Autoimmune Insulin-dependent Diabetes

Question 1

What is Type 1 insulin-dependent diabetes mellitus?

Answer 1

autoimmune destruction of the insulin-secreting islets of Langerhans in the pancreas

Question 2

When does IDDM occur?

Answer 2

up to early adult live

Question 3

What is IDDM characterized by?

Answer 3

islet cell infiltration by lymphocytes, T cell reactivity to islet proteins, and autoantibody response

Question 4

Progressive destruction of beta cells in IDDM is mediated by

Answer 4

CD4 and CD8 T cells

Question 5

Progressive destruction of beta cells in IDDM leads to

Answer 5

gradual loss of insulin secretion and insulin dependence

Question 6

IDDM occurs more frequently in people with which alleles?

Answer 6

HLADR3-DQ2, HLADR4-DQ8

Question 7

What is the pathogenesis of IDDM?

Answer 7

direct beta cell cytotoxicity induced by antigen-specific (or proinsulin-specific) cytotoxic T cells that escape negative selection become activated due to high concentration of antigen in draining lymph nodes of pancreatic islets (some insulin may be altered to look different than insulin previously presented in the thymus thus triggering the response) recognized by presentation by APCs (DCs) migrating from islets to LNs; T cells migrate from LN via bloodstream to islet where Ag is concentrated; damage is induced by activated CD4 T cells and inflammatory cytokine producing macrophages; recognition of beta cells results in damage by CD8 T cells via perforins and granzyme B

Question 8

What are potential mechanisms of control (or cure) of IDDM?

Answer 8

reducing inflammation; enancing Treg production to induce tolerance; prevention of antigen-specific effector T cells; boosting beta cell mass

Question 9

What antibodies are implicated in Type I IDDM?

Answer 9

insulin autoantibodies; glutamic acid decarboxylase (GAD); zinc transporter 8 (ZnT8); IA-2 (tyrosine phosphatase)

Question 10

What are the clinical signs & symptoms of type 1 IDDM?

Answer 10

polydipsia (thirst, drinking); polyuria (passing too much urine); weight loss; ketoacidosis; eventual insulin requirement; autoantibodies

Question 11

Which cell is primarily responsible for beta cell destruction?

Answer 11

cytotoxic CD8 T cells; via cytotoxic granules in the cytoplasm containing perforin and granzyme B

Question 12

How do CD8 cytotoxic T cells cause destruction if islet beta cells?

Answer 12

cytotoxic granules in the cytoplasm containing perforin and granzyme B (both mediate apoptosis)

Question 13

What genetic syndromes are associated with type 1 IDDM?

Answer 13

18%: autoimmune polyglandular syndrome I (APS-I) due to deficiency of AIRE gene involved in central tolerance via thymus; immune dysfunction, polyendocrinopathy, enteropathy, X-linked (IPEX) mutation of FoxP3 gene that controls Tregs - 80% develop IDDM Type 1

Question 14

T cells in IDDM type I primarily recognize what region of insulin?

Answer 14

c-peptide region (in precursor to insulin), not the metabolically active regions (A & B chains) in the context of HLA-DQ8

Question 15

What are suggested environmental triggers for autoimmunity?

Answer 15

UV; diet; drugs; hygiene (early interaction with microbiota is important); tissue specific ie iodine (thyroid); infection (trigger or protection)

Question 16

What are the shortcomings of current treatment?

Answer 16

incapable of mimicking physiological glucose control; can’t prevent complications ie hypoglycaemia and long-term; injections multiple times per day are burdensome; not curative