11.1mmol/L or a fasting plasma glucose concentration > 7.0 mmol/L or wo hour plasma glucose concentration >11.1 mmol/L two hours after 75g anhydrous glucose in an oral glucose tolerance test
Glucose tolerance test
Rarely used for diagnosis
Patient fasted from 8pm the day before
Commence test around 9am with a venous serum glucose test
Administer 75g of glucose by mouth over 5 mins
Take second venous serum glucose two hours later
Long term complications- macrovascular
1% cerebrovascular disease 35% hypertension 3% intermittent claudication 18% abnormal ECG 13% absent foot pulses
Long term complications- microvascular
1% retinopathy 18% nephropathy 3% abnormal vibration threshold 20% erectile dysfunction 6%ischaemic skin changes (foot)
