1B type 1 diabetes mellitus Flashcards
Define type 1 diabetes
- Autoimmune condition where insulin-producing beta cells in pancreas are attacked and destroyed by immune system
- Results in partial or complete deficiency of insulin production leading to hyperglycaemia
What does this hyperglycaemia require to treat?
Life long insulin treatment
How is diabetes classified?
What is the overlap between type 1 and 2 diabetes presentation?
- Type 1 usually presents at more of a younger age, but autoimmune diabetes leading to insulin deficiency can present later in life (latent autoimmune diabetes in adults aka LADA)
- T2DM may present in children
- Diabetic ketoacidosis can be a feature of T2DM (usually a 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
Why is the fact that T1DM can develop in adults important?
- T1DM was traditionally thought to be a condition of childhood or early adulthood
- Now good evidence that it can present through every decade of life
- Clinicians are faced with a challenge of trying to differentiate adult-onset T1DM from the much larger numbers of cases of T2DM
Describe the stages of development of type 1 diabetes
- When you’re early in gestation, amount of beta cells does increase but when you’re born the number is fixed
- Let’s now take someone with a genetic predisposition
- A potential precipitating event happens, classically a viral illness, which causes beta cell mass to start to decline
- There is initially an asymptomatic phase, can’t tell you’re developing T1DM
- When you’ve lost large amount of beta cells, then you become hyperglycaemic
- At the last stage, there is no C-peptide present (which we measure instead of insulin for same reason as last year but also because these patients are on insulin anyway so you wouldn’t be able to tell how much insulin is from the injection and how much they’re making)
Describe this image of immune infiltration of islets
In early T1DM, there is a lot of infiltration of immune cells into islet (in red outline)
In long duration T1DM, there aren’t any/many immune cells to be seen- because the immune process is burnt out and has killed all the beta cells so whole thing has entered a quiescent stage
Why is the immune basis of T1DM important?
- Increased prevalence of other autoimmune diseases too
- Risk of autoimmunity in relatives
- More complete destruction of beta cells
How can the immune basis be used in treatment?
- Auto antibodies can be useful clinically
- Immune modulation offers the possibility of novel treatments but we aren’t there yet
What is the mechanism of the autoimmune destruction of beta cells in T1DM?
There is a defect in the innate and adaptive immune system
- 1st 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 the release of pro-inflammatory cytokines
- Underpinned also by defects in regulatory T cells that fail to suppress autoimmunity
Are all beta cells destroyed in T1DM?
- Not necessarily- some people with T1DM continue to produce small amounts of insulin- this is really good because these people have fewer complications compared to those who make no insulin
- Not enough to negate the need for insulin therapy
What does this graph show?
Graph below shows a lot of variance in amount of insulin produced in people with T1DM (every person here has it). Above red line is decent insulin production and black line is 0 production
What gene mediates genetic susceptibility to T1DM?
By HLA (human leukocyte antigen) area of genes
What does this genome-wide association study show?
HLA has the biggest odds ratio for having T1DM
Most genes are affecting immunity as well out of all mechanisms- people with T1DM have many small changes in various genes and immune system which leads to autoimmunity
T1DM is polygenic and not monogenic
What environmental factors are there that affect T1DM?
Multiple factors implicated but causality not been established
- Enteroviral infections
- Cow’s milk protein exposure
- Seasonal variation
- Changes in microbiota
What are the symptoms of T1DM?
- Excessive urination (polyuria)
- Nocturia
- Excessive thirst (polydipsia)
- Blurring of vision
- Recurrent infections e.g. thrush
- Weight loss
- Fatigue
What are the signs of T1DM?
- dehydration
- Hyperventilation
- Cachexia (extreme weight loss and muscle wasting)
- Smell of ketones
- Ketonuria
- Glycosuria
What is diagnosis of T1DM based on?
- Clinical features and presence of ketones
- In some cases pancreatic autoantibodies/C-peptide may be measured
What pancreatic auto-antibodies could we measure in T1DM patients?
- Insulin antibodies (IAA)
Antibodies against these are proteins in the beta cell:
- Insulinoma-associated-2 autoantibodies (IA-2A)
- Glutamic acid decarboxylase (GADA)- widespread neurotransmitter
- Zinc-transporter 8 (ZnT8)
What does a lack of insulin cause in the body?
- Proteinolysis of muscles into amino acids
- Increased hepatic glucose output from liver
- Lipolysis of fat cells into triglycerides and NEFA
What happens to the NEFAs in the liver?
Undergo oxidation to produce 3 species (acetyl CoA, acetoacetate and acetone + 3 OH-B) → these are ketone bodies which build up and cause ketoacidosis
If left untreated, they make blood acidic
What are the aims of treatment in type 1 diabetes?
People with T1DM require insulin for life with the aim of:
- Maintain glucose levels without excessive hypoglycaemia
- Restore a close to physiological insulin profile
- Prevent acute metabolic decompensation
- Prevent microvascular and macrovascular complications
What are the types of complications of T1DM?
-
Acute
- Diabetic ketoacidosis
-
Chronic microvascular
- Retinopathy: blood vessels in retina affected
- Neuropathy: nerves in feet affected
- Nephropathy: kidneys affected
-
Chronic macrovascular
- Ischaemic heart disease
- Cerebrovascular disease
- Peripheral vascular disease
What is a complication of the insulin treatment itself?
Hypoglycaemia
How do we manage T1DM?
- Insulin treatment
- Dietary support/structured educations
- Technology e.g. glucose pump
- Transplantation e.g. pancreas transplant or islet cell transplant
- T1DM is a ‘self-managed’ condition
Why is insulin never 0?
You’ll start forming ketones, breaking down fat and muscle
Why does the prandial peak have 2 phases?
When we eat, we have 1 main splurge of insulin, then another later on to clean up any left over glucose
What are the 2 types of insulin given to patients?
-
With meals (short/quick-acting insulin)
- Human insulin: exact molecular replicate of human insulin (actrapid)
- Insulin analogue (Lispro, Aspart, Glulisine)
-
Background (long-acting/basal)
- Bound to zinc or protamine (Neutral Protamine Hagedorn, NPH)
- Insulin analogue (Glargine, Determir, Degludec)
Describe a typical basal-bolus regime
- Person wakes up and takes long-acting insulin (main blue line- dotted blue lines are injections from previous and next day)
- We take short acting insulin 3 times a day with meals
Another diagram of a slightly different basal-bolus regime
We’re trying to replicate the physiological insulin profile of a normal person but we haven’t mastered the basal flat level or the dual peaks yet
What does an 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
What are the principles of the dietary advice?
- Dose adjustment for carb content of food
- Where possible, substitute refined carb containing foods (sugary/high glycaemic index) with complex carbs (starchy/low glycaemic index)
What is a closed loop/artificial pancreas?
- Real-time continuous glucose sensor detects a change in glucose
- Algorithm to use glucose value to calculate insulin requirement and insulin pump delivers calculated insulin
- These hybrid closed loop systems are available on the NHS
What issue is there with a closed loop/artificial pancreas?
There’s a 15 min delay when you eat between the glucose measured in the blood and glucose actually in the blood
The sensor detects 15 mins previous glucose levels
When eating the person needs to set insulin themselves
What are the 2 types of transplantation for T1DM treatment?
- Islet cell transplant
- Simultaneous pancreas and kidney transplants
What happens in islet cell transplant?
- Isolate human islets from pancreas of deceased donor
- Transplant into hepatic portal vein
What does an islet cell transplant require for management?
Life long immunosuppression
Why are both pancreas and kidney required for transplants?
Better survival of pancreas graft when transplanted with kidneys
Requires life-long immunosuppression
What is the aim of T1DM treatment?
Try to restore physiological insulin production to the extent that exogenous insulin can be stopped
Even if incomplete, often results in better control
What are the limitations of T1DM treatment?
- Availability of donors
- Complications of life-long immunosuppression
- Some of transplants do fail so patient goes back to insulin supplements
How do we monitor glucose levels?
- Capillary (finger prick) blood glucose monitoring
- Continuous glucose monitoring (restricted availability, NICE guidelines)
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 there’s a linear relationship between how much glucose we have and how high HbA1c is
What happens biologically for HbA1c test?
- When haemoglobin comes into contact with glucose, glucose joins to N-terminal valine residue in beta chain
- Causes a Schiff base
- Then after time this causes an Amadori Product (HbA1c)
- Irreversible reaction
When is HbA1c not the most accurate?
When certain things affect RBC turnover:
- Erythropoiesis
- Altered haemoglobin
- Glycation
- Erythrocyte destruction
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 insulin doses
What are the acute complications from T1DM?
- Diabetic ketoacidosis
- Uncontrolled hyperglycaemia
- Hypoglycaemia
When can diabetic ketoacidosis present?
- Can be a presenting feature of new-onset T1DM
- Occurs in those with established T1DM. Indicates:
- acute illness
- missed insulin doses: especially long acting one (very important for stopping diabetic ketoacidosis)
- inadequate insulin doses
- Can occur in any type of diabetes
- Life-threatening complication
How do we diagnose DKA?
Need to see these 3:
- pH <7.3, ketones increased (urine or capillary blood)
- HCO3- <15 mmol/L
- Glucose >11 mmol/L
What is the case with hypoglycaemia with T1DM?
- To some extent it’s an inevitable feature of the self-management of T1DM
- May become debilitating with increased frequency
- Numerical definition is <3.6 mmol/L
What is severe hypoglycaemia?
Any event requiring 3rd party assistance
Describe the symptoms of hypoglycaemia
When does hypoglycaemia become a problem?
- Excessive frequency
- Recurrent severe hypoglycaemia
- Nocturnal hypoglycaemia
- Impaired awareness (unable to detect low glucose)
Is HbA1c useful at identifying hypoglycaemia?
HbA1c itself may not be useful in identifying hypoglycaemia since it looks at last 3 months altogether
What are the risks of 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 are risk factors for T1DM people for hypoglycaemia?
- Exercise
- Missed meals
- Lack of training around dose-adjustment for meals
- Inappropriate insulin regime
- Alcohol intake
- Lower HbA1c
What are strategies to support problematic hypoglycaemia?
- Indication for insulin pump therapy (CSII)
- May try different insulin analogues
- Transplantation
- Revisit carb counting/structured education
- Behavioural psychology support
Table of acute management of hypoglycaemia
