Type I Diabetes Mellitus: Clinical Features, Pathophysiology, Treatment

Question 1

Most common cause of death in T1DM historically and in the present?

Answer 1

Historically, diabetic coma was very common

Now, the most common cause is cardiovascular

Question 2

Why is T1DM incidence increasing?

Answer 2

T2DM is increasing due to diet and secondary lifestyle factors

T1DM is increasing due to genetic factors but there must also be environmental factors

Question 3

Definition of T1DM?

Answer 3

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

Question 4

How is T1DM diagnosed?

Answer 4

Fasting glucose ≥ 7.0 mmol/l

Random blood glucose ≥ 11.1 mmol/l

AND

Symptoms OR a repeat test

Question 5

How is the type of diabetes diagnosed?

Answer 5

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

Question 6

Difference between what occurs at islets in T1DM and T2DM?

Answer 6

T1DM - lymphocytes attack the islet and cause an insulitis

T2DM - there are assoc. pancreatic islet amyloid deposits

Question 7

When does the risk of T1DM development increase, with regards to FH?

Answer 7

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

Question 8

HLA assoc. with T1DM?

Answer 8

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

Question 9

Environmental observations that relate to T1DM diagnosis?

Answer 9

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)

Question 10

Potential environmental triggers of T1DM?

Answer 10

Viral infection

Maternal factors

Weight gain

Question 11

Relationship between HLA genotype and development of T1DM?

Answer 11

Only 10% of those with susceptible HLA go on to develop T1DM; so, environmental factors are important

Question 12

Different islet auto-antibodies?

Answer 12

ICA (Islet Cell Cytoplasmic Autoantibodies):
• GAD 65 Ab 
• IA-2 Ab 
• IAA
• ZnT8Ab

Question 13

Respective antigens for each auto-antibody?

Answer 13

GAD 65 Ab - Glutamic acid Decarboxylase

IA-2 Ab - Islet antigen 2

IAA - insulin

ZnT8Ab - ZnT8 transporter

Question 14

Sensitivity of GAD 65 Ab?

Answer 14

70-80% have presence at diagnosis

This increases with age and they tend to be +ve in females <10 years

Question 15

Sensitivity of IA-2 Ab?

Answer 15

60-70%

This decreases with age and they tend to be +ve in males

Question 16

Sensitivity of IAA?

Answer 16

50%

More sensitive in children; for both genders, the presence is similar

Question 17

Sensitivity of ZnT8 Ab?

Answer 17

60-80%

More sensitive in older people; for both genders, the presence is similar

Question 18

Presence of ICA antibodies pre-diagnosis?

Answer 18

Can be present for years before the onset of T1DM

Question 19

Risk factors for T1DM in foetal life?

Answer 19

Maternal factors:
• Infection
• Age of mother
• ABO mismatch
• Birth order
• Stress (may contribute)

Question 20

Disease markers for T1DM in foetal life?

Answer 20

Genetic markers:

• HLA or non-HLA

Question 21

Risk factors for T1DM pre-diabetes (months-years)?

Answer 21

Auto-immune trigger factors:
• VIRAL INFECTION
• Vit D deficiency
• Dietary factors
• Environmental toxins

Question 22

Disease markers of T1DM in pre-diabetes?

Answer 22

Auto-immune process:
• Autoantibodies, e.g: GAD 65 and also IAA and IA2, ZnT8
• Candidate antigens
• Presence of insulitis

Question 23

Risk factors for T1DM in clinical diabetes?

Answer 23

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

Question 24

Disease markers for T1DM in clinical diabetes?

Answer 24

Features:
• RAISED GLUCOSE
• KETONES
• Decreased insulin
• Decreased β-cell mass
• Decreased C-peptide

Question 25

Pathogenesis of T1DM?

Answer 25

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

Question 26

Classic triad of T1DM presentation?

Answer 26

* Polyuria (in children, enuresis) * Polydipsia * Weight loss

Question 27

Symptoms and signs of T1DM?

Answer 27

Fatigue and somnolence Blurred vision Candidal infection: • Pruritis vulvae • Balanitis In established ketoacidosis

Question 28

When is hospitilisation required for T1DM?

Answer 28

* DKA * Significant ketonaemia * Vomiting

Question 29

Mx of newly diagnosed T1DM?

Answer 29

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

Question 30

Normal HbA1c levels?

Answer 30

48-58 mmol/mol

Question 31

What must an annual review involve?

Answer 31

``` Check of: • Weight • BP • Bloods (HbA1c, renal function and lipids) • Retinal screening • Foot assessment ```

Question 32

Diabetes in cystic fibrosis (CF) patients?

Answer 32

20% of patients with CF go on to develop secondary diabetes that requires insulin

Question 33

Continuing Mx of T1DM?

Answer 33

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

Question 34

Microvascular complications of T1DM?

Answer 34

Retinopathy, nephropathy and neuropathy

Question 35

Types of diabetes?

Answer 35

T1DM or T2DM ``` There is an overlap between these two: • MODY • LADA • Mitochondrial gene mutations • Amylin gene mutations ```

Question 36

Normal age to develop the different types of diabetes?

Answer 36

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

Question 37

Describe normal insulin secretion in response to a meal

Answer 37

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

Question 38

Insulin secretion in the fasted state?

Answer 38

Continues at a rate of 0.25-1.5 units/insulin/hour

Question 39

Compare T1DM, T2DM and LADA with regards to the time until insulin is required?

Answer 39

T1DM takes less time to require insulin LADA and T2DM take more time (up to 4 years)

Question 40

Classification criteria for T1DM?

Answer 40

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: • +++

Question 41

Classification criteria for T2DM?

Answer 41

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

Question 42

Classification criteria for monogenic diabetes?

Answer 42

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

Question 43

Classification criteria for secondary diabetes?

Answer 43

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: • ++/-

Question 44

How to differentiate between T1DM and T2DM?

Answer 44

ADD TABLE

Question 45

Children diagnosed under the age of 6 are more likely to have?

Answer 45

Monogenic rather than T1DM

Question 46

How is a diagnosis of LADA made?

Answer 46

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

Question 47

What is LADA also known as?

Answer 47

Slowly progressive T1DM OR type 1.5 diabetes

Question 48

When should LADA be suspected?

Answer 48

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

Question 49

Describe diabetes in cystic fibrosis

Answer 49

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

Question 50

What is DIDMOAD?

Answer 50

``` AKA Wolfram syndrome - rare autosomal-recessive genetic disorder that causes childhood-onset of: • Diabetes Insipidus • Diabetes Mellitus • Optic Atrophy • Deafness • Neurological anomalies ```

Question 51

What is Bardet-Biedl syndrome?

Answer 51

``` 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

Question 52

If a person is diabetic in youth, how to tell if the T1DM diagnosis is correct?

Answer 52

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%

Question 53

Steps to follow when diagnosing diabetes in someone <25 years?

Answer 53

1. Diabetes diagnosed <25 years 2. Could this be secondary (unusual or known features)? 3. 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

Question 54

Assoc. autoimmune conditions with T1DM?

Answer 54

``` 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

Question 55

Symptoms and signs of coeliac disease?

Answer 55

Often asymptomatic but can have bloating/diarrhoea and malabsorption Anaemia, low albumin, low calcium Anti-TTG Abs +ve, NB IgA deficiency and duodenal biopsy

Question 56

Symptoms and signs of thyroid disease?

Answer 56

Many are asymptomatic but can have weight chance and hypoglycaemia; FH may be present Deterioration in HbA1c

Question 57

What diseases is type 2 polyglandular endocrinopathy assoc. with?

Answer 57

``` T1DM in this is assoc. with: • Addison's disease • Vitiligo • Primary hypogonadism • Primary hypothyroidism • Coeliac disease ```

Question 58

What diseases is type 1 (autosomal recessive) polyglandular endocrinopathy assoc. with?

Answer 58

* Mild immune deficiency (mucocutaneous candidiasis) * Any of the conditions assoc. with type 2 * Primary hypoparathyroidism, pernicious anaemia and alopecia