Glucose, Glucagon and Diabetes Flashcards
what is glucose stored as?
glycogen
where are the 2 main sites for glucose storage?
muscle and liver
what is glucose used for in cells?
for metabolism/respiration - it is metabolised to give ATP for energy and H2O, CO2
What is the normal circulating blood glucose concentration?
~5mM (no matter how hungry you feel) as the glycogen will be broken down during times of low glucose to replace those used.
what hormone helps with the storage/uptake of glucose from the blood?
insulin
what hormone helps to release glucose from the stored tissue back into the blood?
glucagon
where are insulin and glucagon released from?
The Islets of Langerhans in the pancreas
- What are the 3 main cell types in the islet of langerhan?
- What hormones do they release?
- α cells – produce glucagon
- β cells – produce insulin
- γ cells – produce somatostatin
How is insulin sythesised?
- Made as a polypeptide in the beta cells
- The polypeptide chan is processed in the golgi to give pro-insulin which is biologically inactive
- Pro-insulin is activated by prohormone convertase 1 and 2 which removes 33 amino acids. These 33 amino acids make the C chain.
- Now we are left with the A and B chains with 30 and 21 amino acids respectively.
- The A and B chains are joined by disulfide bridges forming the insulin
what is stored in the secretory granules of the beta cells?
the insulin along with some pro-insulin and c-peptide (the C-chain)
what happens in the 1st phase of insulin secretion?
elevated blood glucose levels causes stored insulin to be released from the secretory granules in the beta cells
what happens in the 2nd phase of insulin secretion?
Synthesis of new insulin and then it’s released in elevated glucose levels
what enzyme degrades insulin and where?
degraded by insulinase mainly in the liver but also in the muscle and kidneys
what is the half-life of insulin?
6minutes so its effects on tissues are rapidly reversible
how does glucose enter the beta-cells?
via the GLUT2 transporter system from the blood into the beta cell
what determines the ATP concentration in the beta cells?
the concentration of glucose in the blood as that determines the amount of glucose that enters the beta-cell there determines how much glucose is metabolised to ATP.
Explain how glucose, K+ channels, and Ca2+ channels play a role in insulin secretion?
- Glucose enters beta-cell via GLUT2 transporter
- High glucose levels cause ATP levels to rise in the beta cell
- The K+ channels are ATP sensitive so a high ATP conc closes the K+ channel so K+ conc increases as it can’t leave the cell.
- This causes depolarisation of the membrane of the cell.
- The Ca2+ channels are then opened due to the depolarisation and Ca2+ enters
- this results in the release of insulin from the beta cells
why is the liver the major site for glucose storage?
- Once insulin is made by the pancreas, it i first drained into the hepatic portal vein therefore the liver is the first organ exposed to insulin
- The glucose from the gut is also transported to the liver via the portal circulation
…..In this way, the insulin makes the liver store the glucose.
what is the insulin receptor like on the target cells?
-dimeric with an alpha-subunit and a beta-subunit.
what happens when insulin binds to the alpha-subunit?
- it promotes dimerization and activation of the receptor
2. Once the receptors dimerise, then the 2 subunits phosphorylate each other at multiple tyrosine residues
Explain the process of insulin receptor signalling?
- Insulin binding causes receptor dimerisation/activation
- The 2 subunits phosphorylate one-another to become active
- Active receptors phosphorylate IRS-1
- IRS-1 activates PI3K
- PI3K stimulates cellular response to the insulin
what type of glucose transporter is found in the liver cells?
GLUT4
Where are GLUT4 transporters found in unstimulated cells of the liver?
in the intracellular membrane vesicles and not in the plasma membrane
what is activated after PI3K in liver cells for insulin sensitivity?
- The PI3K activates PKB
- This evokes the translocation of the GLUT4 to the plasma membrane
- This therefore allows glucose uptake into the hepatocyte
How does glycogen synthesis occur?
- When GSK is active, the glycogen synthaseA is inactive, which prevents glycogen synthesis
- The GSK is inhibited by the PKB, which is activated by insulin. This therefore prevents glycogen synthaseA inhibition
- Therefore glycogen synthaseA is active and glycogen can be synthesised.
what happens when glycogen reserves in the liver are full and theres no more space to store glucose as glycogen?
the glucose is still able to enter the liver via the GLUT4 transporters, however, they are then metabolised into fatty acids which are released into the circulation and stored as fat eventually
what is the main source for cellular metabolism (respiration/ATP production) in the absence of insulin?
free-fatty acids
so why are people with type one diabetes likely to lose weight?
- in the absence of insulin, the body is forced to use free-fatty acids (from fat) for respiration/energy.
- however, in the presence of insulin, glucose is able to be taken up into cells to be used for energy.
- therefore the free-fatty acids aren’t being used so they can be stored as fat.
where does the CNS get its energy from?
- CNS cells (the brain) can take up glucose without the need for insulin to be present.
- this means it doesn’t metabolise fatty acids hence no lactic build-up in the brain
how are fatty acids released from adipoctyte cells/tissue?
- Glucose does not enter the cell due to a lack of insulin
- This causes the hormone-sensitive lipase to breakdown the lipid molecule into 3 free fatty-acid chains and 1 glycerol molecule
- The fatty acids are then released to fuel metabolic processes.
how does insulin prevent fatty acid release from adipocyte cells?
- insulin stimulates glucose entry into the cell via GLUT4 transporters
- Glucose is metabolised to glycerol once in the cell
- The glycerol binds to the 3 free fatty acids to form the triglyceride lipid. (the fatty acids come from the blood and enter the cell)
- Insulin also inhibits the lipase enzyme which usually breaks down the lipid
how does insulin promote new protein synthesis?
- The rise in amino acid levels in the blood promotes insulin release from β cells
- Insulin receptors activates a second PI3K- dependent kinase
- This PI3K- dependent kinase activates Target Of Rapamycin Complex 1 (TORC1), which is a central regulator of protein synthesis in essentially all cells
- When amino acids are abundant, insulin stimulates their incorporation into protein
where is glucagon secreted?
from the pancreatic alpha cells
how many amino acids is glucagon made from?
29 amino acids
how does glucagon work to increase blood glucose?
it promotes the release of glucose from the liver
why is glucagon released during exercise?
To promote the uptake of skeletal muscles by translocating GLUT4 transporters to the surface of the muscle cells
what type of receptor is the glucagon receptor?
G protein-coupled receptor, coupled to Gs and activates the cAMP / PKA-dependent signalling pathway.
What hormone can activate the glucagon pathway to promoting glucose release from liver, and what receptor is activated this way?
Adrenaline via β adrenoceptors.
How does glucagon cause the release of fatty acids from adipose tissue?
Glucagon activates the hormone sensitive lipase enzyme to breakdown triglycerides to release the fatty acids.
what can raise both insulin and glucagon levels?
amino acids
What happens when insulin and glucagon are released due to high amino acid levels?
- insulin secretion promotes increase in amino acid uptake by cells, but also promotes a reduction of plasma glucose
- glucagon secretion will promote an increase in plasma glucose, but glucagon has no effect on amino acid uptake
Once glycogen stores are depleted what happens to meet the demand for glucose?
glucagon stimulates the formation of glucose from lipids and amino acids via complex metabolic processes in liver and kidney called
“gluconeogenesis”
what is normal fasting blood glucose?
~5mM
7mM or more = diabetes
how can urine help to see if a patient is diabetic?
if sugar is present in the urine, then that indicates diabetes
what tissues are damaged by chronic high blood glucose levels?
blood vessels, eyes, kidneys, nerves - almost all tissues
what happens to the body if the patient has untreated type 1 diabetes?
Untreated type 1 diabetes leads to body wasting
how does insulin cause type 1 diabetes?
a failure of insulin secretion
how does insulin cause type 2 diabetes?
insulin resistance in tissues
which of the 2 types of diabetes is gradual onset and which is sudden onset?
gradual onset = type 2
sudden onset = type 1
which of the 2 types of diabetes is associated with obesity?
type 2
what is gestational diabetes?
High blood glucose that develops during pregnancy and tends to disappear after birth
during what trimester does gestational diabetes occur?
2nd or 3rd
how does gestational diabetes occur?
when Beta-cells cannot produce enough insulin to meet the extra- needs in pregnancy
what are the possible consequences of gestational diabetes?
- Baby growing larger than usual
- Premature birth (before 37th weeks)
- Pre-eclampsia (high blood pressure which can lead to complications in pregnancy)
- Jaundice after birth
- An increased risk to develop type 2 diabetes in future
what is the pathogenesis of type 1 diabetes?
- Beta cells are recognised by T-cells because the insulin peptides form a complex with MHC molecules on the surface of the beta cells
- This results in an autoimmune mechanism where CD8 cytotoxic T cells mediate the destruction of beta-cells
- This results in the failure of insulin secretion
what are the symptoms of diabetes due to a lack of insulin?
- Tissues cannot accumulate and store glucose
- Tissues cannot use glucose as metabolic fuel so will use proteins and fatty acids resulting in rapid weight loss
- Body cannot store excess energy as fat therefore weight loss
- Reduced synthesis of protein
- Formation of ketones resulting in metabolic acidosis causing an acidotic coma
- Hyperglycaemia
how does hyperglycaemia affect the kidneys to cause dehydration?
- High [Glucose] enters glomerular filtrate and overwhelms glucose absorbing capacity of proximal convoluted tubule
- Increased fluid osmolarity in tubules
- More water is secreted from cells into the proximal convoluted tubule
- causes increased urine flow – diuresis - and reduced water reabsorption
- This results in Dehydratation, excessive urine production and thirst
what is used to treat type 1 diabetes?
Insulin
what circulation does natural and exogenous insulin enter?
- Natural insulin enters hepatic circulation
- exogenous insulin enters main/general circulation
how does insulin injection cause lipohypertrophy?
insulin promotes the deposition of fat therefore cells close to site of insulin injection are exposed to high [insulin]. If the same site is used everytime time, it will promote the deposition of fat around injection site (lipohypertrophy)
what is the downside of lipohypertrophy besides it being unpleasant to the eyes.
leads to an unpredictable rate of insulin absorption. This could lead to poor glycaemic control and patients could experience hyper/hypoglycaemic events.
Therefore it is important to change site of injection frequently
what are the 3 forms of insulin used for therapy?
- Animal insulin (porcine/bovine)
- Human insulin
- Human insulin analogue
what are the 3 types of human insulin?
- soluble insulin - rapid and short-lived
- Isophane insulin - intermediate acting, forms precipitates
- Insulin zinc suspension - Long acting, forms precipitates
what are the 2 types of insulin analogues?
- Insulin Lispro
2. Insulin glargine
How is insulin lispro obtained and how long does it last?
- obtained by switching a lysine and a proline residue
- very rapid and very short lived so taken just before meals
How is insulin glargine obtained and how long does it last?
- obtained by mutating Asn21 in Gly and by adding 2Arg at the end of the B chain
- Long-acting so normally taking before a meal in combination with a short-acting form
what drug targets the autoimmune reaction in diabetes 1?
Teplizumab
what is the pathogenesis of type 2 diabetes?
- Genetic and environmental
predisposition e.g. Life style, Bad dietary habits, Obesity - Insulin resistance therefore reduced glucose uptake
- Hyperinsulinemia
- β cells failure and hypoinsulinemia (β cells cannot keep up with the peripheral demand of insulin so Insulin secretion decreases)
- Diabetes occurs as total failure of insulin secretion occurs
What 4 factors of obesity cause insulin resistance?
- Free-fatty acids
- Adipokines
- Inflammation
- PPARγ
what is 1st line therapy for type 2 diabetes?
diet and exercise - to reduce weight and reverse the development of normal sensitivity of insulin
what can be possibly used to treat type 2 diabetes during the disease?
- Thiazolidinediones (TZD) e.g. pioglitazone
- Metformin
- Sulphonylureas (e.g. gliclazide)
- α glucosidase inhibitors (Acarbose)
- Insulin
- α2 adrenoreceptor antagonists
- Selective β3 agonists
How does increased glucose and free fatty acids cause microvascular complications?
They cause microvascular vascular complications which can cause nephropathy and retinopathy, therefore resulting in macrovascular complications
how is AGEs formed?
- sugar + protein = schiff base
- Schiff base —> amadori products
- Amadori products —-> AGEs
What are the biological effects of AGEs?
- CVD
- Diabetes
- Kidney disease
- Sarcopenia
- Rheumatoid arthritis
- Alzheimers disease
how does AGEs cause blood vessel damage?
- AGE’s crosslinks with collagen
- The basal membrane of the endothelium thickens
- The thickened endothelium traps LDL and IgGs
- Oxidation, complement activation and inflammation
- Blood vessel damage
what are microvascular diseases?
Formed from damage to small blood vessels:
- retinopathy
- nephropathy
- neuropathy
What are macrovascular diseases?
Damage to medium to large blood vessels:
- Coronary artery disease
- Cerebrovascular disease
- peripheral vascular disease
