Type I Diabetes

Question 1

What is Type 1 diabetes?

Answer 1

Type I diabetes mellitus is characterised by an autoimmune condition in which pancreatic beta-cells of the Islets of Langerhans are dysfunctional.

Question 2

What is the long-term treatment for partial or complete insulin production in T1DM?

Answer 2

Chronic insulin treatment

Question 3

What is LADA?

Answer 3

Autoimmune diabetes leading to insulin deficiency can present later in life = latent autoimmune diabetes in adults (LADA).

Question 4

Which metabolic feature is characteristic of T1DM?

Answer 4

Diabetic ketoacidosis

Question 5

What is the relationship between pancreatic B-cell function and age in those with a genetic predisposition to T1DM?

Answer 5

• The number of pancreatic beta-cells progressively decrease with age, resulting in a decline in insulin output and glucose control.

Question 6

What is the cleavage product of pro-insulin?

Answer 6

C-peptide

Question 7

What is C-peptide used for?

Answer 7

C-peptide is the cleavage product of pro-insulin  Used as a marker of insulin concentrations and beta-cell function.

Question 8

What is the pathoimmunology underlying T1DM?

Answer 8

autoreactive CD4+ T-lymphocyte by antigen-presenting cells.
• CD4+ cells activate CD8+ T lymphocytes.
• CD8+ cells travel to islets and lyse beta cells expressing autoantigen (travel via lymph nodes)
• Release of pro-inflammatory species and reactive oxygen species (Granzyme and perforin are released from cytotoxic granules).

Question 9

Defects in which type of tolerance is evident in T1DM pathoimmunology?

Answer 9

Peripheral tolerance (Impaired regulatory T-cells)

Question 10

Which allele identified in GWAS is implicated in T1DM?

Answer 10

HLA-DR allele

Question 11

What are the environmental factors implicated in T1DM?

Answer 11

Environmental factors 
Multiple factors implicated  Causality not established. 
•	Enteroviral infections
•	Cow’s milk protein exposure
•	Seasonal variation
•	Changes in microbiota.

Question 12

What are the common pancreatic auto-antibodies involved in T1DM?

Answer 12

• Glutamic acid decarboxylase (GADA) – widespread neurotransmitter
• Insulin antibodies (IAA)
• Insulinoma-associated-2 autoantibodies (IA-2A)-Zinc transporter 8 (ZnT8).

Question 13

What is the clinical presentation of type 1 diabetes?

Answer 13

• Polyuria – excessive urination
• Polydipsia – excessive thirst
• Blurring of vision – Diabetic nephropathy
• Recurrent infections e.g thrush
• Weight loss
• Fatigue- Catabolic muscle breakdown (proteolysis considering to produce both glucogenic and ketogenic amino acids).

Question 14

What are the clinical signs of type 1 diabetes?

Answer 14

• Dehydration
• Cachexia – Catabolic catabolism increases to provide alternative substrate including amino acids gluconeogenesis and ketone body formation.
• Hyperventilation – diabetic ketoacidosis (Respiratory compensation to remove carbon dioxide)
• Smell of ketones
• Glycosuria
• Ketonuria

Question 15

Why does hyperventilation occur in T1DM?

Answer 15

Diabetic ketoacidosis (Respiratory compensation to remove carbon dioxide)

Question 16

Why does cachexia occur in T1DM?

Answer 16

Catabolic catabolism increases to provide alternative substrate including amino acids gluconeogenesis and ketone body formation.

Question 17

What is the fate of non-esterified fatty acids in a hyperglycaemic state?

Answer 17

Non-esterified fatty acids undergo beta-oxidation resulting in the production of fatty Acyl-CoA.
• Carnitine shuttle facilitates the transport of fatty acids through the mitochondrial membrane.
• Insulin exerts an inhibitory effect on the shuttle –> Downregulates ketone body formation.
• Glucagon potentiates the rate at which fatty-acyl-CoA undergoes ketogenesis to synthesise ketone bodies.

Question 18

What are the treatment aims for a patient with T1DM?

Answer 18

Insulin dependent for life (Patients with T1DM) + dietary support.
Aim:
• Maintain glucose levels without excessive hypoglycaemia
• Restore a close to physiological insulin profile
• Prevent acute metabolic decompensation
• Prevent microvascular and macrovascular complications.

Question 19

What are the three chronic microvascular complications with T1DM?

Answer 19

• Retinopathy
• Neuropathy
• Nephropathy

Question 20

What are the three macrovascular complications with T1DM?

Answer 20

• Ischaemic heart disease
• Cerebrovascular disease
• Peripheral vascular disease

Question 21

What is first phase insulin release?

Answer 21

Prandial peak of significant exocrine release of preformed insulin into circulation

Question 22

How many phases are associated with prandial insulin release?

Answer 22

First phase insulin release and second phase (2)

Question 23

What is the second insulin release phase associated with?

Answer 23

Second phase is dependent on pancreatic B-cell function

Question 24

What are the two forms of quick acting insulin?

Answer 24

Human insulin

insulin analogue

Question 25

What are the two forms of long-acting basal insulin?

Answer 25

Bound to zinc or protamine | Insulin analogue

Question 26

What is the typical basal bolus regime?

Answer 26

Injected 15 minutes pre-prandially short acting

Question 27

What is insulin pump therapy?

Answer 27

* Continuous delivery of short-acting insulin analogue e.g: Novorapid via pump. * Delivery of insulin into subcutaneous space * Programme the device to deliver fixed units/hour throughout the day (basal) * Actively bolus for meals.

Question 28

What is the available dietary advice for diabetes?

Answer 28

Dose adjustment for carbohydrate content of food. • Patients receive training for carbohydrate counting. • Substitute refined carbohydrate containing goods (high glycaemic index) with complex carbohydrates (starchy/low glycaemic index). NICE Guidelines (NG17) for type I diabetes • Structured Education Programme • DAFNE • 5-day course on skills and training in self-management.

Question 29

Why are starch and complex carbohydrates a better substitute than refined carbohydrates?

Answer 29

Complex carbohydrates have a low glycemic index

Question 30

What is the aim for simultaneous pancreas and kidney transplant?

Answer 30

Aim: Restore physiological insulin production to the extent that administered insulin can stop. • Incomplete --> Results in better control.

Question 31

What are the limitations with a pancreas and kidney transplant?

Answer 31

Limitations: Availability of donors, complications of life-long immunosuppression

Question 32

What is glycated haemoglobin?

Answer 32

* HbA1c represents 3 months of glycaemia (red blood lifespan). * Biased to the 30 days preceding measurement

Question 33

Which amino acid terminal is glucose associated with in HbA1C?

Answer 33

Glycated not glycosylated (enzymatic)  Glucose is associated with the N-terminal valine residue of the B-chain. • Linear relationship • Irreversible reaction

Question 34

What are the four limitations to using HbA1c as a marker?

Answer 34

1. Erythropoiesis Increased HbA1c: Iron, vitamin B12 deficiency, decreased erythropoiesis Decreased HbA1c: Administration of erythropoietin, iron, vitamin B12, reticulocytosis, chronic liver disease. 2. Altered Haemoglobin Genetic or chemical alterations in haemoglobin: Haemoglobinopathies, HbF, methaemoglobin, may increase or decrease HbA1c. 3. Glycation Increased HbA1c: Alcoholism, chronic renal failure, decreased intra-electrolyte pH Decreased HbA1c: Aspirin, Vitamin C and E, certain haemoglobinopathies, increased intra-erythrocyte pH. Variable HbA1c: Genetic determinants. 4. Erythrocyte destruction Increased HbA1c: Increased erythrocyte lifespan: Splenectomy Decreased HbA1c: Decreased erythrocyte lifespan: Haemoglobinopathies, splenomegaly, rheumatoid arthritis or drugs such as antiretrovirals, ribavirin and dapsone.

Question 35

What is the diagnosis for diabetic ketoacidosis?

Answer 35

Diabetic ketoacidosis diagnosis • pH <7.3, ketones increased (urine of capillary blood) • HCO3- <15mmol/L and glucose >11mmol/L.

Question 36

What is the risk of type 1 diabetes?

Answer 36

Complications 1) Diabetic ketoacidosis 2) Uncontrolled hyperglycaemia 3) Hypoglycaemia

Question 37

What is the diagnostic parameter for hypoglycaemia?

Answer 37

<3.6mmol/L  Hypoglycaemia

Question 38

What are the risks of hypoglycaemia?

Answer 38

``` Hypoglycaemia problems • Excessive frequency • Impaired awareness (unable to detect low blood glucose) • Nocturnal hypoglycaemia • Recurrent severe hypoglycaemia ``` * Seizure/coma/death * Impacts on emotional well-being * Impacts on driving * Impacts on day-to-day function * Impacts on cognition

Question 39

What are the risk factors for hypoglycaemia?

Answer 39

``` Risk factors • Exercise • Missed meals • Inappropriate insulin regime • Alcohol intake • Lower HbA1c • Lack of training around dose-adjustment for meals ```