Rahmas Notes FC's Flashcards
Diabetes overview
Prediabetes
Prediabetes, also known asimpaired glucose regulation, describes a state ofinsulin resistancewhereby blood glucose levels are elevated, but not high enough for a diagnosis of diabetes mellitus.
- usually asymptomatic
- increased risk of developing T2DM
What can you divide pre-diabetes into?
impaired fasting glucose (IFG) andimpaired glucose tolerance (IGT)
Impaired fasting glucose vs Impaired glucose tolerance on:
- pathogenesis
- diagnosis
- risks
OGTT - oral glucose tolerance test
WHO diagnostic criteria for the diagnosis of IFG, IGT and diabetes mellitus levels against a healthy individual
Who does NICE recommends that the following patients should undergo a risk assessment with a computerised risk assessment tool, such as the Cambridge diabetes risk score?
Those deemedhigh-riskshould have either afasting glucoseorHbA1c measured:
What is the NICE guideline for management with normal blood results?
NICE guidelines state that those withnormal blood resultsshould be given advice regarding risk factor modification.
What is the management for raised HbA1c?
Those with a raised HbA1c(42-47 mmol/mol)orfasting glucose (≥5.5 mmol/L)*should be referred to an intensive lifestyle change programme.
Must remember about diabetes?
too much blood glucose/not enough insulin
What type of gland is the pancreas?
The pancreas is a heterocrine gland. It’s made up of two types of tissue, endocrine and exocrine.
What is a heterocrine gland?
A heterocrine gland is a gland that serves as both exocrine and endocrine gland.
- Exocrine - where the secretions are carried by ducts to specific organs.
- Endocrine - where secretions are released directly into the bloodstream.
What is the endocrine tissue made up of?
The endocrine tissue is made up of alpha cells and beta cells.
The alpha cells are responsible for secreting a hormone called glucagon.
- Key to remembering → a in glucAgon and Alpha
The beta cells are responsible for secreting insulin.
When is insulin and glucagon released?
- Insulins is responsible for bringing blood glucose levels back down. So its stimulus is hyperglycaemia (what insulin responds to).
- Glucagon is released when you have low blood glucose levels. Or in other words when glucose is gone. So its stimulus is hypoglycaemia.
What is normal blood glucose range?
- Normally blood glucose is between 3.5-8.0mmol/L under all conditions.
- If you are below 4mmmol/L this is referred to as hypoglycaemia
- If you are above 7mmol/L before a meal and above 8.5mmol/L two hours after a meal, this is referred to as hyperglycaemia.
What is the exocrine portion of the pancreas made up of?
The exocrine portion of the pancreas gland is made up of the Acini. This releases the pancreatic juice rich in digestive enzymes and bicarbonate. This is discussed in the GI module later.
What else is present in the endocrine portion of the pancreas?
In the endocrine portion there are other cells like delta and f cells alongside the alpha and beta cells. They are alligned in a cluster.
Around 99% of the pancreas is acini and 1% is the endocrine portion. These structures (cluster of cells) are called the Islets of Langherhan.
How is insulin released from the beta cells in the islets of Langherhan?
- Inside the DNA of the beta cell there is a specific gene that is transcripted and turned into mRNA.
- The mRNA leaves the nucleus and goes to the cytoplasm. It meets with a ribosome.
- It is read by the ribosome and a protein is synthesised.
- The protein goes to the rough endoplamsic reticulum and undergoes modifications.
- It is then packaged in the Golgi apparatus.
- The Golgi apparatus releases a vesicles that contain insulin, C-peptide.
On the pancreatic beta cell there a specific transporters called GLUT-2 (Glucose transporter - type 2). They are insulin independent → this means GLUT-2 transporters don’t need insulin.
The glucose moves in to the beta cell via the GLUT-2 transporter and undergoes glycolysis (glucose→glucose 6 phosphate→ Pyruvate→ Acetyl CoA → Krebs cycle)
The NADH and FADH2’s that are produced in in the Krebs cycle travel to the mitochondria in the beta cell. The mitochondria then produces ATP.
On the pancreatic beta cell there is also a potassium channel that moves potassium into and out of the cell. When ATP binds to the channel it closes it → this leads to potassium being unable to leave the beta cell.
Beta cell is responding to hyperglycaemia - elevated blood glucose levels
What is the action of insulin?
The action of insulin is to reduce blood glucose levels.
How does insulin reduce blood glucose?
- Suppressing hepatic glucose output
- Increase glucose uptake into insulin sensitive tissues i.e. muscle and fat.
- Suppressing Lipolysis and muscle breakdown
How does insulin reduce blood glucose by Suppressing hepatic glucose output?
- Via a reduction in glycogenolysis in the liver, (the breakdown of glycogen into glucose).
- And a reduction in gluconeogenesis in the liver, (formation of glucose).
How does insulin reduce blood glucose by Increasing glucose uptake into insulin sensitive tissues i.e. muscle and fat?
- Tissues like muscle and fat have insulin responsive glucose transporters that allow them to absorb glucose in response to insulin released after meals.
- Glucose taken up by muscle is stored as glycogen or metabolised.
- Fat uses glucose as a substrate for triglyceride synthesis
How does insulin reduce blood glucose levels by Suppressing Lipolysis and muscle breakdown?
- Lipolysis is the breakdown of triglycerides via hydrolysis. It is a metabolic process which releases glycerol. Glycerol is used in hepatic gluconeogenesis (formation of glucose in the liver).
- NOTE: Muscle breakdown increases ketogenesis - so more ketones are made to act as an additional source of energy.
What is the action of glucagon?
The action of glucagon is to increase blood glucose levels.
Glucagon is a counter regulatory hormone to insulin. This means it opposes the actions of insulin.
How does glucagon increase blood glucose levels?
- Increases hepatic glucose output
- Via an increase in glycogenolysis in the liver, (the breakdown of glycogen into glucose).
- And an increase in gluconeogenesis in the liver, (formation of glucose).
- Reduces peripheral glucose uptake
- Stimulates peripheral release of glucogenic precursors such as glycerol and amino acids.
- Lipolysis
- Muscle glycogenolysis and breakdown.
Which hormones have a similar effect as glucagon?
Adrenaline, cortisol and GH have a similar effect to glucagon and reduce glucose utilisation in fat and muscle.
What is the difference between endogenous and exogenous insulin?
- Endogenous is when something is produced inside an organism or a cell. So endogenous insulin is that which the pancreas makes.
- Exogenous is the opposite, so the external production. So Exogenous insulin refers to the insulin people inject or infuse via an insulin pump.
Where is insulin produced?
Insulin is produced in the pancreas. Specifically it is produced by beta cells in the centre of the islets of Langerhans.
What is the precursor to insulin?
Proinsulin is the precursor of insulin.
What does insulin contain?
- Insulin contains alpha and beta insulin chains joined together by C PEPTIDE.
- This is in a 1:1 ratio of insulin:C PEPTIDE.
When insulin is required, C peptide is cleaved off and insulin is released.
- This is in a 1:1 ratio of insulin:C PEPTIDE.
What is the difference between endogenous insulin and synthetic insulin?
- Synthetic insulin does not have a C peptide.
- So the presence of C peptide in the blood indicates the production of endogenous insulin.
- How is glucose transported into cells?
- Cell membranes are not permeable to glucose.
- Glucose transporters (GLUT) protein channels allow glucose to enter cells.
Name the 4 channels of glucose transport into cells.
- GLUT-1
- GLUT-2?
- GLUT-3
- GLUT-4
GLUT-1
- GLUT-1 channels allow non-insulin stimulated glucose uptake into cells.
GLUT-2
- Found in beta cells in the pancreas.
- Senses high glucose levels.
- Low affinity transporter, this means that glucose only enters the cell when the blood glucose concentration is high.
- It stimulate insulin release in response
GLUT-3
GLUT-3 channels allow non-insulin stimulated glucose uptake into cells.
GLUT-4
- GLUT-4 are the main channel allowing glucose uptake into muscles and fat when insulin bind to the receptors on its surface.
- Insulin binding helps to incorporate more GLUT-4 channels into the cell to stimulate greater glucose uptake.
What is Diabetes Mellitus?
Chronic hyperglycemia due to insulin dysfunction.
Clinical definition of diabetes
- Symptoms and random plasma glucose greater than 11 mmol/l (>11 mmol/l)
- Fasting plasma glucose greater than 7 mmol/l (>7 mmol/l)
- No symptoms and an OGTT, oral glucose tolerance test (75g glucose) fasting greater than 7 or a 2 hour value greater than 11mmol/l
Classification of Diabetes
Primary diabetes is classified into Type 1 and Type 2
- Type 1 - Young patients that are insulin dependant
- Type 2 - Due to lifestyle factors i.e., diet high in carbs and glucose
Name secondary causes of diabetes?
- Chronic pancreatitis or haemochromatosis
- Trauma
- Acromegaly and Cushings disease
- Excess GH/cortisol increases insulin resistance
- Drugs – thiazide diuretics or corticosteroids
- Maturity onset diabetes of youth (MODY)
- AD form of T2 diabetes single gene defect
- Presents <25 years
Define Diabetes Mellitus
Syndrome of chronic hyperglycemia due to relative insulin deficiency, resistance or both.
What types of complications are associated with diabetes?
Hyperglycaemia results in serious microvascular (retinopathy, nephropathy, neuropathy) or macrovascular (strokes, renovascular disease, limb ischaemia and heart disease) problems
What are normal levels of blood glucose?
Blood glucose levels should be between 3.5-8.0mmol/L under all conditions.
What is the main organ involved in glucose homeostasis and what is its role?
The liver is the principal organ of glucose homeostasis:
- Stores & absorbs glucose as glycogen - in post-absorptive state
- Performs gluconeogenesis from fat, protein and glycogen
- If blood glucose is HIGH then the liver will make glycogen (convert
glucose to glycogen) in a process called glycogenesis - in the long term
the liver will make triglycerides (lipogenesis) - If blood glucose is LOW then the liver will split glycogen (convert
glycogen to glucose) in process called glycogenolysis - in the longer
term the liver will make glucose (gluconeogenesis) from amino acids/
lactate
How much glucose is produced everyday?
About 200g of glucose is produced and utilised each day
- More than 90% is derived from liver glycogen and hepatic gluconeogenesis
and the remainder from renal gluconeogenesis
Where is glucose utilised?
- The brain is the MAJOR CONSUMER of glucose and its function depends on
an uninterrupted supply of this substrate - Tissues such as muscle and fat have insulin-responsive glucose
transporters and absorb glucose in response to postprandial (post-meal)
peaks in glucose and insulin
Why is the brain so reliant on just glucose, and no other energy forms?
- This is because the brain CANNOT use free fatty acids to be converted to
ketones which can then be converted to Acetyl-CoA and used in the Kreb’s
cycle for energy production, since free fatty acids CANNOT CROSS the
BLOOD BRAIN BARRIER - Glucose uptake by the brain is OBLIGATORY and is not dependent on insulin, and the glucose used is oxidised to CO2 and H2O
How is glucose utilised in muscles?
Glucose taken up by muscle is stored as glycogen or metabolised to lactate
or CO2 and H2O
How is glucose utilised in adipose tissue?
- Fat uses glucose as a substrate for triglyceride synthesis
- Lipolysis of triglyceride releases fatty acids + glycerol - the glycerol is then
used as a substrate for hepatic gluconeogeneis
What is meant by biphasic insulin release?
B-cells can sense the rising glucose levels and aim to metabolise it
by releasing insulin - glucose levels are the major controlling factor
in insulin release!
- First phase response is the RAPID RELEASE of stored insulin
- If glucose levels remain high then the second phase is initiated. This
takes longer than the first phase due to the fact that more insulin
must be synthesised.
What are some roles of glucagon?
- Increases hepatic glucose output - increases glycogenolysis & gluconeogenesis
- Reduces peripheral glucose uptake
- Stimulates peripheral release of gluconeogenic precursors e.g. glycerol & amino acids
- Stimulates:
- Muscle glycogenolysis & breakdown (increased ketogenesis)
- Lipolysis
What are some of the roles of insulin?
- Suppresses hepatic glucose output - decreases glycogenolysis &
gluconeogenesis - Increases glucose uptake into insulin sensitive tissues:
- Muscle - glycogen & protein synthesis
- Fat - fatty acid synthesis
- Suppresses:
- Lipolysis
- Breakdown of muscles (decreased ketogenesis)
What are some other counter-regulatory hormones that are also involved in blood glucose levels?
- Adrenaline, Cortisol and Growth Hormone
- These increase glucose production in the liver and reduce its utilisation in fat and muscle
How is insulin formed?
- Insulin is coded for on CHROMOSOME 11 produced in the BETA CELLS of
the ISLETS of LANGERHANS of the PANCREAS:- Proinsulin is the precursor of insulin
- It contains the Alpha & Beta chains of insulin which are joined together
by a C PEPTIDE - When insulin is being produced, the proinsulin is cleaved from its C
peptide and is then used to make insulin which is then packaged into
insulin secretory granules - Thus when there is insulin release there will also be a high level of C
peptide in the blood from the cleavage of the proinsulin from it - Synthetic insulin DOES NOT have C peptide - thus the presence of C peptide in the blood determines whether release is natural (then C peptide will be present) or synthetic (then C peptide will not be present)
- After secretion, insulin enters the portal circulation and is carried to the liver, its prime target organ
What are main roles of insulin in a fed and fasting state?
- In the fasting state - its main action is to regulate glucose release by the liver
- In the post-prandial state - its main action is to promote glucose uptake by fat and muscle
How does glucose get into the cells?
A family of specialised glucose-transporter (GLUT) proteins carry glucose
through the membrane and into cells.
How many types of GLUT are there and what is their function?
- GLUT-1:
Enables basal NON-INSULIN-STIMULATED glucose uptake into many cells - GLUT-2:
Found in BETA-CELLS of the pancreas
Transports glucose into the beta-cell - enables these cells to SENSE GLUCOSE LEVELS
It is a low affinity transporter, that is, it only allows glucose in when there is a high concentration of glucose i.e. when glucose levels are high and thus WANT insulin release
In this way, via GLUT2, beta-cells are able to detect high glucose levels and thus release INSULIN in response
Also found in the renal tubules and hepatocytes - GLUT-3:
Enables NON-INSULIN-MEDIATED glucose uptake into BRAIN, NEURONS & PLACENTA - GLUT-4:
Mediates much of the PERIPHERAL ACTION of INSULIN
It is the channel through which glucose is taken up into MUSCLE and ADIPOSE TISSUE cells following stimulation of the insulin receptor by INSULIN binding to it
What is the role of the insulin receptor in glucose transport?
- This is a glycoprotein, coded for on the short arm of chromosome 19, which straddles the cell membranes of many cells
- When insulin binds to the receptor it results in the activation of tyrosine kinase and initiation of a cascade response - one consequence of which is the migration of the GLUT-4 transporter to the cell surface and increased transport of glucose into the cell
What conditions might diabetes be secondary to?
- Pancreatic pathology e.g. total pancreatectomy, chronic pancreatitis, haemochromatosis
- Endocrine disease e.g. Acromegaly and Cushing’s disease
- Drug induced commonly by thiazide diuretics and corticosteroids
- Maturity onset diabetes of youth (MODY):
- Autosomal dominant form of type 2 diabetes - single gene defect altering beta cell function
- Tends to present <25 yrs with a positive family history
What are the types of primary diabetes?
T1DM
The type 1 diabetic is young, has insulin deficiency with no resistance and immunogenic markers
Most prevalent in Northern European countries, particularly Finland and the incidence is increasing in most populations
T2DM
Common in all populations enjoying an affluent lifestyle and is also increasing in frequency - particularly in adolescents
