Diabetes Mellitus – Pathogenesis and Metabolic Abnormalities

Question 1

Describe diabetes in the UK

Answer 1

• 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

Question 2

What is diabetes?

Answer 2

• 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

Question 3

Describe insulin

Answer 3

• 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

Question 4

Describe the structure of a pancreatic islet

Answer 4

• 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)

Question 5

What pancreatic cells make what hormone?

Answer 5

• 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)

Question 6

Describe the structure of insulin

Answer 6

-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

Question 7

How is insulin secreted from beta cells?

Answer 7

-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

Question 8

What are sulphonyl urea drugs?

Answer 8

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

Question 9

What are the phases of insulin secretion?

Answer 9

• 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)

Question 10

What are the sites of action of insulin?

Answer 10

• 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

Question 11

What are the principal actions of insulin?

Answer 11

• 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

Question 12

How does insulin affect glucose transport into cells?

Answer 12

• 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

Question 13

Sources of blood glucose

Answer 13

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

Question 14

How does the brain allow glucose uptake?

Answer 14

• GLUT 3 in brain, insulin independent receptor

- Always supply of glucose

Question 15

What are the 3-carbon precursors used in gluconeogenesis?

Answer 15

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

Question 16

What other hormones are used in glucose homeostasis?

Answer 16

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

Question 17

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

Answer 17

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

Question 18

How might insulin deficiency occur?

Answer 18

-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

Question 19

How might insulin resistance occur?

Answer 19

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

Question 20

What are the severe insulin resistance syndromes?

Answer 20

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

Question 21

What are other causes of insulin resistance?

Answer 21

• Acromegaly (GH excess)
• Pheochromocytoma
• Cushing’s

Question 22

What is dysglycaemia?

Answer 22

-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

Question 23

What are the 4 ways to be diagnosed with diabetes?

Answer 23

• 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

Question 24

What is glycated haemoglobin (HbA1c)?

Answer 24

• 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

Question 25

What are the reference ranges for HbA1c?

Answer 25

- Normal ≤41 mmol/mol - Pre-diabetes 42-47 mmol/mol - Diabetes ≥ 48mmol/mol

Question 26

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

Answer 26

``` -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 ```

Question 27

Describe the Oral Glucose Tolerance Test (OGTT)

Answer 27

- 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

Question 28

Describe Impaired Glucose Tolerance

Answer 28

- 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

Question 29

Describe Impaired Fasting Glucose

Answer 29

- 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

Question 30

Describe Pre-Diabetic states

Answer 30

- 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