Flashcards in Metabolism S8 - Diabetes and Metabolic Syndrome Deck (50):
What is Diabetes Mellitus?
A group of metabolic disorders characterised by chronic hyperglycaemia due to insulin deficiency, insulin resistance or both.
How do genetic factors play a role in development of T1 Diabetes?
Likely that genetic predisposition interacting with environmental trigger leads to immune activation
Associated with genetic markers HLA DR3 and HLA DR4
When does T1 Diabetes typically present?
In the teenage years (however can be later)
Strong seasonal link
What does the strong seasonal link to Type 1 Diabetes suggest?
Onset influenced by environmental factors such as viral infection
How does T1 diabetes progress after being triggered?
The trigger leads to an autoimmune response.
Killer lymphocytes, macrophages and antibodies are produced
These attack and progressively destroy B-cells in the pancreas
How does someone initially present with T1 diabetes?
Explain the basis of these symptoms
Polyuria - not all glucose re-absorbed from nephron, extra osmotic load, not enough water re-absorped
Polydipsia - Excess thirst due to polyuria
Weight loss - Fat and protein are metabolised as insulin absent
How is T1 diabetes diagnosed?
Measurement of plasma glucose levels
Why is blood glucose elevated in T1 diabetes?
Because of lack of insulin leading to:
Reduced uptake of glucose into adipose tissue and skeletal muscle
Reduced storage of glucose as glycogen in the liver
Increases gluconeogenesis in the liver
What are the acute effects of very high blood glucose?
Diabetic ketoacidosis (life threatening)
In what populations is Type 2 Diabetes common and what is the prevalence in the UK?
Populations with affluent lifestyles
About 2% in UK
What are the key factors of T2 Diabetes?
At diagnoses patient will typically retains ~50% of B-cells, this gradually falls to none
As this occurs patients develop disorders of insulin secretion or insulin resistance so blood glucose is raised
Compare and contrast T1 and T2 Diabetes
Commonest type in the young
Progressive loss of B-cells (all or most)
Rapidly fatal if not treated
Must be treated with insulin
Affects a large number of older people
Characterised by slow progressive loss of B-cells and disorders of insulin secretion or insulin resistance
May be present for a long time without diagnoses
May not initially need insulin therapy, but all do eventually
What is the typical pattern of presentation for someone with T1 Diabetes?
People can be found with relevant genetic markers and auto-antibodies but not have any glucose or insulin abnormalities.
May then develop impaired glucose tolerance
Then Diabetes manifests, sometimes diet controlled
Then Insulin dependance
What is the typical pattern of presentation for someone with Type 2 Diabetes?
People can be found with insulin resistance, then as insulin production begins to fail they develop impaired glucose tolerance
Finally they will develop diabetes that can be initially diet controlled
Then controlled by tablets
Then by insulin
What blood tests are required to diagnose Diabetes?
Random venous plasma glucose >11.1mmol/L
Fasting venous plasma glucose of >7.0mmol/L
Plasma glucose concentration > 11.1mmol/L 2 hours after 75g anhydrous glucose in an oral glucose tolerance test
Why do you need to be careful diagnosing diabetes from a single plasma glucose test?
What can we do to confirm?
Diagnoses based on a single blood test is never made without accompanying polyuria, polydipsia and weight loss
Diagnoses has significant medical and legal implications for patient, so we must be sure.
Abnormal test with no symptoms requires confirmatory venous plasma glucose test that gives a result in the diabetic range to confirm.
Explain the sequence of events leading to diabetic ketoacidosis in an uncontrolled diabetic
HIgh rates of B-oxidation of fats occurs
Coupled with low insulin/anti-insulin ratio leads to production of huge amounts of ketone bodies.
the H+ associated with ketones produce metabolic acidosis - ketoacidosis
What are the symptoms of diabetic ketoacidosis?
Why is ketone testing the urine important in management of a diabetic patient?
Monitoring of ketone bodies allows you to see if the patient is sticking to treatment
Also allows you to see if a patient needs urgent treatment to prevent them falling into diabetic ketoacidosis.
How might a diabetic become hypoglycaemic?
From insulin or sulponylurea treatment if:
They undertake increased activity
Miss a meal
Accidental or non-accidental overdose
At what point does hypoglycaemia become fatal and why?
Due to the CNS and other glucose dependant tissues requiring a constant supply of glucose that is not being met.
What are the symptoms of hypoglycaemia?
Hint: Long list, so get some of them, probably best if you remember the more severe ones as well
What is the clinical criteria for hyperglycaemia and what are they symptoms?
Hint: Long list, just get some of them
Blood glucose >10mmol/L
Dry or itchy skin
Poor wound healing
Plasma proteins may become heavily glycosylated
Why must insulin be injected?
Injected subcutaneously because it is a peptide hormone that would be digested in the stomach
Why is control of diabetes an issue for patients?
They must be sufficiently educated on their injection regiment and necessary lifestyle changes
There are huge social and psychological implications
Diet and exercise management are big factors in treatment regime, not everyone can/will comply
What factors are involved in treatment/management of T1 Diabetes?
Times for insulin administration
How to administer
Signs of hypoglycaemia
Frequent blood glucose testing (BM stick and reader)
Why might insulin need to be increased in a diabetic patient following trauma or infection?
Risk of ketoacidosis
How is T2 Diabetes managed?
Can be managed by diet
Or can be managed by oral hypoglycaemics such as sulphonylurea (these increase insulin release and reduce insulin resistance) or metformin (reduced gluconeogenesis)
Then eventually insulin therapy (managed as in T1)
In what tissues is glucose uptake not regulated by insulin?
In these tissues, what DOES determine glucose uptake?
Peripheral nerves, the eyes and the kidneys
Extracellular glucose concentration
In tissues where glucose uptake is not controlled by insulin, what is the reaction to persistent hyperglycaemia due to diabetes?
Give a reaction and the consequences of this reaction
Escess glucose is metabolised via aldose reductase
Glucose + NADPH + H+ ---> Sorbitol + NADP+
This depletes NADPH and leads to increased Disulphide bond formation in cellular proteins.
Accumulation of sorbitol causes osmotic damage to cells
Why is glycosylation of plasma proteins linked to diabetes?
Explain how this comes about and what is the effect of glycosylation on proteins
Hyperglycaemia leads to excess glycosylation of plasma proteins
Glucose reacts with free amino groups and forms covalent links
This changes the net charge and 3D structure of the proteins leading to functional disturbances
What factors does the extent of glycosylation of plasma proteins depend on?
Half life of the protein
Glucose plasma concentration
What is the significance of gylcosylated haemoglobin to diabetics?
Percentage glycosylated haemoglobin (HBA1c) is a good indicator of how effective blood glucose control has been
As RBCs remain in circulation for ~3 months, the % HBA1c is related to average blood glucose concentration in the preceding 2-3 months
Poor control can lead to levels above 10%
How is HBA1c produced?
Glucose in the blood reacts with the terminal valine of the haemoglobin molecule.
What are the possible macrovascular complication of Diabetes?
Increased risk of stroke and Myocardial infarction
Poor circulation at the periphery, particularly the feet
What are the microvascualr complications of diabetes?
Diabetic Retinopathy/Eye disease
Explain how Diabetic retinopathy/eye disease comes about and its symptoms
Changes in the lens due to osmotic effects of glucose (glaucoma) and possibly cataracts
Damage to the blood vessels of the retina that may leak (forming protein exudates on the retina) or burst and cause bleeding
New vessels may form (proliferative retinopathy) that are weak and can easily bleed.
What is the cause/are the causes of Diabetic Nephropathy?
Due to damage to the glomeruli
Or poor blood flow because of changes in kidney blood vessels
Or from damage from urinary tract infections (more common in diabetics due to excess glucose in urinary tract)
What is an early sign of diabetic nephropathy?
Increase of protein in the urine (microalbuminuria)
What are the causes of diabetic peripheral neuropathy and what does this cause?
Damage to peripheral nerves which directly absorb glucose
Damage can lead to change or loss of sensation or changes due to alteration of autonomic nervous system function
Why are the feet of someone with diabetes vulnerable?
In the past, what was the common complication of Diabetic feet?
Poor blood supply, nerve damage and increased risk of infection
In the past loss of feet due to gangrene was not uncommon
Describe the synthesis, storage, transport and effect on receptors/target tissue of insulin in detail.
Synthesised in B-cells in pancreatic islets of langerhan
Stored in B-cells storage granules as crystalline-zinc complex
Dissolves in plasma and circulates as a free hormone
Targets liver, adipose tissue and skeletal muscle interacting with surface receptors and stimulates enzymes/proteins inside the cell to act
Describe the synthesis, structure and effect on the cell of glucagon
Synthesised as larger preproglucagon that undergoes post translational processing to produce glucagon
It's a single chain polypeptide lacking Disulphide bridges so has flexible structure
Takes on active conformation after binding to receptor on target cell membrane
Binds to G-protein coupled receptor which activates enzyme adenylate cyclase which increases cyclic AMP (cAMP) intracellularly/
What are the short and long term effects of insulin release?
Clearing absorbed nutrients from blood following a meal
Has effects on cell growth/division that relate to its ability to stimulate protein synthesis and DNA replication
Which of insulin and glucagon is anabolic or catabolic?
Insulin - Anabolic
Glucagon - Catabolic
What are the major actions of glucagon?
Increased glycogenolysis in liver
Decreased glycogenesis in liver
Increased gluconeogenesis in liver
Increased Ketogenesis in liver
Increased Lipolysis in adipose tissue
What are the major actions of Insulin on metabolism?
Relate each effect to location(s)
Hint: This is a long list
Increased glucose transport into adipose tissue/skeletal muscle
Increased glycogenesis and decreased glycogenolysis in liver/skeletal muscle
Decreased gluconeogenesis in the liver
Increased glycolysis in liver/adipose tissue
Decreased lipolysis in adipose tissue
increased lipogenesis and esterification of fatty acids in liver/adipose tissue
Decreased ketogenesis in liver
Increased lipoprotein lipase activity in capillary beds of tissues such as adipose tissue
Increased amino acid uptake and protein synthesis in liver, muscle and adipose tissue
Decreased Proteolysis in liver, skeletal muscle and adipose tissue
What are the cell types of an Islet of Langerhans?
Give proportions and what they produce.
75% Beta cells - Produce insulin
20% alpha cells - Produce glucagon
Describe the features of alpha and beta cells ultrastructure that relate to their specific function in the Islets of Langerhans
Store hormonal products in storage granules (membrane bound vesicles)
Ultrastructural features characterisitic of cell specialised for protein production and export:
Increased RER and Golgi apparatus