Week 8

Question 0

WHat are the key features of type 1 DM?

Answer 0

Commonest type in the young
Characterised by autoimmune destruction of beta cells, often following viral infection.
Absolute insulin deficiency
Causes ketoacidosis if untreated
Must treat with insulin
Fatal if untreated
10% of DM is type 1 - 15 per 100,000 diagnosed each year

Question 1

What is diabetes mellitus?

Answer 1

Chronic hyperglycaemia

Question 2

What triggers type 1 DM?

Answer 2

Genetic predisposition - genetic markers HLA DR3 and HLA DR4
environmental trigger - viral infection
Produce killer lymphocytes, macrophages, antibodies, autoimmune destruction of beta cells.

Question 3

What are the key points of diabetes mellitus type 2?

Answer 3

90% of cases - 2% prevalence
Insulin resistance, progressive loss of beta cells - initially managed by lifestyle, then drugs, then insulin.
May be present for a long time before diagnosis.

Question 4

How many people had diabetes in the uk in 2013?

Answer 4

3.2 million

Question 5

What is the classic presentation of type 1 Diabetes mellitus, what causes these symptoms?

Answer 5

Young person with history of recent viral infection
Polydipsia-due to osmotic effects of glucose on thirst centres, and excess water lost in urine
Polyuria- plasma glucose exceeds renal threshold therefore is not all reabsorbed. Glucose places an extra osmotic load on the nephron, less water is reabsorbed, excreted as copious volumes of urine
Weight loss - insulin is absent, so catabolism of fat and muscle stores is promoted

Question 6

What causes hyperglycaemia?

Answer 6

Lack of insulin causes decreased uptake of glucose into skeletal muscle and adipose tissue.
Decreased glycogenesis is muscle and liver
Increased gluconeogenesis in liver

Question 7

What causes ketoacidosis, what are the symptoms?

Answer 7

Absent insulin production in type one diabetes leads to a high rate of beta oxidation in the liver, acetyl coA is then used for ketone body synthesis rather than cholesterol synthesis.
Produce large amounts of acetone (smelt on breath), acetoacetate and beta hydroxybutyrate.
Ketones are acidic, causes pH of blood to drop - ketoacidosis
Hyperventilation, nausea, vomiting, dehydration, abdominal pain.
Denatures proteins- die.

Question 8

What are the symptoms of type 2 diabetes?

Answer 8

Slow healing of wounds
Infections of genitalia/thrush 
Infections of feet
Tired all the time
Visual difficulties
Polydipsia 
Polyuria

Question 9

How is diabetes diagnosed?

Answer 9

Either symptoms and one of these, or two without symptoms:
Random blood glucose >11.1 mmol/l
Fasting plasma glucose >6.1mmol/l, whole blood>7mmol/l
Plasma glucose >11.1 mmol/l 2 hours after 75g of anhydrous glucose in OGTT

Question 10

When should insulin doses be increased?

Answer 10

Infection or trauma

Question 11

What drugs can be used in T2DM?

Answer 11

Sulphonylureas-increase insulin release from beta cells and reduce insulin resistance
Metformin -reduces gluconeogenesis

Question 12

How can diabetes be prevented?

Answer 12

Lifestyle modifications - diet and exercise

Question 13

What is HbA1c?

Answer 13

Glycosylated haemoglobin- terminal valine of haemoglobin reacts with glucose, since erythrocytes remain 120 days in circulation provides a measure of control of blood glucose over last 3 months.
4-6% in healthy people, >10% in poorly controlled diabetes

Question 14

What are the consequences of poorly controlled hyperglycaemia?

Answer 14

Uptake of glucose into peripheral nerves, the eye and the kidney is not via glut4 receptors therefore does not require insulin.
Metabolised to sorbitol, depletes NADPH.
Depleted NADPH causes disulphide bonds to form in proteins - cataracts.
Sorbitol causes osmotic damage - glaucoma
Also non enzymatic glycosylation of proteins - glucose reacts with free amino groups - affects net charge and 3d structure therefore affects function

Question 15

What are the clinical consequences of diabetes mellitus?

Answer 15

Macrovascular - increased risk of MI, stroke, poor circulation to peripheries especially the feet.
Microvascular - diabetic eye disease - glaucoma, cataracts, retinopathy (damage to blood vessels - leak and form protein exudates, or bleed within the eye/proliferative retinopathy- new vessels weak and bleed easily)
Nephropathy - damage due to poor blood supply, or due to UTIs, damage to glomeruli - causes microalbuminuria
Neuropathy - causes loss of sensation, altered function of ANS
Diabetic feet - due to poor sensation, increased risk of infection, poor blood supply

Question 16

Describe the endocrine pancreas:

Answer 16

Endocrine pancreas is the islets of langerhans (groups of ~6000 cells around 0.25 mm diameter scattered through exocrine tissue)
There are around 1 million islets which represent 1-2% of the weight of the organ.

Question 17

What are the cell types in the endocrine pancreas and what do they secrete?

Answer 17

Alpha cells secret glucagon
Beta cells secrete glucagon and amylin
Delta cells secrete somatostatin
Gamma cells secrete pancreatic polypeptide 
Epsilon cells produce ghrelin

Question 18

What are the major cell types in the endocrine pancreas?

Answer 18

75% beta cells, 20% alpha cells

Question 19

WHat is the structure of insulin?

Answer 19

Two polypeptide chains joined by 2 disulphide bonds, one disulphide bond between cysteine residues on A chain

Question 20

How is insulin synthesised?

Answer 20

As preproinsulin (109 amino acids), enters lumen of RER, pre part (23aas) cleaved
Folds, and disulphide bonds form.
Transported to trans Golgi and packaged into storage vesicles
Cleaved into c - peptide, three arginine and a lysine and insulin in the storage vesicles

Question 21

Why is measuring c peptide levels useful?

Answer 21

Measures the rate of endogenous insulin production

Question 22

How is insulin stored?

Answer 22

In storage granules as crystalline zinc complex

Question 23

What are the major actions of insulin?

Answer 23

Increases glucose transport into adipose tissue and skeletal muscle
Increases glycogenesis and decreases glycogenolysis
Decreases lipolysis in adipose tissue
Decreases gluconeogenesis in liver
Decreases proteolysis of skeletal muscle, heart muscle and liver
Increases amino acid uptake and protein synthesis in liver muscle and adipose
Increases glycolysis in liver and adipose
Increases lipogenesis and esterification of fatty acids
Decreases ketogenesis
Increases lipoprotein lipase activity in the capillary beds of adipose

Question 24

What controls insulin secretion?

Answer 24

Levels of metabolites - glucose, amino acids, FAs,
GI tract hormones - gastrin, secretin, cholecystokinin
Increase secretion
Adrenaline, noradrenaline, acetylcholine decrease secretion

Question 25

How is glucagon synthesised?

Answer 25

AS preproglucagon, undergoes post translational processing to produce active form (single chain polypeptide)

Question 26

What are the main actions of glucagon?

Answer 26

Increase the rate of glycogenolysis and decrease glycogenesis in liver
Increase ketogenesis in liver
Increase gluconeogenesis in liver
Increase lipolysis in adipose tissue

Question 27

How does glucagon produce effects in target cells?

Answer 27

Binds specific glucagon receptor (g protein coupled receptor)
Activates adenylate cyclase, increases levels of cAMP
Activates protein kinase A
Phosphorylates and activates enzymes in target cells