Diabetes Genetics

Question 1

Diabetes

Answer 1

metabolic disease in which body is unable to use glucose because of failure to produce/inability to use insulin
- Type 1 and Type 2 (increasing incidence)

Question 2

Consequences of diabetes

Answer 2

leading cause of end-stage renal disease, adult blindness, non-traumatic leg amputations
- high risk factor for CV disease –> huge effect on vasculature

Question 3

Maturity Onset Diabetes of Young

Answer 3

rare, autosomal dominant

• mutations cause disruption of beta-cell function
• many types

Question 4

Type 1 Diabetes

Answer 4

insulin is not made because pancreatic beta-cells are destroyed by autoimmune process

• over-reactive TCR to self-antigen -> specific viral infection leads to inflammatory response that mimics beta-cell protein –> autoimmune response
• individuals become symptomatic when 80% of beta-cells are destoryed –> irreverisible (tx with insulin)
• HLA-DR3 and DR4 –> altered AA binding site

Question 5

Can Type 1 diabetes be prevented?

Answer 5

insulin deficiency doesn’t become apparent until 80% destroyed -> irreversible at that point
- the autoimmune process starts much earlier -> may be identified by immune changes –> A LOT of research

Question 6

Type 2 Diabetes

Answer 6

OBESITY!!!!!

• excess nutrients -> hyperglycemia and FFA -> inflammation and dysregulated lipid metabolism -> insulin resistance
• higher genetic risk than type 1 (specific genes not known)

Question 7

Insulin resistance

Answer 7

the decreased ability to respond to insulin –> occurs in several tissues -> several processes contribute (inflammation and dysregulated lipid metabolism)

Question 8

Insulin resistance in adipose tissue

Answer 8

1. Non-pathologic increase in size
2. Pro-inflammatory secretion of Monocyte Chemotractant Protein 1 (MCP1) by adipocytes
3. Inflammation - recruitment of macrophages which secrete TNF-alpha
4. TNF-alpha binds to TNFR -> activates JNK -> phosphorylation and inactivation of IRS1 -> ineffective insulin signaling
5. LARGE increase in circulating FFA -> promote systemic insulin resistance

Question 9

Insulin resistance in skeletal muscle

Answer 9

elevated circulating FFA plays major role

- FFA complexed with FetuinA bind to TLR4 -> activates JNK -> phosphorylation of IRS -> inhibit insulin signaling

Question 10

Insulin resistance in adipocytes

Answer 10

1. FFA binds TLR4 -> IRS phosphorylation
2. FFA taken up metabolized to DAG -> PKC -> phosphorylates IRS
3. FFA taken up metabolized to ceramide –> inactivates Akt
4. Glucose taken up by GLUT 2 -> increase FOX01 translocation -> increased gluconeogenesis

Question 11

Metformin

Answer 11

inhibits complex 1 of mitochondrial ETC -> decreased energy charge –> increased AMP:ATP ratio –> increased fatty acid oxidation and decreased lipogenesis`

Question 12

Pancreatic Beta-Cell dysfunction

Answer 12

excess nutrients -> overload of ETC -> excess proton gradient -> generation of ROS -> oxidative stress –> activate inflammatory pathway –> IL-1beta induces apoptosis
- beta-cells have little anti-oxidant enzymes –> easily damaged