Lecture 10 - Diabetes & Pancreas Flashcards
(48 cards)
1
Q
What cells in the pancreas have exocrine functions and which cells have endocrine functions?
A
- Exo: Acinar cells (arranged in clusters) (98%)
- Endo: Islets of Langerhans (2%)
2
Q
What do acinar cells secrete? (exo func)
A
Digestive enzymes and bicarbonate ions (buffers the gastric acid released from the stomach creating appt. pH for digestion)
3
Q
List 3 types of digestive enzymes secreted by acinar cells in pancreas
A
- Proteases: Trypsin & Chymotrypsin (stored as pro-enzymes to prevent digestion of pancreas)
- Lipase
- Amylase
(LAP)
4
Q
List 3 cell types in Islets of Langerhans
A
- α cell: secrete glucagon
- β cell: secrete insulin
- δ cell: secrete somatostatin (inhibit GH secretion from A.P)
5
Q
Compare & contrast insulin and glucagon
A
Similarities
- Both peptide hormones + water sol.
- Both have short half life (~5 mins)
Differences
- Insulin receptor: Tyrosine Kinase
- Glucagon receptor: G-protein coupled receptor
- B.G: Insulin ⬇️, Glucagon ⬆️
- Insulin stimulates glycogenesis, glucose oxidation/uptake, ⬆️lipogenesis/protein synthesis
- Insulin promotes GLUT 4 translocation in muscle, glucagon X effect (no receptors in muscle)
- Insulin acts on liver, adipose & muscle, glucagon acts on liver & adipose
6
Q
Desc. structure of insulin
A
- Made of 2 chains: α & β chain
- Held together by 2 disulphide bonds, 3rd intra-chain bond
- Peptide hormone, water sol
- Stored as pro-insulin (highly stable)
7
Q
Desc. steps of insulin synthesis
A
DNA in β cell (transcription) —> mRNA (translation) –> Preproinsulin (signal peptide cleavage) –> Proinsulin (proteolysis) –> Insulin & C peptide (marker for endogenous insulin secretion)
8
Q
Describe how the ultrastructure of B cells relate to synthesis of insulin
A
- mRNA on ribosomes of ER undergo transcription and translation to form preproinsulin
- Enzymes in ER cleave signal peptide –> proinsulin
- Travel to Golgi
- Secretory vesicles leave Golgi. Enzymes proteolyse proinsulin –> insulin + C peptide
- Exocytosis
- Hormone travel to target
9
Q
How is C-peptide removed from proinsulin?
A
Trimmed off by carboxypeptidase H
10
Q
What are some stimulators and inhibitors of insulin?
A
Stimulators (Parasympathetic N.S)
- Glucose/F.A/a.a⬆️
- Gastrin, adrenaline at B receptor
Inhibitors (Sympathetic N.S)
- Somatostatin
- Leptin
- Adrenaline at α receptor
11
Q
Desc phases of insulin secretion
A
- Initial burst
- Second phase of gradual increment
- No insulin produced when B.G <2.8mmol/L
12
Q
How does insulin exert its effects on cells?
A
- Insulin binds to tyrosine kinase receptor
- Receptor auto-phosphorylates
- Activation of signalling cascade
- ⬆️glucose uptake, glycogenesis, glycolysis (oxidation to energy)
13
Q
Desc insulin effects on cells
A
- Liver: ⬆️ Glycogenesis, Glycolysis, Lipogenesis, ❌Glycogenolysis, gluconeogenesis, lipolysis
- Muscle: ⬆️ Glucose uptake (GLUT 4), Lipogenesis, Glycogenesis, Glycolysis, Protein Synthesis,a/a transport ❌Lipolysis, Proteolysis
- Adipose: ⬆️ Glucose uptake (GLUT 4), Lipogenesis, Glycolysis, ❌Lipolysis
14
Q
Desc. structure of glucagon
A
- Peptide hormone, water sol.
- No disulphide bonds
- Forms preproglucagon(cleaved) –> proglucagon (proteolysis)–> glucagon
- proglucagon is more complex than insulin, contains more peptide hormones
15
Q
What are the effects of glucagon on the body?
A
- Major target is liver: ⬆️Glycogenolysis, Gluconeogenesis, Release of glucose into bloodstream
- Adipose: Lipolysis
16
Q
How does glucagon exert its effects on cells?
A
- Binds to glucagon receptor (GPCR)
- G-protein activation
- Effector protein activation
- 2nd messenger formed
- ⬆️Glycogenolysis, Gluconeogenesis, Lipolysis
17
Q
How is diabetes mellitus characterised?
A
- Chronic hyperglycemia that leads to long-term clinical complications
- Renal threshold for glucose is exceeded (glucosuria)
18
Q
What is the difference between Type 1 and Type 2 diabetes?
A
- Type 1: Absolute insulin deficiency caused by autoimmune destruction of pancreatic β cells
- Type 2: Relative insulin deficiency caused by insulin resistance. β-cells eventually wear off from overproduction
19
Q
Define the condition Diabetes Mellitus
A
A group of metabolic disorders characterised by chronic hyperglycaemia due to insulin deficiency or resistance or both.
20
Q
How does type 2 diabetes present?
A
- Typical symptoms of hyperglycaemia: Polyuria, polydipsia, blurring of vision
- Symptoms of inadequate energy utilisation: Tiredness, weakness, lethargy + weight loss
21
Q
How does a clinician distinguish between type 1 & type 2 diabetes?
A
Type 1:
- Common in young
- Due to progressive loss of β cell
- Rapid onset + fatal
- Must be treated with insulin
- Diabetic Ketoacidosis (DKA)
Type 2:
- Usually older/obese patients
- Slow progressive loss of β-cells + insulin resistance
- May be present for a long time before diagnosed
- May not initially need treatment w insulin
22
Q
How is diabetes diagnosed?
A
- Test fasting glucose level ( ≥ 7.0mmol/L/ ≥6.1 for whole blood)
- Oral Glucose Tolerance Test
- Venous plasma glucose conc (≥11.0mmol/L)
- HbA1c (10% diabetic)
* do more than one test to confirm. X use glucosuria/finger prick to confirm
23
Q
How is type 1 diabetes presented in clinic?
A
- Rapid onset of symptoms (weight loss, polyuria, polydipsia)
- Vomitting due to ketoacidosis
- Young
- Elevated venous plasma glucose conc
- Presence of ketones (breakdown products of fats)
24
Q
How is Type 1 diabetes treated?
A
- Exogenous insulin given subcutaneously several times per day
- Diet/Exercise
- Constant monitoring of blood glucose through finger prick test
- Regular check-ups
25
Define ketoacidosis
- Hyperglycaemia
- Ketonemia
- Acidosis
26
Why is the presence of ketones is an indication for immediate insulin therapy?
N.B
- Measure using ketone meter
- Prevent DKA
| - Life threatening condition: nausea, vomiting, hyperventilation, extreme muscle weakness (prostration)
27
Why does DKA occur in type 1 diabetes?
- Insulin suppresses ketone production. Due to autoimmune destruction of β-cells, X insulin secreted
- Leads to enhanced lipolysis --> increase ketones (acetoacetate, acetone, 3-β- hydroxybutyrate)
- Activation of the ketogenic enzymes in the liver.
28
What is the diagnosis of DKA?
- Ketonaemia (≥ 3.0mmol/L) or sig. ketonuria (more than 2+ standard urine sticks)
- Blood glucose (≥11.0mmol/L)
- Bicarbonate (<15.0) and/or venous pH (<7.3) or Arterial pH 6.9
29
What causes insulin resistance to develop in type 2 diabetes?
- Obesity (particularly central obesity)
- Muscle and liver fat deposition
- Physical inactivity
- Genetic influence
30
Treatment for type 2 diabetes
1. Lifestyle:
- Low calorie diet (liver fat content decreases)
- Non-insulin therapies: Sulphonylureas (increase insulin production), Metformin (decrease gluconeogenesis)
- Insulin
2. Education + regular monitoring of B.G (finger prick)
3. Treat other vascular risk factors (BP, lipids, smoking)
4. Exercise
5. Regular check ups
Bariatric surgery (weight loss surgery)
31
What are some symptoms of type 2 diabetes?
N.B Symptoms variable due to slower rise of blood glucose
- Polyuria, Polydipsia, Weight loss
- No DKA
- May be asymptomatic (diagnosed during routine screening)
- Usually old/obese
32
How can monitoring BG be carried out by patients?
- Capillary testing (rapid test used for assessing the blood flow through peripheral tissues) for type 1 and more complex type 2
- Ketone testing (urine/plasma) for type 1
- Flash continuous glucose monitoring
33
What are some ACUTE complications of diabetes?
1. Complications of hyperglycaemia: [due to dehydration, renal failure]
- Metabolic decompensation (DKA in type 1)
2. Complications of hypoglycaemia: [due to drugs (iatrogenic)]
- Coma (brain has absolute requirement for glucose)
34
What are some CHRONIC complications of diabetes?
1. Macrovascular:
- Myocardial infarction
- Stroke
- Peripheral vascular disease (gangrene due to less blood flow)
- Intermittent claudication (pain to calves/thigh/buttock)
2. Microvascular: (F.E.K.S)
- Diabetic feet: Gangrene due to poor blood supply/increased risk of infection
- Retinopathy: Damage to blood vessels --> burst --> proliferative retinopathy or protein exudates (leak) or blindness OR cataracts
- Nephropathy: Damage to glomeruli/poor blood supply/infection --> microalbuminuria
- Neuropathy: Damage to peripheral nerves --> loss of sensation
35
What is metabolic syndrome?
A cluster of risk factors associated w cardiovascular disease (diabetes, abdominal obesity, high BP/cholesterol)
36
How to determine if an individual suffers from metabolic syndrome?
- Waist measurement: >94cm for men, >80cm for women
Plus 2:
- Raised triglyceride: >1.7mmol
- Reduced HDL cholesterol: <1.0 for men, <1.2 for women
- Raised BP: >135/85 (normal is less than 120/80 mmHg)
- Raised fasting blood glucose (>5.6 or diabetes)
37
What causes metabolic syndrome?
- Insulin resistance
- Central obesity
- Genetics
- Sedentary lifestyle
- Ageing
38
How common is polydipsia and polyuria in the general population?
- Polydipsia is 30%, Polyuria is 25%
39
What is the primary transporter of glucose in pancreatic β cells?
GLUT 2 (bidirectional)
40
The ATP sensitive potassium channel KATP plays a key role in regulating insulin secretion by pancreatic β cells.
What effect would a decrease in the intracellular concentration of ATP have on these channels?
- More KATP channels would be in the open state. ⬆️K+ leaving cell --> more negative membrane --> less calcium channels open (Ca2+ ions stimulate fusion of vesicles and release of insulin) --> less insulin
- KATP are inhibited by ATP.
41
A 41 year old man eats a meal. Shortly afterwards the concentration of the hormone insulin rapidly increases in his blood.
What has occurred in the man's pancreatic beta cells to initiate this rise in hormone concentration?
- Plasma membrane depolarised
- More glucose= more ATP --> Katp X open --> Less K+ leave --> depolarisation --> Ca2+ channels open --> insulin secreted
42
From where does the pancreas emerge as an outgrowth during embryonic development?
Foregut
43
Mutations in the gene coding for which protein could have resulted in neonatal diabetes mellitus?
- Kir6.2
| - Pore forming subunit of the ATP-sensitive potassium channels (KATP) expressed in pancreatic β cells(inhibited by ATP)
44
A 17 year old girl with type 1 diabetes mellitus self administers a subcutaneous injection of the hormone insulin in order to control her plasma glucose level.
What would be the result of this injection? (In terms of C-peptide)
- Plasma C-peptide concentration would remain the same.
| - Commercial insulin preparations for injection just contain insulin (no C-peptide is added to the preparation)
45
State the normal plasma concentration for glucose.
**sometimes question will trick you with diff. units
- 3.3 to 6.0 mmol/litre
46
What process is HbA1c formed?
Glycation: non-enzymatic process that adds glucose to proteins
47
Major structural features of pancreatic B-cell for insulin secretion?
1. ⬆️mitochondria: exocytosis of insulin
2. ⬆️RER: site of synthesis of preproinsulin
3. ⬆️Golgi: Formation of hormone storage vesicles
4. ⬆️Storage vesicles: Contain active insulin + C-peptide
5. ⬆️microtubules + microfilaments: for exocytosis
48
List the factors that affect insulin secretion and explain their physiological significance.
1. ⬆️Glucose, F.A, A. A = ⬆️insulin when the nutrients exceed fasting values --> insulin interacts with target tissues (liver & S.M) --> ⬆️uptake/storage/utilisation of glucose
2. Catecholamines (adrenaline & noradrenaline) inhibit insulin secretion --> ⬆️B.G stress response
3. Gut hormones = ⬆️ insulin --> part of digestion process --> prevent major increase in B.G
