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 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)
