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Flashcards in PBL 1 - Type 1 Diabetes Mellitus Deck (41)
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Describe how blood glucose regulates insulin release.

Can include a diagram.

1. Glucose enters the cell via GLUT2

2. Glucokinase causes phosphorylation of glucose, which then undergoes glycolysis

3. This produces ATP

4. The change in ATP:ADP ratio causes K+-ATP channels to close
a. Normally, these would transport K+ out of the cell
b. Therefore, this causes accumulation of K+ within the cell

5. Accumulation of K+ causes voltage gated Ca2+ channels to open
a. This causes Ca2+ influx into the cell

6. Ca2+ influx stimulates vesicles containing preformed insulin to move towards the cell surface
a. These release insulin via exocytosis


Describe the phases of insulin secretion.

1. Rapid phase (0-10 minutes)
a. Involving potassium and calcium in the beta cell

2. Second phase (sustained)
a. Continues until normal glucose levels are reached


Describe the synthesis of insulin in pancreatic beta cells.

1. Preproinsulin is synthesised in the rough ER of beta cells
a. This contains a signal sequence
b. Signal sequence binds to signal recognition particles (SRP) which transports preproinsulin out of the rough ER

2. This removes the signal sequence to form proinsulin
a. Proinsulin is transferred to the Golgi
b. Proinsulin forms zinc-containing proinsulin hexamers, which are soluble
c. Consists of 3 chains: A, B, C

3. C chain is removed by prohormone convertase to form insulin
a. Structure: consists of A and B chains linked by disulphide bridges
b. Insulin is insoluble and crystallises in storage vesicles


What is the function of zinc in insulin formation?

1. Formation of proinsulin hexamers

2. Makes proinsulin hexamers soluble

3. Precipitation and crystallisation of insulin

4. Crystal formation, which reduces the rate of proteolysis, meaning that insulin can be stored logner


List the different effects of insulin on different organs.

1. Liver
a. Increases glycogenesis (by increasing glucokinase and glycogen synthase activity)
b. Inhibits glycogenolysis (by inhibiting glycogen phosphorylase and G6Pase expression)
c. Inhibits gluconeogenesis (by inhibiting PEPCK and G6Pase expression)
d. Increases FA production

2. Muscles
a. Increases glycogenesis (by increasing glycogen synthase activity)
b. Inhibits glycogenolysis (by inhibiting glycogen phosphorylase expression)
c. Increases glucose uptake (by increasing GLUT4 expression)

3. Adipose tissue
a. Stimulates storage of TAGs (by increasing GLUT4, and FAS expression, and ACC and LPL activity)
b. Inhibits lipolysis (by inhibiting cAMP, thus inhibiting hormone sensitive lipase)
c. Increases glucose uptake (by increasing GLUT4 expression)

4. Other
a. Increases amino acid uptake
b. Increases protein synthesis


Describe the process of insulin signalling.

1. Insulin binds to the IR

2. This causes dimerization of the IR
a. This causes autophosphorylation of the tyrosine kinase molecules

3. Phosphorylated tyrosine molecules bind to the insulin receptor substrate (IRS)

4. IRS activates PI3K (phosphatidylinositol 3 kinase)
a. This phosphorylates PIP2 to form PIP3

5. PIP3 activates PKB/Akt (protein kinase B), which exerts different effects in the cell:
a. Inhibits:
---Gluconeogenesis (in liver)
---Lipolysis (in adipose tissue)
b. Stimulates:
---Glucose uptake (in muscles, adipose tissue)
---Glycogenesis (in muscles, liver)
---Fatty acid synthesis (in liver, adipocytes)


What sort of receptor is the IR?

Tyrosine kinase receptor


What sort of receptor is the glucagon receptor?

G protein coupled receptor


Describe the process of glucagon signalling.

1. Glucagon binds to the glucagon receptor (a G-protein couple receptor)
a. Found in: Hepatocytes

2. This causes a conformational change in the GR, causing the alpha subunit to detach and activate adenylyl cyclase

3. Adenylyl cyclase then stimulates cAMP

4. cAMP then stimulates cAMP-dependent protein kinase and other second messengers


Describe and explain the main 3 symptoms of T1DM.

1. Polyuria
2. Polyphagia
3. Polydipsia

These are caused by the fact that glucose is highly osmotically active, and its presence in the kidney tubules will draw water with it:
1. Increased blood glucose means more glucose is filtered in the glomerulus
2. As filtrate blood glucose levels approach the renal threshold, not all glucose will be reabsorbed
3. This leads to excess glucose in the filtrate and urine (glycosuria)
4. This draw water into the urine, leading to massive fluid loss
a. Therefore, there will be more urine (polyuria)
b. Therefore, there will be increased thirst (polydipsia)
5. Polyphagia is caused because peripheral cells cannot take up as much glucose, so they think that there are low glucose levels and stimulate hunger


List the other symptoms of T1DM.

1. Weight loss (due to diuresis, fluid loss and use of fat stores int he absence of glucose)
2. Blurred vision
3. Fatigue
4. Parasthesias
5. Skin infections
6. Nocturia
7. Genital candidiasis
a. Pruritus vulvae
b. Balanitis
8. Nausea
9. Headache
10. Mood changes (irritability, difficulties in concentrating)


How is T1DM diagnosed?

1. History and examination

2. Blood tests
a. Fasting plasma glucose: 6.9+ mmol/L
b. Random plasma glucose: 11.1+ mmol/L
c. Glucose tolerance test: 11.1+ mmol/L
d. Plasma ketones
e. Glycosylated haemoglobin: 48+ mmol/L
f. Fasting C-peptide levels
g. Autoantibodies

3. Urine tests
a. Urine ketones


List the autoantibodies found in T1DM.

Anti-glutamic acid decarboxylase (GAD)
Islet cell antibody
Islet antigen 2 antibody


Describe how the glucose tolerance test is administered.

Fasting blood glucose taken

75g oral glucose given

Blood glucose levels repeated after 2 hours


Describe the causes of T1DM.

1. Genetic
a. Polygenic
b. Associated with HLA DR3/4

2. Associated factors in early life
a. Enteroviral infections
b. Pre-eclampsia
c. Increased birth weight
d. Parental diabetes

3. Autoimmune disease
a. Autoantibodies:
---Islet cell antibodies
---Glutamic acid decarboxylase antibodies
---Islet antigen 2 antibodies
---Anti-insulin antibodies
b. Other autoimmune conditions
---Thyroid disorders
---Pernicious anaemia

4. Pregnancy

5. Environmental facts
a. Hygiene hypothesis
b. Viral infection and cross reactivity
---Epstein-Barr virus
c. Stress
d. Dietary factors


Define type 1 diabetes mellitus.

A T cell mediated autoimmune disease involving destruction of the insulin secreting beta cells over many years


Describe the pathophysiology of type 1 diabetes.

1. Autoimmunity
a. Hyperglycaemia doesn't appear until 70-90% of beta cells have been destroyed
b. Types of antibodies:
i. Islet cell antibodies (e.g. GAD Ab)
---Cause leukocyte infiltration and T cell destruction of beta cells
ii. Anti-insulin antibodies
---Make insulin unable to bind to receptors, therefore it has no effect

2. Insulitis
a. Leukocyte infiltration of the islets of Langerhans
b. This causes patchy lesions of infiltrated islets next to unaffected lobules
c. Consequences:
---Beta cell destruction
---Decreased insulin production
---Increased blood glucose
---Decreased glucose uptake in peripheral tissues

3. Beta cell specificity of damage

4. Stimulation of glucagon secretion
a. Caused by peripheral cells which have decreased glucose uptake
b. Causes counter-regulatory consequences:
---Increased glycogenolysis
---Increased gluconeogenesis
---Further increase of hyperglycaemia
---Diabetic ketoacidosis

5. Hyperglycaemia
a. Due to insufficient insulin secreiton, therefore:
---Decreased glycogenesis
---Decreased glucose uptake in peripheral tissues
b. Due to increased counter-regulatory hormone (glucagon) secretion, therefore:
---Increased gluconeogenesis
---Increased glycogenolysis
---Increased ketogenesis in liver


Describe the different types of synthetic insulin.

1. Short acting
a. Regular insulin
b. Insulin analogues, e.g.

2. Intermediate acting
a. NPH (isophane insulin)
---added protamine and zinc
b. Lente
---Added excess zinc

3. Long acting
a. Protamine insulin
b. Insulin zinc suspensions, e.g.
---Bovine ultralente insulin
c. Insulin analogues, e.g.


List the different types of insulin regimens.

1. Basal-bolus regimen
2. Once daily regimen
3. Twice daily regimen
4. Continuous subcutaneous insulin infusion/insulin pump


Define hypoglycaemia.

Blood glucose below 3.5 mmol/L


List the risk factors for hypoglycaemia.

1. Over medication with insulin
2. Missed/delayed/inadequate meals
3. Alcohol
4. Errors in insulin dose
5. Poorly designed insulin regimen
6. Lipohypertrophy at injectin site
7. Gastroparesis
8. Malabsorption
9. Other endocrine disorders
10. Factitious (deliberately caused)
11. Breastfeeding


List the risk factors for severe hypoglycaemia.

1. Strict glycaemic control
2. Impaired awareness of hypoglycaemia
3. Age (very young/elderly)
4. C-peptide negativity
5. History of previous severe episodes
6. Renal impairment
7. Genetic


Describe the treatment of hypoglycaemia.

1. Oral carbohydrate
a. Glucose drink/tablets/sweets

2. Snack containing complex carbohydrates

3. Parental treatment if patient is unconscious
a. IV dextrose
b. IM glucagon


Briefly list the main features in the pathophysiology of T1DM.

1. Autoimmunity
2. Insulitis
3. Beta specificity of damage
4. Stimulation of glucagon secretion
5. Hyperglycaemia


List the types of carbohydrate in the diet.

1. Polysaccharides
a. Starch
b. Cellulose

2. Dissacharides
a. Maltose
b. Sucrose
c. Lactose

3. Monosaccharides
a. Glucose
b. Fructose


Why might some starches in the diet be digested more slowly than others?

1. Trapped in intact starch granules/plant cell wall structures

2. Resistant to amylase as their 3D structure is too tightly packed

3. Associated with dietary fibre

4. Carbohydrate foods containing high levels of fat


Describe the normal plasma glucose levels.

Fasting: 4-5 mmol/L
After meals: 8-12 mmol/L


Where are SGLUT 1 transporters found, and what is their function?


1. Cotransports one molecule of glucose/galactose with 2 Na+ ions
2. Do NOT transport fructose


Where are GLUT 1 transporters found, and what is their function?


1. Transports glucose (high affinity)
2. Transports galactose
3. Does NOT transport fructose


Where are GLUT 2 transporters found, and what is their function?

Pancreatic beta cells
Small intestines

1. Transports glucose (low affinity, high capacity)
2. Transports galactose
3. DOES transport fructose