Trigger 1: Insulin Secretion

Question 1

What is your normal blood glucose level (in mol/L)?

Answer 1

4-7

Question 2

What organ is insulin secreted from?

Answer 2

Pancreas

Question 3

Which cell type is glucagon produced from?

Answer 3

Alpha cells

Question 4

Which cell type is insulin produced from?

Answer 4

Beta cells

Question 5

What do the delta cells release?

Answer 5

Somatostatin

Question 6

Does insulin secretion increase or decrease blood glucose?

Answer 6

Decrease

Question 7

Does glucagon secretion increase or decrease blood glucose?

Answer 7

Increase

Question 8

Other than being an endocrine organ, what other role does the pancreas play?

Answer 8

Produces digestive enzymes for use in the duodenum

Question 9

What percentage of the pancreas does the islets of Langerhans make up?

Answer 9

1%

Question 10

What two things are produced at the islets of Langerhans?

Answer 10

Insulin and glucagon (islets of Langerhans are made up of alpha and beta cells, amongst others.)

Question 11

Which are the three main tissues that insulin acts on to lower blood glucose levels?

Answer 11

Liver, muscle and adipose

Question 12

Insulin promotes lipolysis in adipose tissue - true or false?

Answer 12

False

Question 13

What receptors does glucagon act on in the liver and what downstream signalling effect does this produce?

Answer 13

Via glucagon receptors that are GPCRs, increases cAMP and PKA.

Question 14

What does the increase in cAMP and PKA due to glucagon signalling on the liver lead to?

Answer 14

Inhibition of glycolysis and glycogenesis (i.e. decrease in glycogen production)
Stimulation of gluconeogenesis and glycogenolysis (i.e. increase in glucose production)

Question 15

In the action of Glucagon, does inhibition of glycolysis and glycogenesis increase or decrease glycogen production?

What effect does this have on blood sugar levels?

Answer 15

Decrease

Blood sugar increases (hormone helps to reduce hypoglycaemia)

Question 16

In the action of Glucagon, does stimulation of gluconeogenesis and glycogenolysis increase or decrease glucose production?

What effect does this have on blood sugar levels?

Answer 16

Increase

Blood sugar increases (hormone helps to reduce hypoglycaemia)

Question 17

Other than hormones, what other 3 factors can change your blood sugar levels?

Answer 17

Exercise
Illness
Stress

Question 18

Where within the beta cells is insulin stored?

Answer 18

In granules in the cytoplasm

Question 19

Describe the first phase of insulin secretion in response to high blood sugar.

Answer 19

Beta cells exposed to high levels of glucose will cause immediate, high release of insulin secretion, which lasts for up to 15 minutes.

This is caused by an initial rapid but transient burst of insulin secretion. Probably due to the release of insulin from granules that were already docked at the cell membrane

Question 20

Describe the second phase of insulin secretion in response to high blood sugar.

Answer 20

If glucose remains high then insulin release is sustained for a long time in order to reduce blood glucose levels over time.

This is due to due to the release of both stored insulin and newly synthesized insulin.

Question 21

What are the 6 steps that lead to insulin secretion in pancreatic beta cells?

Answer 21

1. Glucose enters the cell via GLUT-2 receptors
2. Glucose is inverted to Glucose-Phosphate via glucokinase
3. Glucose-6-phosphate is converted into pyruvate which can enter the krebs cycle
4. Krebs cycle produces ATP which binds to KATP channels causing them to open and K+ efflux from the cell.
5. Cell membrane depolarises causing Ca2+ channels to open and influx of Ca2+
6. Increased Ca2+ inside the cell mediates insulin secretion from granules at the cell membrane.

Question 22

How is insulin secretion stimulated neuronally?

Answer 22

Stress increases Parasympathetic innervation
Acetylcholine is produced which acts on DAG, producing PKC
PKC stimulates insulin secretion from granules at the cell membrane.

Question 23

How does sympathetic innervation decrease insulin secretion?

Answer 23

It blocks cAMP

Question 24

What is the role of glucokinase?

Answer 24

Sets the threshold for glucose stimulated insulin secretion- glucokinase has a low affinity for glucose.

Question 25

For what phosphorylation process is gucokinase required?

Answer 25

Phosphorylation of glucose to form glucose-6-phosphate

Question 26

Finish the following 4 statements in relation to the important feature of beta cells. 1. Glut2 has a ___ affinity for glucose 2. _____ are highly vascularised 3. ______ of beta cells are tightly controlled 4. Highly _________ cells, with may unique ________ ______

Answer 26

1. Glut2 has a low affinity for glucose 2. Islets are highly vascularised 3. Number of beta cells are tightly controlled 4. Highly differentiated cells, with may unique transcription factors

Question 27

What is the definition of diabetes mellitus?

Answer 27

Hyperglycaemia due to insufficient insulin secretion. Clinical defy nation: Fasting blood glucose over 7mmol/L

Question 28

How does the monogenic form of diabetes occur?

Answer 28

Single gene defects cause diabetes due to beta cell defects

Question 29

How does neonatal diabetes occur? (genetic basis)

Answer 29

Most common mutations are in KCNJ11 and ABCC8 (these code for proteins that for KATP channel subunits

Question 30

Is MODY monogenic or polygenic?

Answer 30

Monogenic

Question 31

What does MODY stand for?

Answer 31

Maturity onset diabetes of the young

Question 32

Does MODY present more like type 1 or type 2 diabetes?

Answer 32

Type 2

Question 33

True or false, people with type 2 diabetes usually have high levels of insulin secretion at diagnosis.

Answer 33

True

Question 34

Define type 2 diabetes

Answer 34

Hyperglycaemia due to insufficient insulin secretion Due to a combination of increased insulin resistance and beta cell defects Can have a very high level of insulin secretion but due to insulin resistance glucose levels remain high

Question 35

How does type 2 diabetes present?

Answer 35

Long duration- months or years Older at diagnosis- 50s and 60s Overweight/ obese Strong family history Thirst, hunger, polyuria (symptoms of high glucose) Oral and vaginal thrush, periodontal disease Tiredness

Question 36

Name 5 treatments for type2 diabetes

Answer 36

1. Diet/ exercise 2. Drugs to improve insulin sensitivity (e.g. metformin, pioglitazone) 3. Drugs to stimulate insulin secretion (egg GLP-1 agonists, sulfonylureas) 4. Drugs to promote glucose excretion via the kidneys (gliflozins) 5. Insulin injections

Question 37

Define type 1 diabetes

Answer 37

Autoimmune destruction of insulin producing beta cells of the pancreas Presence of autoantibodies and auto reactive T cells directed against islet cells or their antigenic constituents

Question 38

What ar the symptoms of type 1 diabetes (4 Ts)?

Answer 38

Toilet Thirsty Tired Thinner

Question 39

What are the characteristics of type 1 diabetes?

Answer 39

``` Young age onset Sudden onset - days to weeks Thin at diagnosis Autoantibodies and T cells present Genetic link - MHCII, I and CTLA 4 Family history - spontaneous in 85% of cases Insulin deficiency Ketoacidosis ```

Question 40

Name 4 treatments for type 1 diabetes

Answer 40

1. Insulin replacement therapy - injections or insulin pump 2. Regular blood glucose monitoring 3. Carbohydrate counting/ exercise 4. Transplantation - islet or pancreas

Question 41

True or false, the insulin receptor is a GPCR?

Answer 41

False- its a tyrosine kinase

Question 42

What is the name of the transporter that allows glucose entry into muscle?

Answer 42

Glut4

Question 43

Which component in the beta cell sets the threshold for glucose stimulated insulin secretion?

Answer 43

Glucokinase

Question 44

True or false, glucokinase has a low affinity for glucose?

Answer 44

True

Question 45

What action does increased ATP levels have on the KATP channel in beta cells?

Answer 45

Closes them

Question 46

True or false, glucose is the only molecule that can moderate insulin secretion?

Answer 46

False

Question 47

Which second messenger does GLP-1 increase in beta cells to promote insulin secretion? a. FA-acyl CoA b. Gsq c. IP3 d. DAG e. cAMP

Answer 47

e. cAMP

Question 48

How do fatty acids stimulate insulin secretion? a. Increasing DAG b. Increasing ATP c. Binding GRP40 d. All of the above

Answer 48

d. All of the above

Question 49

Which one of these transcription factors is NOT present in adult beta cells? a. PDX-1 b. HNF1b c. NeuroD1 d. Nkx6.1

Answer 49

b. HNF1b

Question 50

When might you suspect a diagnosis of Type 1 diabetes in children might not be correct?

Answer 50

A diagnosis of diabetes before 6 months (<1% type1) Family history of diabetes with parenthood affactectd (2.4% of type 1) Evidence of endogenous insulin production outside the honeymoon phase (after 3 years of diabetes with detectable C peptide (1-5% Type 1) When pancreatic islet autoantibodies are absent, especially if measured at diagnosis (3-30% type 1)

Question 51

When might you suspect a diagnosis of Type 2 diabetes in adults might not be correct?

Answer 51

Not markedly obese or diabetic family members who are normal weight (20% type 2) Acanthuses nigricans not detected (10% type 2) Ethic background from a low prevalence type 2 diabetes trace e.g. European Caucasian (0-45% type 2) No evidence of insulin resistance with fasting C peptide within the normal range (0-20% type 2)

Question 52

What are the potential challenges of using ES stem cells for treating diabetes?

Answer 52

The heterogeneity of the ES progeny is unacceptable in clinical settings Uses viruses, transgenes and genetic modification Difficult to generate fully functional insulin producing cells comparable with mature beta cells in vivo Full maturation can be achieved through transplantation of the stem cell progeny in vivo

Question 53

What are the medical applications of iPS cell based generation of insulin producing cells?

Answer 53

Disease/ mutation specific beta cells for research Personalised treatment Replacement therapies Correction of genetic defects Circumvention of requirement of immunosuppressants

Question 54

What are the challenges of iPS cell based generation of insulin producing cells?

Answer 54

Creating clinically relevant numbers of mature beta cells Time/ cost - only available for patients not responding to current treatments Use of viruses causing random integration of pluripotency factors resulting in potential mutagenesis Potential presence of pluripotent cells - teratoma formation

Question 55

What are the advantages of islet transplants?

Answer 55

Improve glucose control Reduce requirement of insulin injections Reduced hypoglycaemic events Improved hypoglycaemic awareness

Question 56

What are the disadvantages of islet transplants?

Answer 56

High levels of cell death occur Require several donor to achieve insulin independence Insulin independence may not last long term Requirement of immunotherapy to prevent rejection Problems at site of injection

Question 57

How might current islet transplant protocols be changed to overcome these problems?

Answer 57

Whole pancreas transplantation Animal sources of islets Alternative sites of injection Improved culture of islets before injection

Question 58

How are insulin analogues modified to alter their properties and why is this useful?

Answer 58

Changing the amino acid sequence will allow insulin to absorb and act more quickly, as it afflatus their normal hexameter formation around zinc which slows insulin absorption Changing their isometric point (how the insulin binds to albumin) can increase the length of time insulin can act for Injecting a combination of these different types of insulin throughout the day allows the patient to mimic the bodies normal insulin production (different types of insulin may be required after food/ exercise/ at different times of day etc)

Question 59

What is 'smart' insulin?

Answer 59

A person with type 1 diabetes would take an injection, or perhaps even a pill, of one of these insulins – enough to cover the needs of a day – and the smart insulin would circulate in the body, inactive, until blood glucose levels start to rise eg Microneedle-array patches - these patches have many tiny needles on one surface to project into the skin. Insulin is only released at high glucose levels.

Question 60

What are the three components of the artificial pancreas?

Answer 60

Continuous glucose monitor, insulin pump and an algorithm for communication between the two

Question 61

Why is it hard to write the algorithm to connect the glucose monitor to the insulin pump in an artificial pancreas?

Answer 61

Very complicated- all sorts of factors that will affect your insulin secretion, such as exercise etc that are difficult to account for