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MP322 > L14 - L17 > Flashcards

L14 - L17 Flashcards

1
Q

Mechanism for Active B12 Absorption
- through ileum

A
  1. Vit B12 released from food & bound to haptocorrin (transcobalamin 1) produced in salivary glands
  2. Haptocorrin takes B12 to duodenum and is degraded by proteases, releasing B12
  3. B12 then captured by Gastric Intrinsic Factor (glycoprotein produced by parietal cells).
    - goes through intestine & is endocytosed by cubam in terminal ileum
  4. Intrinsic factor is degraded in enterocyte releasing B12 which gets released in blood by ABC transporter where it binds to transcobalamin II
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2
Q

Plasma Transport of Vit B12 & Cellular Uptake

A
  1. B12 transported in plasma binded to transcobalamin 1,2 or 3
  2. uptake when transcobalamin binds to its receptor CD320 and is endocytosed. transcobalamin degraded yielding B12
  3. Excess B12 is stored in liver
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3
Q

Pernicious Anaemia
(Autoimmune atrophic gastritis)

A

Destruction of gastric parietal cells and the associated lack of intrinsic factor

  • immune response attacks H+/K+ ATPase
  • also caused by antibodies directed against intrinsic factor
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4
Q

Consequences of Vitamin B12 Deficiency
- normal serum conc. B12 is 115-100pmol/L

A

Megaloblastic anaemia - main symptom

Neurological - Paraesthesia, ataxia, sensory weakness

Digestive - Hunters collitis

Cardiovascular - angina, thrombosis

degeneration of spinal cord
- myelin sheath degeneration

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5
Q

Drug Induced B12 Deficiency
- PPI & H2 antagonists
- Oral Contraceptive
- Metformin
- Cholchicine

A

PPI & H2 antagonists - Less stomach acid so less B12 release from food not broken down

Oral Contraceptives - reduces transcobalamin levels

Metformin - reduces B12 absorption

Cholchicine
- impairs or inhibits receptors in terminal ileum

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6
Q

Treatment of B12 Deficiency
- lifelong treatment

A

Oral - cyanocobalamin
parenteral - hydroxocobalamin

  • must be parenteral if intrinsic factor deficient or surgically removed stomach because B12 will be degraded in stomach
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7
Q

Sources of B9
- folate/folic acid

A
  • dark green vegetables
  • cooking destroys B9 in vegetables

RDA 200mcg / day
400mcg supplement given in pregnancy

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8
Q

Absorption of Folate
- requirements

A
  • natural folates are conjugated into polyglutamyl chain
  • folate must be in monoglutamate form to be absorbed
  • glutamic acid residue on folate is cleaved off by folate conjugase.
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9
Q

Absorption of Folate Steps
- most absorption occurs in proximal small intestine (in duodenum or jejunum) some in colon

A
  1. Polyglutamic Folate made into monoglutamic by folate conjugase. absorbed from lumen by PCFT& RFC - folate is exchanged for organic phosphate (OP)
  2. Enterocytes have folate receptors and internalise it by receptor mediated endocytosis. enterocyte exports it as folate or metabolises it to 5-MTHF
  3. exported to blood via Organic Anion Transporter & circulates in blood (some is albumin-bound)
  4. Cellular uptake again by PCFT, RFT, & Folate receptors
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10
Q

Symptoms & Treatment for Folate Deficiency
- (can cause megaloblastic anaemia)

A

Symptoms:
- sore tongue + swallowing pains
- nausea, vomiting, diarrhoea
- dementia, depression

Treatment: oral folic acid 1-4 months
- oral route is sufficient even with malabsorption patients

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11
Q

Pharmaceutical Analysis
- determines quality of drug via analytical chemistry

A

Step 1 : analysis of pharmaceutical product, make sure contents are correct
- UV/Vis Spectrophotometry
- High-pressure Liquid chromatography

Step 2 : Analysis of solid product, is the material the required product
- infrared Spectroscopy
- X-ray Diffraction

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12
Q

Spectroscopy
- energy gain through levels of excitation

A
  • microwave causes rotational energy from dipoles absorbing energy
  • infrared wavelengths cause vibrational energy when bonds absorb energy and vibrate
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13
Q

Diffraction
- process

A
  • light shined onto diffraction grate, separating polychromatic light into different wavelengths
  • sample cuvette with drug in it is moved into the wavelength of light to be used, rest is blocked out
  • PMT detects amount of light coming through cuvette
    we can work out how much light was absorbed by drug
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14
Q

Quantitative analysis
- Beer Lambert Law

A
  • more drug = more absorption
  • light scattering must be avoided, sample must be homogenous (no undissolved drug or bubbles)
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15
Q

Infrared Spectroscopy

A

< 800nm is “fingerprint” region - you can compare against different molecules unique IR region

  • IR has less energy than UV/Vis
  • causes rotational and vibrational energy level shifts
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16
Q

Gestational Diabetes

A

Gestational Diabetes
- can affect up to 25% of pregnant women
- usually develops in 2nd trimester
- possibly due to hormone changes which may block insulin action

17
Q

Diagnosing Diabetes
- Fasting glucose test

A
  1. Fasting Glucose Test
    - no food/drink for 8-10hrs before (except water)
    - normal range 3.9 - 5.4mmol/L
    - pre-diabetic 5.5 - 6.9, diabetic : >7mmol/L
18
Q

Diagnosing Diabetes
- Oral Glucose Tolerance Test

A
  1. Oral Glucose Tolerance test
    75g glucose dissolved in water
  • 7.9 - 11 mmol/L impaired glucose tolerance
    > 11.1 mmol/L indicates diabetes
19
Q

Diagnosing Diabetes
- HbA1c Test

  • not for type 1
A

HbA1c - haemoglobin A (HbA) and glucose
- gives measure of glucose levels over last 3-4 months

> 48mmol/mol - diabetes
42 - 47mmol/mol - diabetes risk

20
Q

Acute Symptoms of Diabetes
- increased urination, dehydration
- tiredness, hunger

A
  • glucose levels high, kidney can’t absorb
    -unabsorbed glucose in urine draws H2O
  • increased urination, dehydration & blurred vision
  • tiredness, hunger and weight loss as glucose is not stored as energy source so fat stores are broken down
  • damage to blood vessels limits flow of oxygen needed for repair - slows healing
21
Q

Diabetic Ketoacidosis

  • chronic Type 1 diabetes complication
  • metabolic changes in T2 usually not severe enough to cause DKA
A
  • body can’t use glucose as energy source which increases release of Free Fatty Acids from adipocytes
  • FFA’s made into ketones by the liver (acetoacetate) which serves as energy source but it makes blood acidic
  • liver keeps secreting glucose which causes dehydration further lowering blood pH which can be deadly
22
Q

Treatment of DKA

A

Treatment: fluid replacement, insulin, mineral replacement

  • usually develops at time of diabetes diagnosis or during illness/ during growth spurt
23
Q

Chronic Diabetes Complications

  • retinopathy
  • nephropathy
  • neuropathy
  • diabetic foot
A

Diabetic Retinopathy - damage to vessels in eye (leading cause of blindness)

Diabetic Nephropathy - microvascular liver damage

Diabetic Neuropathy - sensory loss by hyperglycaemia and damage to blood vessels

Diabetic Foot - damage to blood vessels leads to slower healing because less oxygen. can lead to amputation

24
Q

Insulin Signalling
- PKB Activation

A
  1. insulin binding to receptor causes autophosphorylation (receptor is a kinase)
  2. IR phosphorylates Tyrosine residues on IRS proteins causing phosphoinositide 3-kinase to bind to IRS
  3. this causes PIP2 -> PIP3. binding to PIP3 activates PDK 1 which activates PKB
  4. activated PKB diffuses through cell wall and activates glucose transport and glycogen synthesis
25
Q

Glucose Uptake Pathway into Adipocytes & Muscle

  • insulin signalling
A
  1. blood glucose rise = insulin release
  2. AS160 phosphorylated by PKB, inactivating it, releasing GLUT-4 from vesicles
  3. allows GLUT4 to bind to plasma membrane, increasing glucose transporter levels at surface
  4. Glucose binds to GLUT-4 and is taken into cell
26
Q

Insulin Signalling
- Repression of Gluconeogenesis

  • Fox01 is transcription factor for gluconeogenic genes
A
  1. insulin signalling = PKB activation.
    PKB phosphorylates Fox01 in cytosol
  2. prevents Fox01 entering nucleus as gluconeogenic transcription factor
  3. leads to loss of gluconeogenic gene expression in liver = less glucose production
27
Q

Type 1 Diabetes
- Autoimmune condition resulting in destruction of
beta-cells, insulin deficiency & hyperglycaemia

A

Causes :
- HLA1 area of genome is susceptible to T1 D

  • autoantibodies against beta-cell antigens
  • glutamic acid decarboxylase-65 (GAD-65), Insulin, IA-2
  • presence of 2 of these autoantibodies increases TD 1 risk within next 10yrs to 75%
28
Q

Inhibition of Insulin Signalling Pathways

  • PTP1B Pathway
  • PKC Pathway
A

PTP1B Pathway:

  1. PTP1B activates PKC
  2. PKC phosphorylates serine residues on IRS
  3. prevents IR phosphorylating tyrosine residues on IRS
29
Q

Obesity Leading to Insulin Resistance
- DAG & Ceramide Pathway

A
  1. triglycerides exceed storage capacity in adipose cells. fat accumulates in muscle + liver
  2. DAG & Ceramide formed from fatty acids
  3. They cause serine residue phosphorylation on IRS
30
Q

Obesity Leading to Insulin Resistance
- TNF-a Pathway

A
  1. Obese patients release more pro-inflammatory cytokines like TNF-a
  2. TNF-a causes expression of PTP1B which dephosphorylates Insulin receptor
31
Q

Obesity Leading to Insulin Resistance
- Adiponectin

A
  1. Adiponectin secreted from adipocytes and promotes insulin sensitivity
  2. obese patients produce less adiponectin leading to insulin resistance

MP322 (4 decks)

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