Metabolism S8 - Diabetes and Metabolic Syndrome Flashcards Preview

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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
Older population
Overweight populations

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

Type 1:
Commonest type in the young

Progressive loss of B-cells (all or most)

Rapidly fatal if not treated

Must be treated with insulin

Type 2:
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?

Abdominal pain


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?

<2mmol/L glucose

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

Weight loss
Blurred vision
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
Peripheral neuropathy
Diabetic Feet


Explain how Diabetic retinopathy/eye disease comes about and its symptoms

Eye disease:
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

Increased Mitochondria


How many storage granules mugh appear in a cell in the Islets of Langerhans and what might they contain?

~13,000 per cell

Insulin or Glucagon