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My DEMS Unit II > Pathophysiology of Type I Diabetes > Flashcards

Pathophysiology of Type I Diabetes Flashcards

1
Q

Normal, impaired and diabetes: Fasting

A

Normal: 126 mg/dl

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2
Q

Normal, impaired and diabetes: oral GT

A

normal: 200

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3
Q

HbA1c diabetes

A

> 6.5%

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4
Q

Type I diabetes

A

Common and increasing T cell mediated autoimmune disease against pancreatic Beta cells

Associated with other autoimmune diseases

Environmental determinants unknown

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5
Q

Incidence/prevalence of T1D by 20 y

A 
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
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6
Q

T1D is rising how much per year

A

3-5%

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7
Q

T1D associated comorbidities (autoimmune and complications)

A

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
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8
Q

*Autoantigens in T1D

A 
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

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9
Q

GWAS in T1D

A

HLA (7-10 fold risk)

INS (insulin genes)

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10
Q

HLA genes and MHC

A

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

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11
Q

Tools for monitoring natural history of T1D

A

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)

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12
Q

Predictability of T1D

A

Two or more of 4 autoantibodies, over time (about 10y) all of them will develop diabetes. (Thus it is a predictable disease)

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13
Q

Potential environmental triggers for T1D

A

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

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14
Q

Assoc b/t immunizations and T1D

A

none

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15
Q

Accelerator hypothesis

A

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

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16
Q

Hygiene hypothesis

A

Hypothesis: Lack of immune stimulation at a young age suppresses natural immune system development leading to more allergies & autoimmune disorders
We are too clean!

17
Q

Latent Autoimmune Diabetes of Adulthood (LADA)

A
  1. Age 30-70 years at diagnosis
  2. At least 6 months of non-insulin requiring diabetes
  3. The presence of diabetes associated autoantibodies
18
Q

Type I vs Type 2 diabetes

A 
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
19
Q

T1D treatment

A

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)

20
Q

Primary prevention

A
  • genetically at risk

- goal: prevent devel of antibodies and diabetes (stop progression to autoimm/beta cell destruction)

21
Q

Secondary prevention

A

-have Ab, want to prevent clinical disease

Effort:
parenteral insulin–> pts did NOT delay devel of T1D
oral insulin–> didn’t change things either

22
Q

Tertiary prevention

A
  • (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

23
Q

Summary

A

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.

24
Q

When do pts present with classic signs and sx of diabetes?

A

When 80-90% of Beta cell mass has been destroyed.

25
Q

VNTR

A

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

26
Q

Effective tx for prevention of T1D

A

-to date, none known

27
Q

Progression/timing

A

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)

28
Q

C peptide

A

production of c-peptide (endogenous insulin) is associated with decreased development of complications and fewer severe hypoglycemic events

My DEMS Unit II (18 decks)

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