pathophys of type 1 diabetes

Question 1

T1D associated comorbidities

Answer 1

autoimmune disorders (thyroid, celiac, addisons dz), macrovascular dz, microvascular dz, psychosocial

Question 2

prevalance of T1D by age 20 in general population, first degree relatives, monozygotic twins

Answer 2

general pop- 1:300. first degree relative - 1:20. Monozygotic twins- 1:3 to 1:11

Question 3

Diabetes is a disease of T or B cells?

Answer 3

T cells! CD4 and CD8

Question 4

Describe the linear chronic model of type 1 diabetes

Answer 4

Genetic predisposition > precipitating event (?) > T cell attack of beta cells in pancreas (normal insulin release) > progressive loss of insulin release but normal glucose > overt diabetes but C-peptide present > no C peptide anymore

Question 5

2. Define the four autoantigens that are characteristic of TID.

Answer 5

insulin, glutamic acid decarboxylase 65 (GAD65), tyrosine phosphatase like protein (IA-2), and a zinc transporter (ZnT8).

Question 6

What is the islet cell autoantibody

Answer 6

antibody against the characteristic antigens of T1D.

Question 7

How does autoantibody numbers correlate with disease progression

Answer 7

With > 2 islet autoantibodies, individuals will eventually progress to T1D with overt hyperglycemia.

Question 8

3. Predict the likelihood of progression to TID given the presence of 1, 2, or 3 autoantibodies in a child over the ensuing 10 years.

Answer 8

1: in 10 years, 20% develop diabetes. 2: in 10 years, 70% develop diabetes. 3: in 10 years 70% develop diabetes

Question 9

First metabolic abnormalities to develop in T1D

Answer 9

states in which the most insulin is required- ie. Decrease in first phase insulin response of a IV glucose tolerance test. This can occur years prior to development of T1D.

Question 10

Oral glucose tolerance testing procedure

Answer 10

Fasting subjects receive a carbohydrate load (glucola) and glucose is measured fasting and 2 hours after the glucose load

Question 11

diagnosis of diabetes

Answer 11

single blood glucose greater than 200 mg/dL in the presence of symptoms of hyperglycemia OR fasting glucose >125mg/dl OR 2hr OGTT >199mg/dL

Question 12

normal blood glucose and 2hr OGTT

Answer 12

fasting <140mg/dl

Question 13

When do pts present with symptoms of diabetes

Answer 13

when 80-90% of Beta cell mass has been destroyed

Question 14

Genetic risk of T1D

Answer 14

80% diagnosed do NOT have relative with T1D. Risk is increased in siblings and offspring though.

Question 15

List the genes associated with T1D risk

Answer 15

HLA and insulin gene

Question 16

Which HLA genes are associated with T1D

Answer 16

HLA DR3/4 is highest risk. Subjects who express this genotype have a risk for the development of T1D by age 20 years of 1:15. First-degree relatives with this genotype have a risk for diabetes of up to 50%.

Question 17

Genes protective for T1D

Answer 17

DQA10102, DQB10602. Only 3% with this genotype develop dz, compared to 20% of population

Question 18

How is the insulin gene associated with risk of T1D

Answer 18

variable number of tandem repeats (VNTR) within the 5’ region of the insulin gene has been associated with risk of T1D. Class 1 (26-63 repeats) is associated with increased risk and class III (140-200 repeats) is associated with decreased risk. Higher classes are incrased in expression in thymus leading to T cell tolerance to insulin

Question 19

T1D genetic additive effects

Answer 19

Subjects with DR3/4 HLA genotypes and Class I/I VNTR of the insulin gene are at an increased risk for the development of diabetes compared with subjects with DR3/4 HLA genotypes and Class III VNTR of the insulin gene.

Question 20

possible environemental factors in T1D

Answer 20

hygeine hypothesis: immune system is bored from too few infections leading to autoimmunity. Diet: increased risk related to shorter duration of breastfeeding, earlier introduction of cows milk and cereals, and Vit D/ omega-3 fatty acids may be protective. Accelerator hypothesis: increased childhood obesity may be linked to increased incidence by causing beta cell stress and exposing beta cell Ags to immune system

Question 21

how are immunizations associated with T1D

Answer 21

They are not!

Question 22

What is latent autoimmune diabetes of adulthood

Answer 22

Diagnosed at 30-70 years, at least 6 months of non-insulin requiring diabetes and presence of diabetes associated with autoantibodies. It is inbetween type 1 and type 2 diabetes.

Question 23

Predictors of insulin requirement

Answer 23

Insulin rquirement increases with autoantibodies and age

Question 24

Metabolism in T1D

Answer 24

Decreased glucose transport into cells, increased glucose production via glycogen and gluconeogenesis, and increased activity of hormone sensitive lipase resulting in mobilization of FFA and ketones

Question 25

name 3 therapies approved for T1D

Answer 25

Continuous glucose monitoring systems, insulins and continuous subcutaneous insulin infusion