Trigger 1: Insulin Secretion Flashcards
What is your normal blood glucose level (in mol/L)?
4-7
What organ is insulin secreted from?
Pancreas
Which cell type is glucagon produced from?
Alpha cells
Which cell type is insulin produced from?
Beta cells
What do the delta cells release?
Somatostatin
Does insulin secretion increase or decrease blood glucose?
Decrease
Does glucagon secretion increase or decrease blood glucose?
Increase
Other than being an endocrine organ, what other role does the pancreas play?
Produces digestive enzymes for use in the duodenum
What percentage of the pancreas does the islets of Langerhans make up?
1%
What two things are produced at the islets of Langerhans?
Insulin and glucagon (islets of Langerhans are made up of alpha and beta cells, amongst others.)
Which are the three main tissues that insulin acts on to lower blood glucose levels?
Liver, muscle and adipose
Insulin promotes lipolysis in adipose tissue - true or false?
False
What receptors does glucagon act on in the liver and what downstream signalling effect does this produce?
Via glucagon receptors that are GPCRs, increases cAMP and PKA.
What does the increase in cAMP and PKA due to glucagon signalling on the liver lead to?
Inhibition of glycolysis and glycogenesis (i.e. decrease in glycogen production)
Stimulation of gluconeogenesis and glycogenolysis (i.e. increase in glucose production)
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?
Decrease
Blood sugar increases (hormone helps to reduce hypoglycaemia)
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?
Increase
Blood sugar increases (hormone helps to reduce hypoglycaemia)
Other than hormones, what other 3 factors can change your blood sugar levels?
Exercise
Illness
Stress
Where within the beta cells is insulin stored?
In granules in the cytoplasm
Describe the first phase of insulin secretion in response to high blood sugar.
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
Describe the second phase of insulin secretion in response to high blood sugar.
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.
What are the 6 steps that lead to insulin secretion in pancreatic beta cells?
- Glucose enters the cell via GLUT-2 receptors
- Glucose is inverted to Glucose-Phosphate via glucokinase
- Glucose-6-phosphate is converted into pyruvate which can enter the krebs cycle
- Krebs cycle produces ATP which binds to KATP channels causing them to open and K+ efflux from the cell.
- Cell membrane depolarises causing Ca2+ channels to open and influx of Ca2+
- Increased Ca2+ inside the cell mediates insulin secretion from granules at the cell membrane.
How is insulin secretion stimulated neuronally?
Stress increases Parasympathetic innervation
Acetylcholine is produced which acts on DAG, producing PKC
PKC stimulates insulin secretion from granules at the cell membrane.
How does sympathetic innervation decrease insulin secretion?
It blocks cAMP
What is the role of glucokinase?
Sets the threshold for glucose stimulated insulin secretion- glucokinase has a low affinity for glucose.
For what phosphorylation process is gucokinase required?
Phosphorylation of glucose to form glucose-6-phosphate
Finish the following 4 statements in relation to the important feature of beta cells.
- Glut2 has a ___ affinity for glucose
- _____ are highly vascularised
- ______ of beta cells are tightly controlled
- Highly _________ cells, with may unique ________ ______
- Glut2 has a low affinity for glucose
- Islets are highly vascularised
- Number of beta cells are tightly controlled
- Highly differentiated cells, with may unique transcription factors
What is the definition of diabetes mellitus?
Hyperglycaemia due to insufficient insulin secretion.
Clinical defy nation: Fasting blood glucose over 7mmol/L
How does the monogenic form of diabetes occur?
Single gene defects cause diabetes due to beta cell defects
How does neonatal diabetes occur? (genetic basis)
Most common mutations are in KCNJ11 and ABCC8 (these code for proteins that for KATP channel subunits
Is MODY monogenic or polygenic?
Monogenic
What does MODY stand for?
Maturity onset diabetes of the young
Does MODY present more like type 1 or type 2 diabetes?
Type 2
True or false, people with type 2 diabetes usually have high levels of insulin secretion at diagnosis.
True
Define type 2 diabetes
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
How does type 2 diabetes present?
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
Name 5 treatments for type2 diabetes
- Diet/ exercise
- Drugs to improve insulin sensitivity (e.g. metformin, pioglitazone)
- Drugs to stimulate insulin secretion (egg GLP-1 agonists, sulfonylureas)
- Drugs to promote glucose excretion via the kidneys (gliflozins)
- Insulin injections
Define type 1 diabetes
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
What ar the symptoms of type 1 diabetes (4 Ts)?
Toilet
Thirsty
Tired
Thinner
What are the characteristics of type 1 diabetes?
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
Name 4 treatments for type 1 diabetes
- Insulin replacement therapy - injections or insulin pump
- Regular blood glucose monitoring
- Carbohydrate counting/ exercise
- Transplantation - islet or pancreas
True or false, the insulin receptor is a GPCR?
False- its a tyrosine kinase
What is the name of the transporter that allows glucose entry into muscle?
Glut4
Which component in the beta cell sets the threshold for glucose stimulated insulin secretion?
Glucokinase
True or false, glucokinase has a low affinity for glucose?
True
What action does increased ATP levels have on the KATP channel in beta cells?
Closes them
True or false, glucose is the only molecule that can moderate insulin secretion?
False
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
e. cAMP
How do fatty acids stimulate insulin secretion?
a. Increasing DAG
b. Increasing ATP
c. Binding GRP40
d. All of the above
d. All of the above
Which one of these transcription factors is NOT present in adult beta cells?
a. PDX-1
b. HNF1b
c. NeuroD1
d. Nkx6.1
b. HNF1b
When might you suspect a diagnosis of Type 1 diabetes in children might not be correct?
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)
When might you suspect a diagnosis of Type 2 diabetes in adults might not be correct?
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)
What are the potential challenges of using ES stem cells for treating diabetes?
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
What are the medical applications of iPS cell based generation of insulin producing cells?
Disease/ mutation specific beta cells for research
Personalised treatment
Replacement therapies
Correction of genetic defects
Circumvention of requirement of immunosuppressants
What are the challenges of iPS cell based generation of insulin producing cells?
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
What are the advantages of islet transplants?
Improve glucose control
Reduce requirement of insulin injections
Reduced hypoglycaemic events
Improved hypoglycaemic awareness
What are the disadvantages of islet transplants?
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
How might current islet transplant protocols be changed to overcome these problems?
Whole pancreas transplantation
Animal sources of islets
Alternative sites of injection
Improved culture of islets before injection
How are insulin analogues modified to alter their properties and why is this useful?
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)
What is ‘smart’ insulin?
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.
What are the three components of the artificial pancreas?
Continuous glucose monitor, insulin pump and an algorithm for communication between the two
Why is it hard to write the algorithm to connect the glucose monitor to the insulin pump in an artificial pancreas?
Very complicated- all sorts of factors that will affect your insulin secretion, such as exercise etc that are difficult to account for
