Diabetes lecture 1

Question 1

Aetiological classification of type 1 diabetes

Answer 1

B cell destruction, usually leading to absolute insulin deficiency, autoimmune, idiopathic

Question 2

Aetiological classification of type 2 diabetes

Answer 2

May range from relative insulin deficiency to a predominantly secretory defect with or without insulin resistance

Question 3

Aetiological classification of other types of diabetes

Answer 3

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

Question 4

Characteristics of type 1 diabetes

Answer 4

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

Question 5

Characteristics of type 2 diabetes

Answer 5

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

Question 6

Effects on the liver of high blood glucose

Answer 6

High blood glucose:
Increases glycogen storage
Decreases gluconeogenesis
Decreases glycogenolysis
Leads to glucose uptake/storage

Question 7

Effects on the liver of low blood glucose

Answer 7

Low blood glucose:
Increases glycogenolysis
Increases gluconeogenesis
Decreases glycogen storage
Leads to glucose production

Question 8

Features of the endocrine pancreas

Answer 8

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

Question 9

Cell types within the pancreas

Answer 9

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

Question 10

Insulin structure

Answer 10

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

Question 11

Insulin release

Answer 11

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

Question 12

Rate of insulin release

Answer 12

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

Question 13

The insulin receptor

Answer 13

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

Question 14

The insulin receptor 2

Answer 14

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

Question 15

Insulin’s second message

Answer 15

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

Question 16

Effects of insulin on its tissue targets

Answer 16

Essentially, insulin promotes storage of glucose and fat within target cells
Primarily this occurs in:
Muscle- myocytes
Fat- adipocytes
Liver- hepatocytes

Question 17

Effects of insulin- reversal of catabolic effects in the liver

Answer 17

Inhibits glycogenolysis
Inhibits conversion of fatty acids and amino acids to keto acids
Inhibits conversion of amino acids to glucose

Question 18

Effects of insulin- anabolic effects in the liver

Answer 18

Promotes storage of glycogen

Increases triglyceride synthesis and VLD lipoprotein formation

Question 19

Effects of insulin- increased protein synthesis in muscle

Answer 19

Increased amino acid transport

Increased ribosomal protein synthesis

Question 20

Effects of insulin- increased glycogen synthesis

Answer 20

Increased glucose transport

Increased glycogen synthase and inhibits phosphorylase

Question 21

Effects of insulin- effects on adipose tissue

Answer 21

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

Question 22

Pathophysiology of type 1 diabetes

Answer 22

Acute insulin deficiency
Unrestrained hepatic glycogenolysis and gluconeogenesis output
Decreased glucose uptake in insulin sensitive tissues i.e. adipose and muscle
Hyperglycaemia

Question 23

Pathophysiology of type 2 diabetes

Answer 23

Gradual decrease in insulin
Unrestrained hepatic glycogenolysis and gluconeogenesis output
Decreased glucose uptake in insulin sensitive tissues i.e. adipose and muscle
Hyperglycaemia

Question 24

Insulin resistance

Answer 24

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

Question 25

Clinical manifestations

Answer 25

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

Question 26

WHO criteria for diagnosis

Answer 26

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

Question 27

Glucose tolerance test

Answer 27

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

Question 28

Long term complications- macrovascular

Answer 28

1% cerebrovascular disease
35% hypertension
3% intermittent claudication
18% abnormal ECG
13% absent foot pulses

Question 29

Long term complications- microvascular

Answer 29

1% retinopathy
18% nephropathy
3% abnormal vibration threshold
20% erectile dysfunction
6%ischaemic skin changes (foot)