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Type 1 Diabetes
An organ-specific autoimmune disease, representing a…
Type 1 Diabetes
An organ-specific autoimmune disease, representing a failure of self-tolerance
PATHOGENESIS
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Immune Response
B Cells
- Autoreactive beta-cell specific BCs should be circulating in periphery
T Cells
- Beta-cell specific TCs (CD4+ and CD8+) circulate in periphery
- But they're hard to find as they don't secrete distinctive molecules
- Effector/memory phenotype instead of naive phenotype
- Pro-inflamm cytokines (IFNγ) instead of regulatory cytokines
- CD8+ count correlates with HLA Class I molecule count
Detect with
- TC Proliferation Assay
- MHC Tetramer Detection Assay
- Insulin C-peptide specific CD4+s detectable in peripheral blood
- In 61% of recent-onset T1D
Other Peptide epitopes
- GAD65
- IA-2
- ZnT8
- Proinsulin (exclusive)
- IGRP (exclusive)
- IAAP (exclusive)
- Chromogranin A
Insulitis
- Pathologic hallmark of T1D- immune cell infiltration of islets in PBCs
- Alpha cells are not affected
- Invasion is not homogenous, but heterogeneous
- Only 10-30% islets show insulitis at any time
- Detect by culturing + taking a response assay to measure TC activation
MANAGEMENT
Exogenous Insulin
Injections
- ≥ 4x day
- Rapid/Intermediate/Long acting OR Basal/Bolus (can be mixed)
- Emergency glucose source (lollies) for hypoglycaemic events
- Hard to mimic physiological release
- Keep glucose levels btwn 4-6 mmol/L
Requires lots of discipline, glucose level is v hard to control consistently
Monitoring Progress
- Measure HbA1c for 3-month average
- Aim for < 7%
- 8% or higher :arrow_right: risk of long-term complications is higher
Life expectancy has significantly improved after exogenous insulin was rolled out
Need to cater to
- Honeymoon phase
- Different meals
- Physical activity
- Illness
- Stress
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Tool Kit
For
- Monitoring glucose
- Having insulin
- Delivering insulin
- Having sugar
Sources
- Porcine/Bovine Insuline
- Requires immunosuppression
- Porcine Islets
- Requires immunosuppression + technology
- Cadaveric Donor Islets
- Could potentially share one pancreas among multiple patients
- iPSC
- Debatable ethics, but it's possible
- Need to prevent tumour growth from progenitors
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Treating Complications
Diabetic Ketoacidosis
Fluids, insulin, electrolytes (K+)
TREATMENT//CURE
Goal
- Fully independent of exogenous insulin, ie. replacing beta cells
- Improved quality of life, without long-term complications
Will require different immunotherapy combinations, and beta-cell replacement. Amount of each depends on stage of disease
Artificial Pancreas?
- Some improvement, but still needs more work
Cell Therapy?
- Need highly-functioning insulin-producing cells
- Need to protect implanted cells from immune (auto/alloimmune) response
- Need an optimal impantation site
Protective Encapsulation
- Actual implant is credit-card sized
- Material encapsulates the cells
- Need to make sure it doesn't get anaerobic because of the barrier
- Easily removable in case of complications
Islet Transplantation
- Transplanted in liver, mimicking insulin delivery to portal system. Can't put in pancreas
- Normally need >1 transplant to be independent of exogenous insulin
Immunosuppression
- Use collection of immunosuppressors to increase success chance of transplant
Pros
- Islet isolating is possible at multiple sites
- Independence from exogenous insulin achieved in ~50% patients after a year
- Regardless of independence, glycaemic control :arrow_up:
- Treats hypoglycaemia unawareness :arrow_right: no more severe hypo events
Cons
- Not enough organ donors
- Need immunosuppression
- Islet graft may eventually lose function
- $150,000 per transplant (no insurance cover) BUT apparently covered in AU, just not USA
BACKGROUND//NORMAL
Glucose Metabolism
INSULIN
Lowers glucose
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Genetics//Biochemistry
- A chain, S-S, B chain :scissors: C-peptide
- Stored as a hexamer, transported by zinc ions
- Leaves cell as a monomer
- Amplified by Glucagon, GIP, GLP-1
- Inhibited by Norepinephrine, Somatostatin
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Anabolic Hormone
Converts small energy molecules :arrow_right: large storage molecules
- Glucose :arrow_right: Glycogen
- Fatty acids :arrow_right: Fat
- Amino acids :arrow_right: Protein
GLUCAGON
Raises glucose
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Genetics//Biochemistry
- Preproglucagon :scissors: Signal Peptide :arrow_right: Proglucagon :arrow_right: Glucagon
- Stored as granule in alpha cell
- Stimulated by Adrenaline, CCK
- Inhibited by Insulin, Somatostatin
Catabolic Hormone
Promotes breakdown of large storage molecules
- Glycogen :arrow_right:Glucose
- Fat :arrow_right: Fatty Acids
Types of Diabetes
T1D- Autoimmune disease, destroying insulin-producing beta cells. 5-10% cases
T2D - Insulin resistance :arrow_right: deficiency. 90-95% cases
Gestational Diabetes - Caused by hormonal changes during pregnancy. 3-5% of pregnancies
Other - Genetic defects. 1-2%
Pancreas
Regulates macronutrient digestion for metabolism/energy homeostasis by releasing digestive enzymes/hormones
EXOCRINE
Through ducts and onto epithelium, not the blood
Enzymes
Acinus
- Cluster of acinar cells
- Secretes digestive enzymes (zymogens first, activated later)
- Amylase
- Lipase
- Trypsinogen
- Secretes HCO3- to neutralise stomach acid
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HLA
Class I
- Present peptides to CD8+
- Alpha chain, Beta chain
Class II
- Presents peptides to CD4+
- Alpha chain, Beta-2 microglobulin chain
- Confer highest risk of T1D
Link to T1D
- Beta-cell Ags might not be presented as efficiently in thymus by DQ2/DQ8 HLA molecules
- Lets low-affinity TCs escape :arrow_right: beta-cell Ags activated (and they're highly concentrated in the pancreas)
EPIDEMIOLOGY
Genetics
HLA
Chromosome 6
DQ2, DQ8
More risk if heterozygous
- Thought to be less efficient at presenting beta cell self-Ags in the thymus :arrow_right: they escape negative selection
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Heredity
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Chances increase if
- Parental history (3-5%)
- Sibling history (~8%)
- Twin history (>50%)
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Non-HLA Genes
INS
- Polymorphisms here can affect how insulin Ags are expressed in thymus during -ve selection
VNTR
- Class I has predisposing alleles :arrow_right: increases T1D
- Class III has protective alleles :arrow_right: decreases T1D
PTPN22
- -ve regulator of TCR signalling and BCR signalling
- Substituting wrong amino acid :arrow_right: less apoptosis induction by TCs, defective BC tolerance :arrow_right: autoreactive BCs and TCs escape thymus :arrow_right: increases T1D
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Life Expectancy
- Was much lower pre-exogenous insulin
Australia
- Approx > 120,000 cases
- Average new cases: 7/day
- Costs $ $570 mil/year
Age
- Highest increases of incidence are in children < 15 yo
- But, adult incidence is declining
- Global incidence could double by 2030 if not treated now
Geography
- Worldwide T1D: > 18 mil
- Distribution is v varied across the world
- More research dedicated to T2D than T1D
- Currently at risk: > 2.3 mil
- Seems to be some kind of bias towards countries further from equator
- Temperature link to T1D incidence supported by NOD mouse model
Environmental Factors
Hard to determine properly; not enough conclusive info
- Gut microbiome
- Viral infections
- will cause IFNα to be present in pancreas
- Sunlight/Vit D
- Diet
Sex
- No clear gender influence
DIAGNOSIS
We need more biomarkers. Current diagnosis tests are too late in the disease (~Stage 3); harder to treat
Blood Glucose Test
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Glucose :arrow_right: Gluconolactone (H202 byproduct)
Detect H202, measure level
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Family History
Not indicative, but still useful
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HbA1c
Glycosylated Haemoglobin, 3 month average
High performance liquid chromatography
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Insulin?
Detects insulinomas, but won't help with diagnosis because early stages of T1D still have normal levels of insulin
Clinical Presentation
ACUTE
Over 70% T1D cases already have these symptoms prior to diagnosis
- Polydypsia, polyuria
- Weight loss
- Extended lethargy, fatigue
SUB-ACUTE
Sudden + severe symptoms, caused by diabetic ketoacidosis
- Nausea, vomiting
- Dehydration
- Unconsciousness
RESEARCH
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Limitations of Human Research
- Can't take pancreatic biopsies before/once diagnosed with T1D
- Can only access peripheral blood, unless using cadavers
- Need controlled inbreeding + isolation to control variables better
