3.15 - Type 1 diabetes Flashcards
1
Q
What is type 1 diabetes?
A
- autoimmune condition in which insulin-producing beta cells in the pancreas are attacked and destroyed by the immune system
- the result is a partial or complete deficiency of insulin production, which results in hyperglycaemia
2
Q
What does the hyperglycaemia caused by T1DM require to treat?
A
Life-long insulin treatment
3
Q
What is a flowchart of T1DM like?
A
environmental trigger / genetic risk –> autoimmune destruction of islets –> absolute insulin deficiency –> hyperglycaemia
4
Q
What is a flowchart of T2DM like?
A
obesity / genetic risk –> insulin resistance –> relative insulin deficiency –> hyperglycaemia
5
Q
What is the overlap between T1DM and T2DM presentation?
A
- T1DM usually presents at a younger age, but autoimmune diabetes leading to insulin deficiency can present later in life - latent autoimmune diabetes in adults (LADA)
- T2DM may present in childhood
- diabetic ketoacidosis can be a feature of T2DM (usually feature of T1DM)
- monogenic diabetes can present phenotypically as T1DM or T2DM (e.g. MODY, mitochondrial diabetes)
- diabetes may present following pancreatic damage or other endocrine disease
6
Q
Why is the fact that T1DM can develop in adults important?
A
- traditionally thought to be a condition of childhood/early adulthood
- now good evidence that it can present throughout every decade of life
- clinicians are faced with a challenge of trying to differentiate adult-onset T1DM from the much larger number of cases of T2DM
7
Q
Describe the graph showing the stages of development of T1DM?
A
- early gestation - beta cell mass increases
- after birth, beta cell mass is fixed
- some people have a genetic predisposition
- a potentially precipitating event happens (e.g. viral illness), causing beta cell mass to decline
- there is initially an asymptomatic phase (cannot tell you are developing T1DM):
- overt immunological abnormalities; normal insulin release
- progressive loss of insulin release; glucose normal
- overt diabetes; C-peptide (insulin) present
- last stage, no C-peptide (insulin) present
8
Q
What molecule do we use to measure insulin?
A
C-peptide (proinsulin made by beta cell –> insulin + C-peptide)
9
Q
Why do we measure C-peptide instead of insulin (T1DM)?
A
- easier to measure as insulin has short half life and undergoes hepatic first pass metabolism
- also patients are on insulin anyway so you would not be able to tell how much insulin from injection and how much from pancreas
10
Q
What are the stages of the immune response in T1DM?
A
- genetic risk (15x increased risk in those with relatives)
- immune activation - beta cells attacked
- immune response - development of single autoantibody
- stage 1: normal blood sugar, >2 autoantibodies
- stage 2: abnormal blood sugar, >2 autoantibodies
- stage 3: clinical diagnosis, >2 autoantibodies
- stage 4: long-standing T1D, no autoantibodies
11
Q
Why does the immune response stop in long-standing T1DM?
A
Immune attack stops/reduced as all beta cells are destroyed –> quiescent stage (no infiltration of immune cells into islet) = seronegativity
12
Q
Why is the immune basis of T1DM important?
A
- increased prevalence of other autoimmune disease too
- risk of autoimmunity in relatives
- more complete destruction of beta cells
- autoantibodies can be useful clinically
- immune modulation offers the possibility of novel treatments (not there yet)
13
Q
Is there a defect in the innate or adaptive immune response in T1DM?
A
Defect in both innate and adaptive response
14
Q
What is the mechanism of the autoimmune destruction of beta cells in T1DM?
A
- first step is presentation of auto-antigen on beta cells to autoreactive CD4+ T lymphocytes
- CD4+ cells activate CD8+ T lymphocytes
- CD8+ cells travel to islets and lyse beta cells expressing auto-antigen
- exacerbated by release of pro-inflammatory cytokines
- underpinned also by defects in regulatory T cells that fail to suppress autoimmunity
Stained image shows infiltration of immune cells into islet
15
Q
Are all beta cells destroyed in T1DM?
A
- not necessarily - some people with T1DM continue to produce small amounts of insulin (these patients have fewer complications)
- not enough to negate the need for insulin therapy
16
Q
What gene (and allele) mediates genetic susceptibility to T1DM?
A
HLA-DR allele (HLA = human leukocyte antigen)
17
Q
Is T1DM polygenic or monogenic?
A
Polygenic
18
Q
What environmental factors are there that affect T1DM?
A
Multiple factors implicated but causality not been established:
- enteroviral infections
- cow’s milk protein exposure
- seasonal variation
- changes in microbiota
19
Q
What are pancreatic auto-antibodies?
A
- detectable in the sera of people with T1DM at diagnosis
- now recommended for diagnosis in NICE guidelines:
- insulin autoantibodies (IAA)
- glutamic acid decarboxylase (GAD-65) - widespread neurotransmitter
- insulinoma-associated-2 autoantibodies (IA-2)
- zinc-transporter 8 (ZnT8)
20
Q
What are the symptoms of T1DM? (7)
A
- polyuria (excessive urination)
- nocturia
- polydipsia (excessive thirst)
- blurring of vision
- recurrent infections e.g. thrush
- weight loss
- fatigue
21
Q
What are the signs of T1DM? (6)
A
- dehydration
- cachexia (extreme weight loss and muscle wasting)
- hyperventilation
- smell of ketones
- glycosuria
- ketonuria
22
Q
What is the diagnosis of T1DM based on?
A
- clinical features and presence of ketones
- in some cases pancreatic autoantibodies/C-peptide may be measured
23
Q
What does a lack of insulin do to the body?
A
- proteinolysis of muscles –> AAs
- increased HGO from liver
- lipolysis of fat cells into glycerol and NEFA
24
Q
What happens to the NEFAs in the liver?
In the absence of insulin, fat cells undergo lipolysis –> NEFA + glycerol
A
Undergo oxidation to produce three species: acetyl CoA, acetoacetate, acetone + 3 OH-B - these are ketone bodies which build up and cause ketoacidosis (acidic blood if left untreated)
25
What do people with T1DM require?
Insulin for life
26
What are the aims of treatment in T1DM?
- maintain glucose levels without excessive hypoglycaemia
- restore a close to physiological insulin profile
- prevent acute metabolic decompensation (DKA)
- prevent microvascular and macrovascular complications
27
What is an acute complication of hyperglycaemia?
Diabetic ketoacidosis
28
What are the chronic microvascular complications of hyperglycaemia? (3)
- retinopathy (blood vessels in eye)
- neuropathy (nerves in feet)
- nephropathy (kidneys)
29
What are the chronic macrovascular complications of hyperglycaemia? (3)
- ischaemic heart disease
- cerebrovascular disease (stroke)
- peripheral vascular disease
30
What is a complication of the insulin treatment itself (iatrogenic) in T1DM?
Hypoglycaemia
31
How do we manage T1DM?
- insulin treatment
- dietary support/structured education
- technology e.g. pump
- transplantation (pancreas / islet cell)
- T1DM is a 'self-managed' condition
32
What does a physiological insulin profile in a normal person look like?
- plasma insulin level peaks at every meal
- prandial peak has two phases - one main splurge of insulin, another later on to clean up any left over glucose
- basal insulin has a flat profile
- insulin is never completely suppressed
33
Why is insulin never completely suppressed in a physiological insulin profile?
You start forming ketones, breaking down fat and muscle --> DKA --> death
34
What are the two types of insulin given to patients?
- with meals (short/quick-acting/bolus insulin)
- background (long-acting/basal insulin)
35
What are examples of short/quick-acting insulin?
- human insulin - exact molecular replicate of human insulin (actrapid)
- insulin analogue (Lispro, Aspart, Glulisine)
36
What are examples of long-acting/basal insulin?
- bound to zinc or protamine (Neutral Protamine Hagedorn, NPH)
- insulin analogue (Glargine, Determir, Degludec)
37
How does the basal-bolus insulin regime work?
- patient wakes up and takes long-acting insulin
- they take short-acting insulin three times a day with meals
38
What is another option of the basal-bolus insulin regime?
- actrapid three times a day with meals
- twice daily intermediate acting insulin
39
What are we not able to master with the basal-bolus regime?
We are trying to replicate the physiological insulin profile of a normal person but have not mastered the basal flat level or the dual prandial peaks
40
What does insulin pump therapy do?
- 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 across the hour of every day
- actively bolus for meals
41
What are the advantages of insulin pump therapy? (3)
- variable basal rates
- extended boluses
- greater flexibility
42
What do NICE guidelines say about dietary advice to those with T1DM?
All people with T1DM should be offered a Structural Education Programme e.g. DAFNE (dose adjustment for normal eating) - 5 day course on skills and training in self-management
43
What are the principles of dietary advice for those with T1DM?
- dose adjustment for carbohydrate content of food
- all people with T1DM should receive training for carb counting
- where possible, substitute refined carb containing foods (sugary/high glycaemic index) with complex carbs (starchy/low glycaemic index)
44
What is a closed loop system/artificial pancreas?
- real-time continuous glucose sensor detects a change in glucose
- algorithm to use glucose value to calculate insulin requirement
- insulin pump delivers calculated insulin
- available on NHS
45
What are the two types of transplantation for T1DM management?
- islet cell transplant
- simultaneous pancreas and kidney transplants
46
What happens in an islet cell transplant?
- isolate human islets from pancreas of deceased donor
- transplant into hepatic portal vein
47
What is the advantage of doing a simultaneous pancreas and kidney transplant?
Better survival of pancreas graft when transplanted with kidneys
48
What do both transplantation methods require?
Life-long immunosuppression
49
What is the aim of transplantation methods to manage T1DM?
- try and restore physiological insulin production to the extent that insulin can be stopped
- even if incomplete, often results in better control
50
What are the limitations of transplantation? (3)
- availability of donors
- complications of life-long immunosuppression
- some fail = back to insulin supplements
51
How do we monitor glucose levels? (2)
- capillary (finger prick) blood glucose monitoring
- continuous glucose monitoring (restricted availability, NICE guidelines)
52
What does glycated haemoglobin (HbA1c) show?
- reflects last 3 months (RBC lifespan) of glycaemia
- biased to the 30 days preceding measurement
- glycated not glycosylated (enzymatic)
- therefore linear relationship between how much glucose we have and how high HbA1c is
- irreversible reaction
53
What happens biologically to show relationship between BGC and HbA1c?
- when Hb comes into contact with glucose, glucose joins to N-terminal valine residue in beta chain
- produces a Schiff base (fast hrs, reversible)
- after time this produces an Amadori product (HbA1c) - slow, days
- irreversible
54
When is HbA1c not perfect?
When certain things affect RBC turnover:
- erythropoiesis
- altered Hb
- glycation
- erythrocyte destruction
55
What is used to guide insulin doses?
- use self-monitoring of blood glucose results at home and HbA1c results every 3-4 months
- based on results, increase or decrease doses
56
What are the acute complications from T1DM? (3)
- diabetic ketoacidosis
- uncontrolled hyperglycaemia
- hypoglycaemia
57
When can diabetic ketoacidosis present?
- can be a presenting feature of new-onset T1DM
- occurs in those with established T1DM (indicates acute illness, missed/inadequate insulin doses esp long-acting)
- can occur in any type of diabetes
- life-threatening complication
## Footnote
Treatment: IV fluids 0.9% NaCl --> insulin infusion +/- K+ supplementation
58
How do we diagnose diabetic ketoacidosis?
- pH <7.3
- ketones increased (urine/capillary blood)
- HCO3- <15mmol/L
- glucose >11mmol/L
59
What is the case with hypoglycaemia with T1DM?
- to some extent an inevitable feature of the self-management of T1DM
- may become debilitating with increased frequency
- numerical definition is <3.6 mmol/L
60
What is severe hypoglycaemia?
Any event requiring third party assistance
61
What are the adrenergic symptoms of hypoglycaemia? (4)
- tremors
- palpitations
- sweating
- hunger
62
What are the neuroglycopenic symptoms of hypoglycaemia? (4)
- somnolence (drowsy)
- confusion
- incoordination
- seizures, coma
63
When does hypoglycaemia become a problem? (4)
- excessive frequency
- recurrent severe hypoglycaemia
- nocturnal hypoglycaemia
- impaired awareness (unable to detect low blood glucose)
64
What are the risks of hypoglycaemia? (5)
- seizure / coma / death
- impact on emotional wellbeing
- impacts on driving
- impacts on day to day function
- impacts on cognition
65
Is HbA1c useful at identifying hypoglycaemia?
HbA1c itself may not be useful in identifying hypoglycaemia since it looks at last 3 months altogether
66
What are risk factors for T1DM people for hypoglycaemia? (6)
- exercise
- missed meals
- lack of training around dose-adjustment for meals
- inappropriate insulin regime
- alcohol intake
- lower HbA1c
67
What are strategies to support problematic hypoglycaemia? (5)
- indication for insulin pump therapy (CSII)
- try different insulin analogues
- transplantation
- revisit carb counting/structured education
- behavioural psychology support
68
What is the acute management of hypoglycaemia?
- if alert and oriented - oral carbs; rapid acting (juice/sweets); longer acting (e.g. sandwich)
- if drowsy/confused but swallow intact - buccal glucose e.g. Hypostop/glucogel; complex carb
- unconscious/concerned about swallow - IV access; 20% glucose IV
- deteriorating/refractory/insulin-induced/difficult IV access: **consider IM/SC 1mg glucagon**
69
What is the language matters movement with T1DM?
Use language that empowers people with T1DM rather than disengage them
Phrases to avoid:
- poor control
- not coping
- how's your control
- they're diabetic
- you can't eat that
- diabetes sufferer
- poor compliance
Empowering language:
- person living with diabetes
- sounds like your diabetes has been challenging to manage recently
- what are your thoughts on your recent glucose levels
- let's talk through different options and see what suits you
