Type I Diabetes Mellitus: Clinical Features, Pathophysiology, Treatment Flashcards
Most common cause of death in T1DM historically and in the present?
Historically, diabetic coma was very common
Now, the most common cause is cardiovascular
Why is T1DM incidence increasing?
T2DM is increasing due to diet and secondary lifestyle factors
T1DM is increasing due to genetic factors but there must also be environmental factors
Definition of T1DM?
State of absolute insulin deficiency
Probably caused by an environmental trigger in a genetically susceptible individual mediated, for the most part, by an autoimmune process of varying severity occurring within the pancreatic β-cells
How is T1DM diagnosed?
Fasting glucose ≥ 7.0 mmol/l
Random blood glucose ≥ 11.1 mmol/l
AND
Symptoms OR a repeat test
How is the type of diabetes diagnosed?
Often, T1DM is diagnosed on the Hx and presentation, e.g: DKA, alone
Although, GAD/IA2 antibodies and C-peptide can be checked if there is doubt
Difference between what occurs at islets in T1DM and T2DM?
T1DM - lymphocytes attack the islet and cause an insulitis
T2DM - there are assoc. pancreatic islet amyloid deposits
When does the risk of T1DM development increase, with regards to FH?
Risk increases if they have T1DM:
• Monozygotic and dizygotic twins
• HLA identical sibling and even in a sibling with one shared HLA gene
• Mother
• Father (3 times more likely to develop diabetes if father has diabetes than if mother does)
• Both parents
HLA assoc. with T1DM?
HLA genes represent half of familial risk of T1DM; the highest risk genotype is [DR3-DQ2 / DR4-DQ8]
Most people diagnosed with T1DM <30 years old have one/both of these genotypes
Environmental observations that relate to T1DM diagnosis?
Seasonality (more diagnoses in winter months)
Timing of birth (older the mother is, higher chance of gestational diabetes and thus higher risk of child with T1DM)
Potential environmental triggers of T1DM?
Viral infection
Maternal factors
Weight gain
Relationship between HLA genotype and development of T1DM?
Only 10% of those with susceptible HLA go on to develop T1DM; so, environmental factors are important
Different islet auto-antibodies?
ICA (Islet Cell Cytoplasmic Autoantibodies): • GAD 65 Ab • IA-2 Ab • IAA • ZnT8Ab
Respective antigens for each auto-antibody?
GAD 65 Ab - Glutamic acid Decarboxylase
IA-2 Ab - Islet antigen 2
IAA - insulin
ZnT8Ab - ZnT8 transporter
Sensitivity of GAD 65 Ab?
70-80% have presence at diagnosis
This increases with age and they tend to be +ve in females <10 years
Sensitivity of IA-2 Ab?
60-70%
This decreases with age and they tend to be +ve in males
Sensitivity of IAA?
50%
More sensitive in children; for both genders, the presence is similar
Sensitivity of ZnT8 Ab?
60-80%
More sensitive in older people; for both genders, the presence is similar
Presence of ICA antibodies pre-diagnosis?
Can be present for years before the onset of T1DM
Risk factors for T1DM in foetal life?
Maternal factors: • Infection • Age of mother • ABO mismatch • Birth order • Stress (may contribute)
Disease markers for T1DM in foetal life?
Genetic markers:
• HLA or non-HLA
Risk factors for T1DM pre-diabetes (months-years)?
Auto-immune trigger factors: • VIRAL INFECTION • Vit D deficiency • Dietary factors • Environmental toxins
Disease markers of T1DM in pre-diabetes?
Auto-immune process:
• Autoantibodies, e.g: GAD 65 and also IAA and IA2, ZnT8
• Candidate antigens
• Presence of insulitis
Risk factors for T1DM in clinical diabetes?
Accelerating factors: • Infection • Insulin resistance • PUBERTY • Diet • WEIGHT GAIN(patients with T1DM are normally lean but they go on to GAIN WEIGHT; so, they develop co-existing metabolic syndrome and insulin resistance) • Stress
Disease markers for T1DM in clinical diabetes?
Features: • RAISED GLUCOSE • KETONES • Decreased insulin • Decreased β-cell mass • Decreased C-peptide
Pathogenesis of T1DM?
There is immune dysregulation due to the interaction between genes imparting susceptibility and resistance
Environmental triggers cause:
• Variable insulitis develops and β-cell sensitivity to injury
• Pre-diabetes develops (with +ve IAA and GAD antibodies)
• Overt diabetes develops (with loss of 1st phase insulin release after a meal and development of glucose intolerance)
• Patients may initially be C-peptide +ve (due to some endogenous insulin remaining) but this eventually becomes -ve
Classic triad of T1DM presentation?
- Polyuria (in children, enuresis)
- Polydipsia
- Weight loss
Symptoms and signs of T1DM?
Fatigue and somnolence
Blurred vision
Candidal infection:
• Pruritis vulvae
• Balanitis
In established ketoacidosis
When is hospitilisation required for T1DM?
- DKA
- Significant ketonaemia
- Vomiting
Mx of newly diagnosed T1DM?
Blood glucose and ketone monitoring; carbohydrate estimation is also important
Insulin (usually basal) bolus once daily with meals
Regular check of prevailing glycaemic control using HbA1c
Annual review
Record severe hypoglycaemic or any episodes of DKA
Normal HbA1c levels?
48-58 mmol/mol
What must an annual review involve?
Check of: • Weight • BP • Bloods (HbA1c, renal function and lipids) • Retinal screening • Foot assessment
Diabetes in cystic fibrosis (CF) patients?
20% of patients with CF go on to develop secondary diabetes that requires insulin
Continuing Mx of T1DM?
Insulin therapy:
• Intensified treatment regimen for adults with T1DM should include either regular human OR rapid-acting insulin analogues
• Basal insulin analogues are recommended in adults with Type 1 who are experiencing severe/nocturnal hypoglycaemia and who are using an intensified insulin regimen
• Children and adolescents may use either insulin analogues (rapid-acting or basal), regular human insulin and NPH preparations; an appropriate combination of these may be used
• Insulin regimen should be tailored to the individual child to achieve the best possible glycaemic control without disabling hypoglycaemia
Microvascular complications of T1DM?
Retinopathy, nephropathy and neuropathy
Types of diabetes?
T1DM or T2DM
There is an overlap between these two: • MODY • LADA • Mitochondrial gene mutations • Amylin gene mutations
Normal age to develop the different types of diabetes?
T1DM - 1-30 years
T2DM - used to be uncommon in youngsters but is now extending to those who are 10 years old
MODY - tends to occur between teen years to the age of 30
LADA - occurs between the ages of 20-30 years
Secondary diabetes - occurs between 20-30 years
Describe normal insulin secretion in response to a meal
Biphasic secretion:
• Rapid phase of pre-formed insulin release that lasts 10-15 mins (this is 5% of the overall insulin in the body)
• Slow phase over 1-2 hours
Insulin is secreted into the portal vein
Insulin secretion in the fasted state?
Continues at a rate of 0.25-1.5 units/insulin/hour
Compare T1DM, T2DM and LADA with regards to the time until insulin is required?
T1DM takes less time to require insulin
LADA and T2DM take more time (up to 4 years)
Classification criteria for T1DM?
Age:
• Peak period is <5 years and 10-14 years
FH:
• Possible
Duration/severity of symptoms:
• Short and severe
Complications at presentation:
• Never
Weight loss:
• Usual
Ketonuria:
• +++
Classification criteria for T2DM?
Age:
• Unusual <25 years
FH:
• Frequent (>30%)
Duration/severity of symptoms:
• Months or more but usually mild symptoms
Complications at presentation:
• Up to 30%
Weight loss:
• Not usual
Ketonuria:
• Usually none
Classification criteria for monogenic diabetes?
Age:
• Neonate to adulthood
FH:
• Almost always
Duration/severity of symptoms:
• Months but usually mild
Complications at presentation:
• Unusual
Weight loss:
• Not usual
Ketonuria:
• Usually none
Classification criteria for secondary diabetes?
Age:
• Usually later in life
FH:
• Rare
Duration/severity of symptoms:
• Weeks/months but depends on cause
Complications at presentation:
• Unusual
Weight loss:
• Depends on cause
Ketonuria:
• ++/-
How to differentiate between T1DM and T2DM?
ADD TABLE
Children diagnosed under the age of 6 are more likely to have?
Monogenic rather than T1DM
How is a diagnosis of LADA made?
AKA LAtent onset Diabetes of Adulthood - established by presence of elevated levels of pancreatic auto-antibodies in patients with “recently diagnosed” diabetes who do not initially require insulin
What is LADA also known as?
Slowly progressive T1DM OR type 1.5 diabetes
When should LADA be suspected?
Young adults (25-40 years) and a male preponderance
Usually, non-obese
Auto-Ab +ve and assoc. with autoimmune conditions
Non-insulin requiring at diagnosis
Sub-optimal control on oral agents
Describe diabetes in cystic fibrosis
Common (1/4) and usually found in “severe” mutations, e.g: ∆508
Prone to comps. and screening from age of 10 years is recommended
Insulin therapy is preferred for treatment
What is DIDMOAD?
AKA Wolfram syndrome - rare autosomal-recessive genetic disorder that causes childhood-onset of: • Diabetes Insipidus • Diabetes Mellitus • Optic Atrophy • Deafness • Neurological anomalies
What is Bardet-Biedl syndrome?
Ciliopathic genetic disorder that affects many body systems and causes: • Polydactyly (extra fingers) • Hypogonadism • Visual and hearing impairments • Mental retardation • Diabetes
Patients are often very obese and it tends to occur in people with consanguineous parents
If a person is diabetic in youth, how to tell if the T1DM diagnosis is correct?
Diabetes diagnosed <6 months - chance of T1DM to below 1%
FH of DM - chance of T1DM is 2-4%
Detectable insulin production ≥3 years after diagnosis - chance of T1DM is 1-5%
Undetectable pancreatic antibodies (at diagnosis) - chance of T1DM is 3-30%
Steps to follow when diagnosing diabetes in someone <25 years?
- Diabetes diagnosed <25 years
- Could this be secondary (unusual or known features)?
- Consider:
• History
• FH
• Ketones
4:
• T1DM - short severe, ketones +++, +ve antibodies
• LADA - longer/variable, ketones 0/++, +ve antibodies and insulin delayed
• MODY - variable, ketones 0/+, -ve antibodies and inheritance
• T2DM - long/mild symptoms, ketones 0, -ve antibodies and overweight patient
Assoc. autoimmune conditions with T1DM?
Fairly common: • Thyroid disease • Coeliac disease (1/20 in T1DM compared to 1/100 in population) • Pernicious anaemia • Addison's disease • IgA deficiency
Rare:
• Autoimmune polyglandular syndromes (type 1 and type 2)
• AIRE mutations
• IPEX syndrome
Symptoms and signs of coeliac disease?
Often asymptomatic but can have bloating/diarrhoea and malabsorption
Anaemia, low albumin, low calcium
Anti-TTG Abs +ve, NB IgA deficiency and duodenal biopsy
Symptoms and signs of thyroid disease?
Many are asymptomatic but can have weight chance and hypoglycaemia; FH may be present
Deterioration in HbA1c
What diseases is type 2 polyglandular endocrinopathy assoc. with?
T1DM in this is assoc. with: • Addison's disease • Vitiligo • Primary hypogonadism • Primary hypothyroidism • Coeliac disease
What diseases is type 1 (autosomal recessive) polyglandular endocrinopathy assoc. with?
- Mild immune deficiency (mucocutaneous candidiasis)
- Any of the conditions assoc. with type 2
- Primary hypoparathyroidism, pernicious anaemia and alopecia
