Diabetes Type 1 Flashcards
What is diabetes mellitus? How many types are there?
Pathologically high plasma glucose (hyperglycemia)
Type 1 and Type 2
What is type 1 diabetes?
A metabolic disease involving insulin deficiency / insulin-dependent diabetes mellitus
What could caus T1 diabetes?
Malfunction of insulin production by the pancreas
What percentage of diabetes diagnoses accounts for T1 diabetes?
5-10%
When are most patients usually diagnosed?
First 2 decades of life; incidence reaches peak at 10-14 years of age
Describe the proposed linear beta cell decline hypothesis
- Interaction between susceptibility and protection genes and
the susceptibility genes dominate, thus triggering onset of diabetes - Linear beta-cell decline hypothesis –
most widely referenced model for type 1
diabetes - Some argue that type 1 disease
progression not linear; variable pace in
individual patients - Number of autoantibodies rather than
specificity important in disease
progression - At high end of genetic risk spectrum –
requirement for one or more
environmental triggers = low; β-cell mass
decreases anyway - Targeted destruction may go undetected
for years; first clinical symptoms
apparent only after majority of β–cells
destroyed
Name the steps of the pathogenesis model of type 1 diabetes
- genetic susceptibility
- trigger event
- active autoimmunity
- immune abnormality and loss of insulin secretion
- overt diabetes with few remaining pancreatic B-cells
- complete loss of pancreatic B-cells
Name the inherited susceptibility gene loci for type 1 diabetes
- HLA (Human Leukocyte Antigen)
region on chromosome 6 – crucial in development of type 1 diabetes - HLA class II genes – major genetic contributor e.g., DR3 and DR4 haplotypes; only 30-50% of Type 1 diabetes patients
- Most prevalent autoantibodies directed at 65 kDa isoform of glutamic acid decarboxylase (GAD65)
- Lesser predisposition – e.g., insulin gene region, interleukin-2 receptor-α gene
Describe what happens at “trigger event”
- Genes linked to immune function
- Environmental triggers act on system involving
immune dysregulation - Infiltration of immune cells into the pancreas
causing insulitis - Thus, a loss of beta cell mass
Environmental factors associated with type 1 diabetes - Factors starting decline of beta cells
- Viruses associated
- Some studies link viruses and dietary factors
Autoantibodies versus enteroviruses seasonal variation
(Finland) - Top graph = autoantibody investigation over 12
months - Seasonal variation towards end of year marker
of type 1 diabetes progression - Bottom graph: number of enterovirus infections
which spike as well - Not a causal relationship but a correlation
- Provides insights into effects of enteroviruses as
a potential environmental trigger
Gut microbiota and type 1 diabetes - Most environmental factors influence gut
microbiota which in close interaction with
immune system – potentially reshape it - Can increase gut permeability to allow for
passage of potentially diabetogenic
antigens and thus leading to islet-directed
autoimmunity - alterations in gut microbiome (diet,
breastfeeding, antibiotics) - This may affect immune system and play
into hypothesis of beta cell decline to
pathogenesis of type 1 diabetes - Ties into gut permeability
- Bacteria can leak into system
Environmental factors associated with type 1 diabetes - Enteroviruses – a prime candidate, specifically coxsackieviruses
- Conversely, rubella eliminated in wealthy countries but still rising incidence of type 1 diabetes
- Disturbed microbial balance in the intestine
- Cow’s milk – especially albumin component; the idea that early introduction of cow’s milk triggers
immune response - However, evidence to prove clear-cut cause & effect still lacking
- Factors are associations developing to hypothesis development
Describe what happens at “active autoimmunity”
- Beta cell mass starts to decline
- After initial inflammatory response T cells
recruited which attack host beta cells - This leads to apoptosis of beta cells
- There is also an appearance of autoantibodies
Describe what happens at “immune abnormality and loss of insulin secretion”
- Beta cell mass has dropped characterised by
loss of insulin secretion - First phase of insulin release diminished in
biphasic response - Glucose intolerance
Describe what happens at “overt diabetes with few remaining pancreatic B-cells”
- Functionality severely limited
Describe what happens at “complete loss of pancreatic B-cells”
- Accompanied by C peptide loss
- This can be used to measure the functionality
of the pancreatic beta cells
Suggest an alternative pathogenic model
What are the metabolic effects of t1 diabetes?
- Glucagon = dominant
- It is pronounced and chronic due
to type 1 diabetic condition - Breakdown of muscle protein is
facilitated and amino acids feed
into gluconeogenesis - Glycogenolysis results in glucose
production in liver and an output
of glucose from the liver - Low insulin reduced glucose
uptake hyperglycaemia - In adipocytes, lipolysis occurs and
FFA liberated - Higher FA in circulation moves to different sites in liver
- FA metabolism in liver contributes to ketone bodies
- Ketone body formation is dysregulated and the chronic increase results in ketoacidosis
- Low tissue availability but high plasma glucose levels – referred to as ‘’starvation in the midst of
plenty’’ - Low insulin: high glucagon: glucagon & catabolic effects predominate
- Thus increased breakdown of carbohydrates, proteins & fats – leads to hyperglycaemia,
hypertriglyceridemia, ketoacidosis & dehydration - Note that hyperglycaemia caused by decreased glucose uptake, glycogenolysis & gluconeogenesis
What are some clinical outcomes of t1 diabetes?
What are some major clinical symptoms of t1 diabetes?
- Glucose not taken into tissues resulting in constant appetite
- 3 P’s
What tests can be perfromed to diagnose t1 diabetes?
- Genetic screening – e.g., HLA loci, families with history
- Screen for autoantibodies – can fluctuate & even disappear
- Presence of autoreactive T-cells – not routinely assessed, lack of robust assays
- Assess β–cell mass – in vivo tools to improve; can use antibodies that bind β–cell surface & then
detect using imaging techniques - Determine plasma glucose (have to think about specificity and sensitivity), C-peptide values
What are current T1 diabetes therapies?
- Daily insulin injections (rapid-acting, long-acting insulin analogues)
* Regular monitoring of glucose levels
* Adjust insulin injections based on glucose responses
* Monitor meal intake and time injections are administered
* Closed-loop system (‘’artificial pancreas’’) –
continuous glucose monitors + insulin pumps used
together - Islet transplantation to treat type 1 diabetes
* 2/3 recipients
enjoyed insulin independence for 1 year after islet transplantation
* Islets prepared and transferred via a catheter
guided into portal vein of the liver
* However, long-term results not good; islet function
decreases over time; after 5 years only 10% patients remained independent of insulin
What are future t1 diabetes therapies?
Stem cells:
* Cells can be guided to produce pancreatic hormones and transplant cells into recipients
* Controlled culture conditions resulted in production of hormones after 3 days in culture
* D = cells started to produce C-peptide (pancreatic
morphology)
What are primary prevention strategies?
Individuals with genetic risk but no autoantibodies (primary prevention):
- Dietary modifications early in infancy e.g. use different baby formula.
These infants less likely to develop more autoantibodies vs. those on conventional formula
What are secondary prevention strategies?
Individuals with multiple autoantibodies but without hyperglycemia (secondary prevention):
- Insulin treatment – individuals with elevated autoantibodies display delayed diabetes onset (by 5 years)
