🧪Endocrinology🧪 - Type 1 Diabetes Mellitus Flashcards
What is type 1 diabetes?
An autoimmune condition where insulin secreting beta-cells are attacked and destroyed
What are the consequences of T1DM?
Partial/complete insulin deficiency, leading to hyperglycaemia
Life-long insulin treatment
What is LADA?
Latent autoimmune diabetes in adults
Autoimmune diabetes leading to insulin deficiency can present later in life
What is diabetic ketoacidosis?
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
What is monogenic diabetes?
Some rare forms of diabetes result from mutations or changes in a single gene - called monogenic
Can present as T1/T2DM
What can trigger a presentation of diabetes?
Diabetes may present following pancreatic damage or another endocrine disease
What ages can T1DM present?
Usually childhood/early adulthood
Can present throughout entire adult life
Challenges arise trying to distinguish adult-onset T1DM vs much more common T2DM
How is Insulin produced?
Pro-Insulin is cleaved into insulin and C-peptide
What are the first stages of T1DM development?
Genetic predisposition, then there is a potential precipitating event
What is the series of events after a potential precipitating event?
Overt immunological abnormalities - normal insulin release
Progressive loss of insulin release - glucose still normal
Overt diabetes - C-peptide still present
No C-peptide present
What happens to the mass of beta-cells in the pancreases as each stage of the progression of T1DM occurs?
It continually declines
Why is the immune aspect of T1DM specifically highly clinically relevant?
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)
What immunological defects lead to T1DM?
Presence of autoreactive CD4+ T lymphocytes
Exacerbation by pro-inflammatory cytokines
Defects in T-reg cells that fail to suppress the autoimmunity
How do autoreactive CD4+ cells lead to the destruction of beta-cells?
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
Are all beta-cells destroyed in all cases of T1DM?
No
Some people with T1DM have some beta-cells, small amount of insulin production
Not enough to negate need for insulin therapy however
Which HLA-DR alleles have an effect on genetic susceptibility to T1DM?
DR1-DR9
T1DM and T2DM are polygenic disorders, what does this mean?
Multiple tiny changes in a large number of genes
Which gene can often be used to measure genetic susceptibility?
HLA-DR allele
What does the DR1 mutation in the HLA-DR allele mean for risk level of T1DM?
Slight risk
What does the DR2 mutation in the HLA-DR allele mean for risk level of T1DM?
Protective
What does the DR3 mutation in the HLA-DR allele mean for risk level of T1DM?
Significant risk
What does the DR4 mutation in the HLA-DR allele mean for risk level of T1DM?
Significant risk
What does the DR5 mutation in the HLA-DR allele mean for risk level of T1DM?
Slight risk
What does the DR6 mutation in the HLA-DR allele mean for risk level of T1DM?
Neutral/protective
What does the DR7 mutation in the HLA-DR allele mean for risk level of T1DM?
Protective
Risk in African descent
What does the DR8 mutation in the HLA-DR allele mean for risk level of T1DM?
Neutral/slight risk
What does the DR9 mutation in the HLA-DR allele mean for risk level of T1DM?
Risk in far east Asian descent
What is the significance of environmental factors in T1DM prevelance?
Multiple factors are implicated, causality has not been established
Which factors have been implicated with T1DM?
Enteroviral infections
Cow’s milk protein exposure
Seasonal variation
Changes in microbiota
What can be detected in the sera of people with T1DM that can confirm a diagnosis?
Pancreatic autoantibodies
The presence of what substances is now recommended for T1DM diagnosis?
Insulin antibodies (IAA)
Glutamic acid decarboxylase antibodies (GAD-65)
Insulinoma-associated-2 antibodies (IA-2)
Zinc-transporter 8 (ZnT8)
What are the symptoms of T1DM?
Polyuria
Nocturia
Polydipsia
Blurring of vision
Recurrent infections (e.g. thrush)
Weight loss
Fatigue
What are the signs of T1DM?
Dehydration
Cachexia
Hyperventilation
Smell of ketones
Glycosuria
Ketonuria
What are the effects of insulin?
Stimulates protein synthesis
Decreases hepatic glucose output
Inhibits lipolysis
What are the consequences of insulin deficiency?
Increased proteinolysis (so more AAs)
Increased hepatic glucose output
Increased lipolysis (and so glycerol and NEFAs)
How are ketone bodies produced?
Fatty Acyl-CoA in liver
Converted to acetoacetate
Then acetone + 3 OH-B
Leaves the liver as ketone bodies
What are the aims of treatment for T1DM?
Maintain glucose levels, without excessive hypoglycaemia
Restore a physiological insulin profile
Prevent acute metabolic decompensation
Prevent microvascular and macrovascular complications
What are the acute complications of hyperglycaemia (in the context of diabetes)?
Diabetic ketoacidosis
What are the chronic complications of hyperglycaemia (in the context of diabetes)?
Microvascular:
Retinopathy
Neuropathy
Nephropathy
Macrovascular:
Ischaemic heart disease
Cerebrovascular disease
Peripheral vascular disease
Outline the managements for T1DM
Insulin Treatment
Dietary support / structured educations
Technology
Transplantation
Type 1 diabetes is a condition that is ‘self-managed’
What are the main features of a physiological insulin profile?
What 2 different types of insulin can be given?
With meals (short/quick-acting insulin)
Background (long-acting/basal)
What is given as a short-acting insulin?
Human insulin – exact molecular replicate of human insulin (actrapid)
Insulin analogue (Lispro, Aspart, Glulisine)
What is given as a long-acting insulin?
Bound to zinc or protamine (Neutral Protamine Hagedorn, NPH)
Insulin analogue (Glargine, Determir, Degludec)
What is a typical insulin routine?
Basal bolus regime
3x Daily - short acting - with meals
1x daily - long acting
Outline insulin pump therapy
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
What are the principles of the dietary advice for T1DM?
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
What are the 2 options for transplantation to treat T1DM?
Islet cells transplants
Simultaneous pancreas & kidney transplants
Outline islet cell transplants
Isolate human islets from pancreas of deceased donor
Transplant into hepatic portal vein
Why is a pancreas simultaneously transplanted with kidneys?
Better survival of pancreas graft when transplanted with kidneys
What is the biggest drawback for both transplantation options to treat T1DM?
Both require life-long immunosuppression
How ca glucose levels be monitored?
Capillary (finger prick) blood glucose monitoring
Continuous glucose monitoring (restricted availability)
Outline HbA1c
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
Why is HbA1c flawed?
Other factors can lead to increased HbA1c
What is used to guide insulin doses?
Using self-monitoring of blood glucose results at home and HbA1c results every 3-4 months
Based on results, increase or decrease insulin doses
What are the acute complications from T1DM?
Diabetic ketoacidosis
Uncontrolled hyperglycaemia
Hypoglycaemia
Outline diabetic ketoacidosis as a consequence of diabetes
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
How can diabetic ketoacidosis be diagnosed?
pH <7.3
Ketones increased (urine or capillary blood)
HCO3- <15 mmol/L
Glucose >11 mmol/L
What is the definition of hypoglycaemia?
Blood glucose ,3.6mmol/L (variable)
What is the definition of severe hypoglycaemia?
Any hypoglycaemic event requiring 3rd party assistance
When does hypoglycaemia become problematic?
Excessive frequency
Impaired awareness (unable to detect low blood glucose)
Nocturnal hypoglycaemia
Recurrent severe hypoglycaemia
What are the risks associated with hypoglycaemia?
Seizure / coma/ death (dead in bed)
Impacts on emotional well-being
Impacts on driving
Impacts on day to day function
Impacts on cognition
What may put someone with T1DM at risk of hypoglycaemia?
Exercise
Missed meals
Inappropriate insulin regime
Alcohol intake
Lower HbA1c
Lack of training around dose-adjustment for meals
What strategies can be used to support problematic hypoglycaemia?
Indication for insulin-pump therapy (CSII)
May try different insulin analogues
Revisit carbohydrate counting / structured education
Behavioral psychology support
Transplantation
What is used for the acute management of hypoglycaemia when someone is alert and orientated?
What is used for the acute management of hypoglycaemia when someone is Drowsy / confused but swallow intact?
What is used for the acute management of hypoglycaemia when someone is Unconscious or concerned about swallow?
