Pathophysiology of Type I Diabetes Flashcards
Normal, impaired and diabetes: Fasting
Normal: 126 mg/dl
Normal, impaired and diabetes: oral GT
normal: 200
HbA1c diabetes
> 6.5%
Type I diabetes
Common and increasing T cell mediated autoimmune disease against pancreatic Beta cells
Associated with other autoimmune diseases
Environmental determinants unknown
Incidence/prevalence of T1D by 20 y
General population: 1:300 First degree relatives 1:20 High genetic risk general population 1:15 High genetic risk FDR: 1:4 to 1:2 Monozygotic twins: 1:3 to 1:1
T1D is rising how much per year
3-5%
T1D associated comorbidities (autoimmune and complications)
Autoimmune disorders:
Thyroid Autoimmunity
~15-20%
TSH testing
Celiac Disease
~ 5-10%
Transglutaminase Autoantibodies
Addison’s Disease
~ 1-1.5% 21(OH) Autoantibodies
Complications:
Macrovascular
-CVD
-PVD
Microvascular
- Retinopathy
- Nephropathy
- Neuropathy
Psychosocial
- Depression
- Anxiety
*Autoantigens in T1D
Islet cell autoantibodies react to: insulin glutamic acid decarboxylase 65 (GAD65) tyrosine phosphatase like protein (IA-2) Zinc transporter (ZnT8)
Measurement of these antibodies makes T1D a predictable disease
-with 2 or more islet autoantibodies, individuals will progress to T1D with overt hyperglycemia
GWAS in T1D
HLA (7-10 fold risk)
INS (insulin genes)
HLA genes and MHC
Genotype of HLA is 2 haplotypes together
Class II:
DP, DQ, DR (most risk in DQ and DR)
Class III
Class I: BCA
Genes in class II region are most highly linked to development of diabetes.
Highest risk HLA genotype: DR3/4
Protective: The DQA10102, DQB10602 haplotype
50% of genetic risk for T1D is attributed to HLA genes
Tools for monitoring natural history of T1D
Markers of immune system response to the beta-cell:
Autoantibodies
(Islet cell autoantibodies: insulin, IA-2, GAD65, ZnT8)
T cell response (active area of research)
Markers of the metabolic changes:
IV glucose tolerance test
Oral glucose tolerance test
Mixed Meal Tolerance Test (MMTT)
Predictability of T1D
Two or more of 4 autoantibodies, over time (about 10y) all of them will develop diabetes. (Thus it is a predictable disease)
Potential environmental triggers for T1D
Infections:
Viruses
Immunizations
Diet:
Breast feeding/cow’s milk
Timing of introduction of foods in infancy
Omega-3 fatty acids/Vitamin D: protective/decreased risk
Weight
Hygiene Hypothesis
Assoc b/t immunizations and T1D
none
Accelerator hypothesis
The increase in T1D incidence has occurred parallel to the increase in obesity
Hypothesis: Obesity causes beta-cell stress and results in exposure of beta-cell antigens to the immune system
Hygiene hypothesis
Hypothesis: Lack of immune stimulation at a young age suppresses natural immune system development leading to more allergies & autoimmune disorders
We are too clean!
Latent Autoimmune Diabetes of Adulthood (LADA)
- Age 30-70 years at diagnosis
- At least 6 months of non-insulin requiring diabetes
- The presence of diabetes associated autoantibodies
Type I vs Type 2 diabetes
Type I: age: peak in early childhood, adolescence ketosis at onset: common FH: 10-20% Pathophysiology: Autoimmune disease Assoc Conditions: Autoimmune thyroid disease Celiac Disease Addison’s disease
Type 2: Age of onset: post-pubertal ketosis at onset: uncommon but possible FH: >50% pathophysiology: insulin resistance Assoc cond: Obesity Lipid abnormalities PCOS NAFLD
T1D treatment
Decreased glucose transport into cell:
GLUT4 glucose channel
Increased glucose production:
Glycogen
Gluconeogenesis
Increased activity of hormone sensitive lipase:
mobilization of FFA
beta-hydroxybuterate and acetoacetate (ketones)
Primary prevention
- genetically at risk
- goal: prevent devel of antibodies and diabetes (stop progression to autoimm/beta cell destruction)
Secondary prevention
-have Ab, want to prevent clinical disease
Effort:
parenteral insulin–> pts did NOT delay devel of T1D
oral insulin–> didn’t change things either
Tertiary prevention
- (diagnosed with diabetes)
- preserve beta cells and stop complications
- If you can make some of your OWN insulin it is a very good thing
-Anti-CD3 antibodies depletes T cells: young children good preservation and if
Summary
T1D is caused by the autoimmune destruction of the pancreatic beta cells, involves CD4 and 8 Tcells
T1D is a predictable disease with the measurement of islet autoantibodies (insulin, IA-2, GAD65, & ZnT8).
The natural history is characterized progression through stages culminating in hyperglycemia.
Prospective studies into the etiology of T1D have implicated genetic and environmental risk factors.
Prevention trials have targeted multiple stages of the disease process.
When do pts present with classic signs and sx of diabetes?
When 80-90% of Beta cell mass has been destroyed.
VNTR
variable number of tandem repeats within 5’ region of the insulin gene has been associated with risk of T1D
-higher classes are associated with increased expression of insulin iwthin thymus and less risk for T1D
Class I VNTR alleles: increased risk for T1D, class III: decreased risk
Can have additive risk along with HLA DR 3/4
Effective tx for prevention of T1D
-to date, none known
Progression/timing
Genetically at risk
single Ab positive
multiple Ab positive
Loss of first phase insulin response; dysglycemia (pre diabetes)
Diabetes (can monitor C-peptide levels; beta cell function)
C peptide
production of c-peptide (endogenous insulin) is associated with decreased development of complications and fewer severe hypoglycemic events
