🧪Endocrinology🧪 - Type 1 Diabetes Mellitus

Question 1

What is type 1 diabetes?

Answer 1

An autoimmune condition where insulin secreting beta-cells are attacked and destroyed

Question 2

What are the consequences of T1DM?

Answer 2

Partial/complete insulin deficiency, leading to hyperglycaemia
Life-long insulin treatment

Question 3

What is LADA?

Answer 3

Latent autoimmune diabetes in adults
Autoimmune diabetes leading to insulin deficiency can present later in life

Question 4

What is diabetic ketoacidosis?

Answer 4

Cells (particularly hepatocytes) start making ketones as alternative fuel source due to lack of glucose (can’t enter from bloodstream), leads to ketoacidosis - acutely unwell patient
Usually sign of T1DM, but can also occur in T2DM

Question 5

What is monogenic diabetes?

Answer 5

Some rare forms of diabetes result from mutations or changes in a single gene - called monogenic
Can present as T1/T2DM

Question 6

What can trigger a presentation of diabetes?

Answer 6

Diabetes may present following pancreatic damage or another endocrine disease

Question 7

What ages can T1DM present?

Answer 7

Usually childhood/early adulthood
Can present throughout entire adult life
Challenges arise trying to distinguish adult-onset T1DM vs much more common T2DM

Question 8

What precursor molecule does insulin come from?

Answer 8

Pro-Insulin is cleaved into insulin and C-peptide

Question 9

What are the first stages of T1DM development?

Answer 9

Genetic predisposition, then there is a potential precipitating event

Question 10

What is the series of events after a potential precipitating event for the development of T1DM?

Answer 10

Overt immunological abnormalities - normal insulin release
Progressive loss of insulin release - glucose still normal
Overt diabetes - C-peptide still present
No C-peptide present

Question 11

What happens to the mass of beta-cells in the pancreases as each stage of the progression of T1DM occurs?

Answer 11

It continually declines

Question 12

Why is the immune aspect of T1DM specifically highly clinically relevant?

Answer 12

Increased prevalence of other autoimmune disease
Risk of autoimmunity in relatives
More complete destruction of beta-cells (compared to infection etc…)
Immune modulation offers possibility of future novel treatments (none in existence yet)

Question 13

What immunological defects lead to T1DM?

Answer 13

Presence of autoreactive CD4+ T lymphocytes
Exacerbation by pro-inflammatory cytokines
Defects in T-reg cells that fail to suppress the autoimmunity

Question 14

How do autoreactive CD4+ cells lead to the destruction of beta-cells?

Answer 14

Auto-antigens presented to autoreactive CD4+ T lymphocytes
CD4+ cells active CD8+ cells
CD8+ cells travel to islets and lyse beta-cells
Exacerbated by release of pro-inflammatory cytokines

Question 15

Are all beta-cells destroyed in all cases of T1DM?

Answer 15

No
Some people with T1DM have some beta-cells, small amount of insulin production
Not enough to negate need for insulin therapy however

Question 16

Which HLA-DR alleles have an effect on genetic susceptibility to T1DM?

Answer 16

DR1-DR9

Question 17

T1DM and T2DM are polygenic disorders, what does this mean?

Answer 17

Multiple tiny changes in a large number of genes

Question 18

Which gene can often be used to measure genetic susceptibility?

Answer 18

HLA-DR allele

Question 19

What does the DR1 mutation in the HLA-DR allele mean for risk level of T1DM?

Answer 19

Slight risk

Question 20

What does the DR2 mutation in the HLA-DR allele mean for risk level of T1DM?

Answer 20

Protective

Question 21

What does the DR3 mutation in the HLA-DR allele mean for risk level of T1DM?

Answer 21

Significant risk

Question 22

What does the DR4 mutation in the HLA-DR allele mean for risk level of T1DM?

Answer 22

Significant risk

Question 23

What does the DR5 mutation in the HLA-DR allele mean for risk level of T1DM?

Answer 23

Slight risk

Question 24

What does the DR6 mutation in the HLA-DR allele mean for risk level of T1DM?

Answer 24

Neutral/protective

Question 25

What does the DR7 mutation in the HLA-DR allele mean for risk level of T1DM?

Answer 25

Protective Risk in African descent

Question 26

What does the DR8 mutation in the HLA-DR allele mean for risk level of T1DM?

Answer 26

Neutral/slight risk

Question 27

What does the DR9 mutation in the HLA-DR allele mean for risk level of T1DM?

Answer 27

Risk in far east Asian descent

Question 28

What is the significance of environmental factors in T1DM prevelance?

Answer 28

Multiple factors are implicated, causality has not been established

Question 29

Which factors have been implicated with T1DM?

Answer 29

Enteroviral infections Cow's milk protein exposure Seasonal variation Changes in microbiota

Question 30

What can be detected in the sera of people with T1DM that can confirm a diagnosis?

Answer 30

Pancreatic autoantibodies

Question 31

The presence of what substances is now recommended for T1DM diagnosis?

Answer 31

Insulin antibodies (IAA) Glutamic acid decarboxylase antibodies (GAD-65) Insulinoma-associated-2 antibodies (IA-2) Zinc-transporter 8 (ZnT8)

Question 32

What are the symptoms of T1DM?

Answer 32

Polyuria Nocturia Polydipsia Blurring of vision Recurrent infections (e.g. thrush) Weight loss Fatigue

Question 33

What are the signs of T1DM?

Answer 33

Dehydration Cachexia Hyperventilation Smell of ketones Glycosuria Ketonuria

Question 34

What are the effects of insulin?

Answer 34

Stimulates protein synthesis Decreases hepatic glucose output Inhibits lipolysis

Question 35

What are the consequences of insulin deficiency?

Answer 35

Increased proteinolysis (so more AAs) Increased hepatic glucose output Increased lipolysis (and so glycerol and NEFAs)

Question 36

How are ketone bodies produced?

Answer 36

Fatty Acyl-CoA in liver Converted to acetoacetate Then acetone + 3 OH-B Leaves the liver as ketone bodies

Question 37

What are the aims of treatment for T1DM?

Answer 37

Maintain glucose levels, without excessive hypoglycaemia Restore a physiological insulin profile Prevent acute metabolic decompensation Prevent microvascular and macrovascular complications

Question 38

What are the acute complications of hyperglycaemia (in the context of diabetes)?

Answer 38

Diabetic ketoacidosis

Question 39

What are the chronic complications of hyperglycaemia (in the context of diabetes)?

Answer 39

Microvascular: Retinopathy Neuropathy Nephropathy Macrovascular: Ischaemic heart disease Cerebrovascular disease Peripheral vascular disease

Question 40

Outline the managements for T1DM

Answer 40

Insulin Treatment Dietary support / structured educations Technology Transplantation Type 1 diabetes is a condition that is ‘self-managed’

Question 41

What are the main features of a physiological insulin profile?

Answer 41

Question 42

What 2 different types of insulin can be given?

Answer 42

With meals (short/quick-acting insulin) Background (long-acting/basal)

Question 43

What is given as a short-acting insulin?

Answer 43

Human insulin – exact molecular replicate of human insulin (actrapid) Insulin analogue (Lispro, Aspart, Glulisine)

Question 43

What is given as a long-acting insulin?

Answer 43

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

Question 44

What is a typical insulin routine?

Answer 44

Basal bolus regime 3x Daily - short acting - with meals 1x daily - long acting

Question 45

Outline insulin pump therapy

Answer 45

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 46

What are the principles of the dietary advice for T1DM?

Answer 46

Dose adjustment for carbohydrate content of food. All people with type 1 diabetes should receive training for carbohydrate counting Where possible, substitute refined carbohydrate containing foods

Question 46

What are the 2 options for transplantation to treat T1DM?

Answer 46

Islet cells transplants Simultaneous pancreas & kidney transplants

Question 47

Outline islet cell transplants

Answer 47

Isolate human islets from pancreas of deceased donor Transplant into hepatic portal vein

Question 48

Why is a pancreas simultaneously transplanted with kidneys?

Answer 48

Better survival of pancreas graft when transplanted with kidneys

Question 49

What is the biggest drawback for both transplantation options to treat T1DM?

Answer 49

Both require **life-long immunosuppression**

Question 50

How can glucose levels be monitored?

Answer 50

Capillary (finger prick) blood glucose monitoring Continuous glucose monitoring (restricted availability)

Question 51

Outline HbA1c

Answer 51

Reflects last 3 months (red blood cell lifespan) of glycaemia Biased to the 30 days preceding measurement Glycated NOT glycosylated (enzymatic) Therefore linear relationship Irreversible reaction

Question 52

Why is HbA1c flawed?

Answer 52

Other factors can lead to increased HbA1c

Question 53

What is used to guide insulin doses?

Answer 53

Using self-monitoring of blood glucose results at home and HbA1c results every 3-4 months Based on results, increase or decrease insulin doses

Question 54

What are the acute complications from T1DM?

Answer 54

Diabetic ketoacidosis Uncontrolled hyperglycaemia Hypoglycaemia

Question 55

Outline diabetic ketoacidosis as a consequence of diabetes

Answer 55

Can be a presenting feature of new-onset type 1 diabetes Occurs in those with established T1DM Acute illness Missed insulin doses Inadequate insulin doses Life-threatening complication Can occur in any type of diabetes

Question 56

How can diabetic ketoacidosis be diagnosed?

Answer 56

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

Question 57

What is the definition of hypoglycaemia?

Answer 57

Blood glucose ,3.6mmol/L (variable)

Question 58

What is the definition of severe hypoglycaemia?

Answer 58

Any hypoglycaemic event requiring 3rd party assistance

Question 59

When does hypoglycaemia become problematic?

Answer 59

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

Question 60

What are the risks associated with hypoglycaemia?

Answer 60

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

Question 61

What may put someone with T1DM at risk of hypoglycaemia?

Answer 61

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

Question 62

What strategies can be used to support problematic hypoglycaemia?

Answer 62

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

Question 63

What is used for the acute management of hypoglycaemia when someone is alert and orientated?

Answer 63

Question 64

What is used for the acute management of hypoglycaemia when someone is Drowsy / confused but swallow intact?

Answer 64

Question 65

What is used for the acute management of hypoglycaemia when someone is Unconscious or concerned about swallow?

Answer 65