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Endocrine & Diabetes > Diabetes Mellitus – Pathogenesis and Metabolic Abnormalities > Flashcards

Diabetes Mellitus – Pathogenesis and Metabolic Abnormalities Flashcards

1
Q

Describe diabetes in the UK

A
  • Affects 5% of total population -Affects 10% of people over 65
  • Around 3.2 million people are known to have diabetes -Many people have undiagnosed diabetes
  • About 25% require insulin therapy
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2
Q

What is diabetes?

A
  • Diabetes mellitus is a condition associated with an elevated blood glucose.
  • This is a consequence of deficiency of INSULIN, or of its reduced action, or of a combination of both
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3
Q

Describe insulin

A
  • Hormone secreted in pancreas (islets)
  • Anabolic hormone (actions centred around storage of nutrients and energy sources)
  • Mitogenic= growth and proliferation of calls stimulated
  • Essential for fuel storage and cell growth
  • Promotes uptake of glucose into cells for energy
  • Prevents breakdown of fat and protein
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4
Q

Describe the structure of a pancreatic islet

A
  • Clusters of beta cells secreting insulin, central location
  • Alpha cell, secreting glucagon, tend to sit peripherally in islets
  • Delta cell (secretes somatostatin)
  • F cell (secretes pancreatic polypeptide)
  • Exocrine acinus surrounds (exocrine go to pancreatic duct, endocrine directly into bloodstream, drain out through portal circulation)
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5
Q

What pancreatic cells make what hormone?

A
  • Alpha cell= glucagon, 11%
  • Beta cell= insulin, 85%
  • Delta cell= somatostatin, 3% (inhibitory, analogues used therapeutically for excess hormones in acromegaly)
  • F cell= pancreatic polypeptide, 1% (excess= diarrhoea)
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6
Q

Describe the structure of insulin

A

-Protein
-Complex quaternary structure
-Alpha subunit and beta subunit linked by directly by disulphide bonds and indirectly by c peptide (in the middle, proinsulin)
=c peptide cleaved away by B-cell peptidases to form insulin

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7
Q

How is insulin secreted from beta cells?

A

-Insulin secretion from beta cells directly coupled to glucose influx (interstitial fluid)
-GLUT2 glucose transporter= glucose into cells without insulin
=Amount of beta cells concentration dependent
=metabolised by glycolysis cycle
=ATP generated
=ATP sensitive potassium channel allowing K+ out into cells along concentration closed
=Concentration of K+ increases so depolarisation closing voltage gated calcium channel
=Affect levels of calcium in cells so exocytosis of insulin into blood

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8
Q

What are sulphonyl urea drugs?

A

-Bind to SUR1 proteins to close potassium channel
=bypass glucose intake
=stimulate insulin production

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9
Q

What are the phases of insulin secretion?

A
  • Pro-insulin is converted to insulin and C-peptide in equimolar amounts
  • In response to ingestion of food, stored insulin is released first (in secretory granules), followed by newly synthesised insulin
  • This gives a biphasic response of insulin secretion
  • C-peptide can be used as a measure of endogenous insulin secretion in people with diabetes (exogenous has no c peptide)
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10
Q

What are the sites of action of insulin?

A
  • Secreted into portal vein
  • Acts first on LIVER (much higher concentrations in portal circulation)
  • Passes through liver into systemic circulation
  • Acts on MUSCLE and FAT
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11
Q

What are the principal actions of insulin?

A
  • Increase Glucose uptake in FAT and MUSCLE
  • Increase Glycogen storage in LIVER and MUSCLE
  • Increase Amino Acid uptake in MUSCLE
  • Increase Protein Synthesis

-Increase Lipogenesis in ADIPOSE TISSUE

  • Decrease Gluconeogenesis from 3-Carbon precursors
  • Decrease Ketogenesis (in LIVER)
  • Increase Cell proliferation
  • Decrease Apoptosis
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12
Q

How does insulin affect glucose transport into cells?

A
  • Causes translocation of GLUT4 to cell membranes from cytoplasm to allow insulin-dependent glucose uptake into cells
  • Glucose transporter in adipose and muscle cells in cytoplasm
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13
Q

Sources of blood glucose

A
  • Carbohydrates broken down into portal system
  • Glycogen in liver hydrolysed (starvation= gluconeogenesis)
  • Kidneys also do gluconeogenesis
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14
Q

How does the brain allow glucose uptake?

A
  • GLUT 3 in brain, insulin independent receptor

- Always supply of glucose

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15
Q

What are the 3-carbon precursors used in gluconeogenesis?

A
  • Alanine (from ingested protein)
  • Pyruvate (from muscle protein)
  • Lactate (from muscle glycogen)
  • Glycerol (from fat)
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16
Q

What other hormones are used in glucose homeostasis?

A

-Adrenaline
-Epinephrine
-Norepinephrine
-Cortisol
=important in times of stress
=high metabolic demand

17
Q

Why is blood glucose maintained within a narrow range by homeostatic mechanisms?

A
  • Optimal functioning of brain (can’t switch to ketones as quickly)
  • Maintenance of energy source for most tissues
  • Integrity and health of blood vessels
18
Q

How might insulin deficiency occur?

A

-Destruction of islets (type 1 autoimmune)
=infiltration of inflammatory cytotoxic lymphocytes
=insulitis
-Toxins
=alcohol can cause acute and chronic pancreatitis where islets can get damaged

19
Q

How might insulin resistance occur?

A

-Problem in insulin signalling pathway (can be multiple blockages/ suboptimal function occurs)

20
Q

What are the severe insulin resistance syndromes?

A

-Mostly very rare, problems with insulin receptors
=Leprechaunism
=Rabson-Mendenhall syndrome
=Type A insulin resistance

21
Q

What are other causes of insulin resistance?

A
  • Acromegaly (GH excess)
  • Pheochromocytoma
  • Cushing’s
22
Q

What is dysglycaemia?

A 
-Spectrum of impaired fasting glycaemia
=Normal= up to 6.0 mmol/l
=Impaired fasting glycaemia= 6.0-7.0 mmol/l
=diabetes above 7.0 mmol/l
*Risk of diabetic retinopathy
23
Q

What are the 4 ways to be diagnosed with diabetes?

A
  • Fasting plasma glucose > 7.0 mmol/l
  • 2hr plasma glucose in OGTT> 11.1 mmol/l
  • Random plasma glucose > 11.1 mmol/l
  • HbA1c > 48 mmol/mol
  • If the patient is asymptomatic, the same test should be repeated to confirm the diagnosis of diabetes
  • Do not delay urgent care waiting for a second test
24
Q

What is glycated haemoglobin (HbA1c)?

A
  • Rate of formation of glycated haemoglobin is directly proportional to ambient blood glucose concentration
  • Reflects integrated blood glucose (BG) concentrations during lifespan of erythrocyte (120 days)
  • Blood sample can be taken at any time of day, irrespective of food consumption
25
Q

What are the reference ranges for HbA1c?

A
  • Normal ≤41 mmol/mol
  • Pre-diabetes 42-47 mmol/mol
  • Diabetes ≥ 48mmol/mol
26
Q

What are the situations where HbA1c should not be used as a diagnostic test?

A 
-Rapid onset of diabetes
=Suspected Type 1 Diabetes
=Children
=Drugs – steroids; antipsychotics
-Pregnancy
=Glucose levels can rise rapidly
=HbA1c is lower 
-Conditions where red cell survival may be reduced
=Haemoglobinopathy
=Haemolytic anaemia
=Severe blood loss
=Splenomegaly
=Antiretroviral drugs
-Increased red cell survival
=Splenectomy
-Renal dialysis
=Reduced HbA1c, especially if treated with erythropoietin
-Iron and vitamin B12 deficiency
=Small effects on HbA1c
27
Q

Describe the Oral Glucose Tolerance Test (OGTT)

A
  • Used to assess state of glucose tolerance
  • 75g oral glucose load
  • No restriction or modification of carbohydrate intake for preceding three days
  • Fast overnight
  • Test is performed in morning – seated; no smoking
  • Blood samples for plasma glucose taken at 0hrs and 2 hrs
28
Q

Describe Impaired Glucose Tolerance

A
  • Fasting plasma glucose: <7.0 mmol/l
  • 2 hours after 75g oral glucose load: 7.8-11.0 mmol/l
  • Affects 20% of population aged 40-65 years (UK)
  • Increased mortality from cardiovascular disease (doubled)
  • Natural history - 15% develop diabetes in 5 years, 15% return to normal
  • Check fasting plasma glucose annually
29
Q

Describe Impaired Fasting Glucose

A
  • Fasting hyperglycaemia
  • Fasting plasma glucose: 6.0 – 6.9 mmol/l
  • Intermediate state between normal glucose metabolism and diabetes
  • Impaired glucose tolerance often present also (but not always)
  • Found in 5% of population and prevalence increases with age
  • Increased risk of vascular complications
30
Q

Describe Pre-Diabetic states

A
  • Fasting blood glucose 6.0-6.9 mmol/l
  • 2 hr OGTT blood glucose 7.8-11.0 mmol/l
  • HbA1c 42-47 mmol/mol

-Fasting hyperglycaemia and Impaired Glucose Tolerance often co-exist

Endocrine & Diabetes (45 decks)

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