Download Endocrinology 9a – Pathophysiology of Type 1 Diabetes Mellitus

Endocrinology 9a - Pathophysiology of Type 1 Diabetes Mellitus
Anil Chopra
1. To understand the definition & classification of type 1 diabetes
2. To understand the basis of the immunological mechanisms responsible for B-cell
loss
3. To understand the biochemical effects of insulin deficiency
4. To understand the principles of insulin treatment in type 1 diabetes
5. To understand the physiology and treatment of hypoglycaemia.
6. To understand the physiology and treatment of diabetic ketoacidosis.
Type 1 Diabetes
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Characterised by absolute insulin deficiency either through
autoimmune attack on pancreas, a viral infection or is idiopathic.
Cells in the islets of Langerhans in the pancreas are destroyed:
hypoinsulinaemia is a result.
Hyperglycaemia resulting from this has a number of microvascular,
macrovascular and metabolic complications.
There is also a significant genetic component: 
o The HLA-DR3 and HLA-DR4 are associated with increased
risk of type 1 diabetes.
o HLA-DR2 however is shown to be protective.
o If the HLA-DR is identical then the risk is increased 90-fold.
There are also some environmental triggers:
o Viral trigger that destroys the β cells.
o Viral proteins get incorporated into the β –cell membrane and hence cause
immune response.
o Viruses may alter the β-cell’s antigen expression.
o Viruses may directly affect the immune system causing it to malfunction.
o Viral mimicry
o Exposure of a normally hidden antigen
Biochemistry of Type 1 DM
Effects of insulin deficiency:
 Increased hepatic production of glucose
 Reduced muscle uptake of glucose and utilisation.
 Increase proteolysis (protein breakdown)
 Increase lipolysis (lipid breakdown)
 Increase ketogenesis
 Dyslipidaemia (generally hyperlipidaemia)
 Impaired growth
Glucose Metabolism
Ketone Metabolism
Clinical Presentation of Diabetes
• polyuria
• nocturia
• polydipsia
• blurring of vision
• ‘thrush’
• weight loss
• fatigue
•
•
•
•
•
•
dehydration
cachexia
hyperventilation
smell of ketones
glycosuria
ketonuria
Treatment of Diabetes
The aims of treatment are to reduce mortality and morbidity by preventing
ketoacidosis, and reduce the risk of long term complications such as retinopathy,
neuropathy, nephropathy, and vascular disease.
Diet:
- patients should reduce fat intake
- reduce the amount of refine carbohydrate
- increase the amount of complex carbohydrate
- increase soluble fibre
- regular meals and snacks
Insulin treatment
- previously treated with animal insulin – how with human
- Soluble - short acting
- NPH - intermediate acting (Neutral Protamine Hagedorn)
- Insulin analogues are now available
o Lispro/ novorapid - very rapid onset and short duration action
o Glargine - long-acting with ‘flat’ 24h action profile
- A number of different regimes possible:
o Twice daily mixed soluble and NPH insulin (bd regime)
o NPH insulin at bedtime and soluble insulin with meals (‘basal bolus
regime’)
o Continuous subcutaneous infusion of soluble insulin or rapid acting
analogue (CSII)
Glycosylated haemoglobin – Hb1Ac is a measure of blood glucose over long periods
of time – currently the gold standard test It is monitored
in diabetic patients and maintaining a low Hb1Ac can
improve prognosis.
Glycaemic control in DCCT
intense
11
conventional
HbA1c (%)
10
9
8
7
6
5
0
1
2
3
4
5
Time (years)
6
7
8
9
The graphs show that intense control of blood glucose can keep HbA1c low.
Monitoring HbA1c is the gold standard test for diabetes prognosis. Fructosamine is
also used in patients with haemoglobinopathy and pregnancy.
Complications of Type I Diabetes
Ketoacidosis
One of the more acute complications of diabetes
Decompensates for type 1 diabetes
- hyperglycaemia
- ketone production
- metabolic acidosis
- dehydration
- incidence is from 1 - 8 % of diabetic patients per year
- Mortality in 5-10% of all cases
Results from Insulin Deficiency
- glucose utilisation in tisues reducued
- glucose production in liver increased
- NEFA (non esterified fatty acids) increased
- acetoacetate & hydroxybutyrate increased
- osmotic dehydration and acidosis results
INSULIN DEFICIENCY
Hyperglycaemia
Osmotic diuresis
FASTING
Ketosis
STRESS HORMONES
hyperventilation
Acidosis
Vomiting
Fever
DEHYDRATION
Renal hypoperfusion
Diabetic Ketoacidosis has Specific Clinical Features:
 Polyuria and polydipsia due to osmotic diuresis
 dehydration
 hyperventilation (Kussmaul)
 abdominal pain, vomiting
 coma
 look for precipitating factor
 glycosuria and ketonuria
Impaired H+
excretion
Treatment for Ketoacidosis
 Normal saline – patient can be up to 8L deficient
 Insulin IV
 Bicarbonate
 Potassium replacement as low K+ can be fatal
 General supportive measures
 Education for future prevention
Hypoglycaemia
These are inevitable with the treatment of diabetes.
- it occurs when plasma glucose goes below 3.5mmol/l
o mental functions become impaired at <3mmol/l
o consciousness becomes impaired at <2mmol/l
- causes great anxiety and stress in families
- can result in arrhythmias and death if untreated
Results from Poor Glycaemic control
- more frequent in patients with low HbA1c
- occur at any time (but a pattern soon develops)
o before meals, especially lunch
o nocturnal are common but often unrecognised
Can be due to:
- unaccustomed exercise
- missed meals
- inadequate snacks
- alcohol
- inappropriate insulin regime
Symptoms of Hypoglycaemia:
Due to increased autonomic activation
- palpitations (tachycardia)
- tremor
- sweating
- pallor / cold extremities
- anxiety
Due to impaired CNS function
- drowsiness
- confusion
- altered behaviour
- focal neurology
- coma
Treating Hypoglycaemia
- give patient glucose
o either i.v. or as rapidly absorbed tablet
o if not in hospital –lucozade, chocolate
o maintain with complex carbohydrates
- if patient loses consciousness
o IV dextrose e.g 10% glucose infusion
o 1mg Glucagon IM
o avoid concentrated solutions if possible (e.g 50% glucose)