Obesity, Insulin Resistance II, and Type I Diabetes Flashcards
Most important environmental risk factor for insulin resistance?
Obesity
Why does insulin resistance usually occur?
Combination of factors involving numerous genes and environmental risk factors
Obese people and those with glucose intolerance often have impaired what?
Satiety mechanisms - poorly-characterized “leptin resistance”
Satiety signals? (5)
- Leptin (from adipocytes)
- GLP1 (from SI)
- CCK
- PYY (from LI)
- Vagal afferents
Hunger signal?
Ghrelin (released by stomach fasting)
What do non-esterified fatty acids (NEFA) do?
Increase insulin resistance
Does central or peripheral fat release more NEFAs?
Central fat > peripheral fat
What does increased intracellular [NEFAs] cause?
Serine phosphorylation of insulin receptor = inactivation
What are adipokines? What do they do?
- Protein hormones from fat cells
- Modify sensitivity of insulin receptor
What mediates increased NEFA oxidation?
Protein kinase A
What drug activates AMP-K?
Metformin
Anti-hyperglycemic adipokines? (2)
- Leptin
- Adiponectin
Hyperglycemic adipokines? (2)
- Resistin
- Retinol-binding-protein 4
Pro-inflammatory cytokines secreted by fat cells _______ insulin receptor sensitivity
Decreased
Who produces more VLDL?
Those that are insulin-resistant
Lipoprotein lipase is ______ in a wide variety of tissues in those that are insulin-resistant
Down-regulated
Where especially is LPL reduced in those with insulin-resistance?
Skeletal muscle and adipose tissue
What is produced by the liver in an insulin-resistant state that inhibits LPL?
ApoC-III Protein
Is HDL increased or reduced during insulin resistance?
Reduced
Why is visceral obesity bad for you? (2)
- Excessive lipid buildup = stress on adipocyte (ROS)
- High [FFA] may bind PAMP-R in adipocyte
What can buildup of stress and high [FFA] in the adipocyte lead to the production of?
Pro-inflammatory cytokines IL-6 and TNF-alpha
5-10% of diabetes cases?
Type I
Epidemiology of TID?
Can develop at any age but usually diagnosed < 20 yo
TID is characterized by what of beta cells?
Autoimmune destruction = absolute deficit
Twin concordance rate of TID?
30-50%
Types of genes implicated in TID?
- Major histocompatibility genes
- Genes that teach immune system to “self-tolerate” self tissues
Histocompatibility genes?
- HLA DR3
- HLA DR4
- HLA DQ8
What genes account for 50% of the genetic risk of TID?
Histocompatibility genes
People with one copy of both ______ and ______ show increased risk for TID
DR3 and DR4
Histocompatibility gene polymorphisms are within what portion of the gene?
Antigen-presenting portion
“Tolerance” genes?
- CTLA-4
- PTPN-22
What does CTLA-4 do?
- Down-regulates APCs
- Interacts with CD-28 (Treg)
What does PTPN-22 do?
Important in the development of central Tregs in thymus
Environmental theory of TID of viral infection involvement?
Association with mumps, rubella, coxsackie B, or CMV
3 mechanisms for involvement of viral infection in TID?
- Bystander damage
- Beta-cell antigen mimickers
- Precipitating virus
Viral infections induce islet injury and inflammation, leading to release of β-cell antigens and activation of autoreactive T cells
Bystander damage
Viruses produce proteins that mimic β-cell antigens, and immune response to viral protein cross-reacts with self-tissue
Beta-cell mimicker
Viral infections early in life persist in pancreas, and re-infection
with a related virus that shares antigenic characteristics leads to immune response against infected islet cells
Precipitating virus
What likely causes gradual loss of beta-cell mass?
Destruction by cytotoxic T-cells
TID disease manifestation appears after _____ of beta-cells are destroyed
90%
What cells are the main problem in TID? Why?
T-cells
- Self reactive ones not destroyed in thymus
- Defects in Treg
- Antigens likely attacked
What happens as you kill beta-cells?
Remaining cells become hyperproductive
What does it mean for beta-cells to be hyperproductive?
When glucose goes up, cells make insulin and glucose go down again
Ability of remaining β-cells to become hyper-productive and compensate for failing insulin response
Honeymooning
What happens once the honeymooning cells fail?
Deterioration is rapid
Typical initial presentation of TID?
Diabetic ketoacidosis
Patients presenting with TID generally have a subacute history of what?
- Polyphagia (hunger not satisfied)
- Polydipsia (excessive thirst)
- Polyuria (excessive urination)
As patients lose the ability to use serum glucose to generate ATP, what happens?
Adipose tissues release FAs => ketogenesis
How does the liver generating ketones affect blood pH?
Makes it more acidic = pH drop
For unclear reasons, patients who experience DKA often experience fairly severe what?
Generalized abdominal pain
An absolute insulin deficiency leads to a catabolic state,
culminating in ketoacidosis and severe volume depletion - causing what?
CNS compromise and eventual diabetic coma/death
Elevated blood glucose => an ______________ in the kidney
Osmotic diuresis
Excess sugar in the urine causes?
Drawing water from blood into urine => dehydration
