Type 1 Diabetes Mellitus

Question 1

What is T1DM?

Answer 1

• An autoimmune condition in which pancreatic beta-cells of the Islets of Langerhans are dysfunctional

Question 2

What is LADA?

Answer 2

• Latent autoimmune diabetes in adults: Autoimmune diabetes leading to insulin deficiency that presents later in life

Question 3

What are the environmental risk factors implicated in T1DM (4)?

Answer 3

• Enteroviral infections
• Cow’s milk protein exposure
• Seasonal variation
• Changes in microbiota
• Environmental (possibly viral) variation

Question 4

Which allele identified in Genome wide association (GWAS) is implicated in T1DM?

Answer 4

• HLA-DR allele

Human leukocyte antigen (HLA)

Question 5

What are the stages of development of T1DM (4)?

Answer 5

1. Genetic Risk
2. Immune activation
3. Immune response
4. Type 1 Diabetes Mellitus

Question 6

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

Answer 6

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

Question 7

What is C-peptide used for?

Answer 7

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

Question 8

What is the cleavage product of pro-insulin?

Answer 8

• C-peptide

Question 9

What is the pathoimmunology underlying T1DM (4 steps)?

Answer 9

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

Question 10

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

Answer 10

• Peripheral tolerance (Impaired regulatory T-cells)

Question 11

What are the common pancreatic auto-antibodies involved in T1DM (4)?

Answer 11

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

Question 12

What is the clinical presentation of T1DM (6)?

Answer 12

• 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 13

What are the clinical signs of T1DM (6)?

Answer 13

• 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 14

Which metabolic feature is characteristic of T1DM?

Answer 14

• Diabetic ketoacidosis

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 & ketone body formation

Question 17

How is T1DM diagnosed?

Answer 17

Diagnosis is based on clinical features and presence of ketones (in some cases pancreatic autoantibodies / C-peptide may be measured)

Question 18

What are the effects of insulin deficiency (4)?

Answer 18

• Increased production of amino acids
• Increased release of glucose
• Increased glycerol
• Increased non-esterified fatty acid -> Increased ketones

Question 19

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

Answer 19

• 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 20

What are the treatment aims for a patient with T1DM (4)?

Answer 20

• Maintain glucose levels without excessive hypoglycaemia
• Restore a close to physiological insulin profile
• Prevent acute metabolic decompensation
• Prevent microvascular & macrovascular complications

Question 21

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

Answer 21

• Chronic insulin treatment

Question 22

How many phases are associated with prandial insulin release?

Answer 22

• 2

Question 23

What is first phase insulin release?

Answer 23

• Prandial (around food intake time) peak of significant exocrine release of preformed insulin into circulation

Question 24

What is the second phase insulin release?

Answer 24

• Second phase is dependent on pancreatic B-cell function and amount of food consumed

Question 25

What are the 2 forms of insulin?

Answer 25

* **Short / quick-acting insulin** (with meals) * **Long-acting / basal** (background)

Question 26

What is the typical basal bolus regime?

Answer 26

* TDS (three times/day) short-acting * Once daily long-acting

Question 27

What are the 2 forms of quick acting insulin?

Answer 27

* **Human insulin** (Actrapid) * **Insulin analogue** (Lispro / Aspart / Glulisine)

Question 28

What are the 2 forms of long-acting basal insulin?

Answer 28

* **Bound to zinc or protamine** (Neutral Protamine Hagedorn, NPH) * **Insulin analogue** (Glargine / Determir / Deyludec)

Question 29

What is insulin pump therapy?

Answer 29

* **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 30

What is an artificial pancreas?

Answer 30

## Footnote Many advances in this field – some closed loop systems developed. Hybrid closed loop systems available on the NHS

Question 31

What are the two forms of transplantation used to treat T1DM?

Answer 31

* **Islet cell transplants** * Isolate human islets from pancreas of deceased donor * Transplant into hepatic portal vein * Requires life-long immunosuppression * **Simultaneous pancreas and kidney transplants** * Better survival of pancreas graft when transplanted with kidneys * Requires life-long immunosuppression

Question 32

What is the aim of transplantation for treatment of T1DM?

Answer 32

* **Restore physiological insulin production to the extent that administered insulin can stop** * Incomplete → Results in better control

Question 33

What are the limitations with transplantation for treatment of T1DM (2)?

Answer 33

* **Availability of donors** * Complications of life-long **immunosuppression**

Question 34

What is the available dietary advice for diabetes?

Answer 34

* **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)

Question 35

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

Answer 35

* Complex carbohydrates have a **low glycemic index**

Question 36

How can a T1DM patient monitor glucose levels?

Answer 36

* **Capillary** (finger prick) blood glucose monitoring * **Continuous glucose monitoring** (restricted availability, NICE guidelines)

Question 37

What is glycated haemoglobin (HbA1c)?

Answer 37

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

Question 38

Which amino acid terminal is glucose associated with in HbA1C?

Answer 38

* Associated with the **N-terminal valine residue of the B-chain** * Linear relationship * Irreversible reaction

Question 39

What are the 4 limitations to using HbA1c as a marker?

Answer 39

* **Erythropoiesis** * Increased HbA1c: * Iron * Vitamin B12 deficiency * Decreased erythropoiesis * Decreased HbA1c: * Administration of erythropoietin / iron / vitamin B12 * Reticulocytosis * Chronic liver disease * **Altered Haemoglobin** * Variable HbA1c: * Genetic or chemical alterations in haemoglobin: * Haemoglobinopathies * HbF * Methaemoglobin * **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 * **Erythrocyte destruction** * Increased HbA1c - Increased erythrocyte lifespan: * Splenectomy * Decreased HbA1c - Decreased erythrocyte lifespan: * Haemoglobinopathies * Splenomegaly * Rheumatoid arthritis * Drugs such as antiretrovirals, ribavirin and dapsone

Question 40

What are the acute complications of T1DM?

Answer 40

* Diabetic ketoacidosis * Uncontrolled hyperglycaemia * Hypoglycaemia

Question 41

How is diabetic ketoacidosis diagnosed (4)?

Answer 41

* pH < 7.3 * Ketones increased (urine or capillary blood) * HCO₃^- < 15 mmol/L * Glucose > 11 mmol/L

Question 42

How is hypoglycaemia diagnosed?

Answer 42

Blood glucose < 3.6 mmol

Question 43

What are the risk of hypoglycaemia (5)?

Answer 43

* **Seizure** / **coma** / **death** (dead in bed) * Impacts on **emotional well-being** * Impacts on **driving** * Impacts on **day-to-day function** * Impacts on **cognition**

Question 44

What are the risk factors of hypoglycaemia (5)?

Answer 44

* **Exercise** * **Missed meals** * **Inappropriate insulin** regime * **Alcohol** intake * **Lower HbA1c**

Question 45

What is problematic hypoglycaemia (4)?

Answer 45

* **Excessive frequency** * **Impaired awareness** (unable to detect low blood glucose) * **Nocturnal** hypoglycaemia * **Recurrent severe** hypoglycaemia

Question 46

What are the strategies to support problematic hypoglycaemia (5)?

Answer 46

* Indication for **insulin-pump therapy** (CSII) * May **try different insulin analogues** * Revisit carbohydrate counting / structured **education** * **Behavioral psychology** support * **Transplantation**

Question 47

What is the acute management of hypoglycaemia? ## Footnote Different at: * Alert & Orientated * Drowsy / confused but swallow intact * Unconscious or concerned about swallow

Answer 47