Insulin Secretion Flashcards
What is the normal glucose level?
4-7mmol/L
Where is insulin secreted?
Pancreas
Where is glucagon produced?
Alpha cells
Which cells secrete insulin?
Beta cells
What are the three main tissues that act on low blood sugar?
Liver, muscle and adipose tissue
True or False: insulin does not promote lipolysis in adipose tissue?
True
What is lipolysis?
Turns fats into fatty acids
What does activated PKB/Akt promotes?
GLUT4 translocation to the plasma membrane/ glucose uptake in adipocyte and skeletal muscle
Glycogen synthesis in skeletal muscle
Increased lipogenesis and inhibition of gluconeogenesis in liver
What are the actions of glucagon
Acts on the liver via glucagon receptors (G protein coupled receptors) to increase cAMP and PKA
The increase cAMP and PKA leads to
inhibition of glycosis and glycogenesis (i.e. decrease glycogen production)
Stimulation of gluconeogenesis and glycogenolysis (i.e. increase glucose production)
How is insulin stored?
In granules in the cytoplasms of beta-cells.
What happens in the “first phase” of insulin release?
initial rapid but transient burst of insulin
What happens in the “second phase” of insulin release?
if the blood glucose concentration remains high, then the rise in insulin secretion is sustained, due to the release of both stored and newly synthesised insulin
What happens in nutrient stimulated insulin release? (amino acids and Fatty acids) on a GLUT2
Amino acids stimulate:*
Fatty acids stimulate FA-acyl-CoA stimulating:*
Fatty acids GPR40 (Gsq) stimulating:*
*the ER increasing calcium causing release.
What happens when glucose stimulates insulin release?
Glucose = Glucose-6-phophate (Glucokinase)
Which activates pyruvate increasing ATP and NADP,H+ , causing potassium channels to close and calcium channels to remain open causing depolarisation, calcium leads to insulin release.
How does the parasympathetic nervous system intervene with insulin secretion?
Parasympathetic innervation, releases acetylcholine which activates DAG which activates Protein Kinase C, causing insulin release
How does the sympathetic nervous system intervene with insulin secretion?
The sympathetic nervous system, decreases the amount of cAMP in the GLUT2, which then decreases PKA, which would normally cause insulin secretion, this reduces insulin secretion.
How are beta cells specialised to allow glucose regulated insulin secretion to occur?
- Member of Hexokinase family
- Key component of glucose sensing machinery
- Sets threshold for glucose stimulated insulin secretion
- Low affinity for glucose
- Lack of inhibition by substrate
What are some other important features of beta-cells?
- GLUT2 has low affinity for glucose
- Islets are highly vascularised
- Number of beta cells tightly controlled
- Highly differentiated -many unique transcription factors
What are the consequences of diabetes?
- Diabetes reduces life expectancy
- Also a major contributor to Kidney Failure, cardiovascular disease, including heart attack and stroke
Definition of diabetes mellitus
Hyperglycaemia due to insufficient insulin secretion
What are the different forms of monogenic diabetes?
- Single gene defects cause diabetes
- Neonatal diabetes
- MODY (maturity onset diabetes of the young)
How is type 2 diabetes caused?
Hyperglycaemia due to insufficient insulin secretion
-Combination of increase insulin resistance and beta cell defects. Can have high resistance to insulin, so glucose levels remain high.
What is the treatment of type 2 diabetes?
- Diet/Exercise
- Drugs to improve insulin sensitivity
- Drugs to simulate insulin secretion
- Drugs to promote glucose excretion via the kidneys
- Insulin injections
How is type 1 diabetes caused?
- 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
Type 1 diabetes patients have more or less insulin secreting B cells
Less
What are the four symptoms of type 1 diabetes? (4T)
Toilet
Thirsty
Tired
Thinner
Characteristics of type 1 diabetes?
Young age of onset Sudden onset Thin Family history - 85% spontaneous Insulin deficient Ketoacidosis
Treatments of type 1 diabetes?
- Insulin replacement therapy: injections of insulin pump
- Regular blood glucose monitoring
- Carbohydrate counting/ exercise
- Transplantation - islets or Pancreas
How does insulin cause the lowering of glucose levels?
- Liver, muscle and fat cells to uptake glucose, if the body has enough energy insulin signals the liver to uptake glucose stored as glycogen (glycogenesis).
- Inhibition of lipolysis, which breaks down lipids producing energy.
- (glycolysis) breaking down of glucose for energy.
Where are GLUT4 receptors mostly found?
On the muscle and fat cells.
When insulin binds there is an increase in glucose receptors to aid in the uptake of glucose.
How does glucagon cause the blood sugar levels to increase?
Glucagon works on the hepatocytes in the liver; converting glycogen to glucose released in the blood.
Promoting gluconeogenesis; the manufacture of new glucose from lactic acid and other metabolites.
what are the four subunits of the insulin receptor and what bonds them together?
Two extracellular a subunits and two intracellular b subunits linked together by disulphide bonds.
When insulin bind to the receptor, what happens to the receptor?
The insulin binds to the alpha receptor, which causes a conformational change in the beta receptor, cause there to be auto-phosphorylation in the beta subunits of the tyrosine residues.
What happens when the tyrosine residues are phosphorylated in the insulin signalling pathway?
- The residues are recognised by the members of the insulin receptor substrate family (IRS1).
- Phosphorylating p85 and p110, converting PIP2 into PIP3.
- Activating glycogen synthesis, lipogenesis and decreasing gluconeogenesis.
What are the enzymes used when converting glucose in to glycogen?
Glucose to Glycogen - Glycogen synthase
Glycogen to Glucose - Glucose synthase
Glucagon inhibits Glycogen synthase and promotes glucose synthase
What does hexokinase do?
Phosphorylates glucose to form glucose-6-phosphate
What are monogenic forms of diabetes?
Single gene defects causing diabetes (due to beta-cell defects)
What are GAD and anti-GAD antibodies?
Antibodies to glutamic acid decarboxylase (anti-GAD)
They are markers of insulin-dependent diabetes mellitus.
Why is important C reactive peptide important?
Per one molecule of insulin released C-peptide is released, it is a useful marker of insulin production.
TRUE or FALSE
The insulin receptor is a G-protein coupled receptor.
False it is a tyrosine kinase
What is the name of the transporter that allows glucose entry to muscle?
Glut 4
What impact does glucagon have on glycolysis?
Inhibits
Which componant 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 K+ATP channel in the beta-cell
Closes
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?
cAMP
How do fatty acids stimulate insulin secretion?
Increasing DAG and ATP and binding to GRP40
What does GRP40 do once bound by fatty acids?
Stimulate G protein coupled receptor Gsq which increases DAG and cAMP which increase PKC and PKA.
A 50 year old white Caucasian man is diagnosed with diabetes. He is lean with no evidence of insulin resistance.
What type of diabetes is he likely to have?
Type 1
A baby is diagnosed with diabetes in the first week of life.
What type of diabetes is the baby likely to have?
Neonatal diabetes
When might you suspect a diagnosis of type 1 diabetes in children might not be correct?
- A diagnosis before 6m
- Family history of diabetes with a parent affected
- Evidence of endogenous insulin production
- When pancreatic islets autoantibodies are absent, especially if measured at diagnosis
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
- Ethnic background from a low prevalence Type 2 diabetes race (e.g. European Caucasian)
- No evidence of insulin resistance
Need to add the end of the lecture
it is on treatments of diabetes
What are the actions of insulin in maintaining blood glucose levels?
- Increase glucose transport into cells such as muscle and adipose by causing insertion of GLUT4 transporters into the cell membranes.
- Promotes the formation of glycogen from glucose in the liver and muscle also inhibiting glycogenolysis (glycogen breakdown)
- Inhibits Gluconeogenesis (synthesis of glucose) by increasing production of fructose, using up the substrate that would otherwise be used for glucose.
Stimulates fat deposition and inhibits lipolysis.
What are the actions of glucagon in maintaining blood glucose levels?
- Stimulates glycogenolysis and inhibits glycogen formation from glucose.
- Increases Gluconeogenesis by decreasing production of fructose, substrate can then be used to form glucose.
- Increases lipolysis and inhibits fatty acid synthesis, which also put forward substrates towards gluconeogenesis.
What causes the secretion of insulin from beta-cells?
- Transport of glucose into the beta cell via GLUT2, from blood into the cell through facilitated diffusion.
- Metabolism of glucose inside the beta-cell. Glucose is phosphorylated to glucose-6-phosphate by glucokinase, which is then oxidised.
- ATP closes ATP-sensitive channels K+. Depolarises beta cell membrane.
- Depolarisation opens V-sensitive Ca2+ channels Ca2+ flows in the beta-cell.
- Increased intracellular calcium causes insulin secretion.
Is the insulin receptor G-protein coupled?
False
What is the name of the transporter that allows glucose entry into muscle?
GLUT4
What impact does glucagon have on glycolysis?
Inhibits
Which component in the beta-cell sets the threshold for glucose stimulated insulin secretion?
Glucokinase
Does Glucokinase have a low or high affinity for glucose?
Yes
What action does increased ATP levels have on the K+ATP channel in beta-cells?
Close
Is Glucose the only molecule that can moderate insulin secretion?
Fasle
Which second messenger does GLP-1 increase in beta-cells to promote insulin secretion?
cAMP
How do fatty acids stimulate insulin secretion?
By increasing DAG and ATP and binding to GRP40
What does GLP1 do? and why is it important?
activates adenyl cyclase and then through cAMP as a second messenger increases PKA, amplifying the effect of calcium, increasing insulin secretion
IMPORTANT: It will only act if blood glucose levels are elevated, useful in therapies because you wont get the hyperglycaemic events
What does Sulfonyl urea do
It closes the potassium channel which stimulates insulin secreation usually used when the patients have a variant in the gene which codes for the potassium channel.
A 50 year old white Caucasian man is diagnosed with diabetes. He is lean with no evidence of insulin resistance. What type of diabetes are they likely to have?
Type 1 - Not type 2 because there is no insulin resistance and he is lean.
A baby is diagnosed with diabetes in the first week of life. What type of diabetes are they likely to have?
Neonatal diabetes - not type 1 because there is no time for the beta cells to all be attacked likely to be caused by a mutation. Rare type 1 at an early age.
Characteristics of type 1 diabetes
Young age of onset Sudden onset Thin at diagnosis Immune - autoantibodies, T-cells Genetic - MHC class II & class I, CTLA4 Family history -spontaneous in 85% Insulin deficient - need insulin to live Ketoacidosis
When might you suspect a diagnosis for type 1 diabetes in children might not be correct?
- A diagnosis before 6 months
- Family history with parent affected
- Evidence of endogenous insulin production outside the ‘honeymoon’ phase (after 3 years of diabetes)
- When pancreatic islet autoantibodies are absent, especially if measured at diagnosis
Presentation of type 2 diabetes
Long duration
Older at diagnosis - 50s and 60s
Overweight/ Obese
Strong family history
Thirst, hunger, polyuria (symptoms of high glucose)
Tiredness sleepiness, change of behaviour
Type 2 diabetes defining complications
Microvascular disease - Retinopathy, neuropathy or foot ulcers.
Macrovascular disease - Myocardial infarction, stroke, peripheral gangrene.
