T2D Flashcards
What is T2D?
low grade chronic inflammatory condition characterized by insulin resistence and failure of pancreatic beta cells to compensate
What is T2D strongly linked to?
obesity
What is human obesity defined as?
BMI >= 30
What are the two types of adipose tissue and what do they do? Which type is more present in apple shaped people?
brown adipose tissue –> dissipates energy as heat
white adipose tissue –> energy storage, visceral – cushions organs (people with apple shape have more visceral fat)
What are the metabolic effects of insulin signaling?
glucose uptake and storage
- surface translocation of GLUT4
- glycogen synthesis
- limits gluconeogenesis
triglyceride storage
- enhances lipid synthesis
- reduces lipolysis
protein metabolism
- a.a. uptake
- decreased proteolysis
Describe the insulin signaling cascade briefly
insulin –> IR –> P13K –> AKT
When insulin resistance begins, what happens to beta cells in the short term vs the long term?
- short term: appropriate compensation – elevated insulin, normal glucose
- long term: failure to compensate – T2D
What happens when there is insulin resistance and inflammation in adipose tissue?
- adipocytes produce and release free fatty acids (FFAs) and insulin-resistance-provoking pro-inflammatory cytokines (IL-6, TNF, resistin).
- These factors contribute to the accumulation of toxic lipid metabolites in myocytes and hepatocytes, which impair insulin signaling and activate inflammatory pathways which impair the insulin signal transduction.
- mitochondrial dysfunction predisposing to DAG accumulation and nuclear PKC activation as well as generation of ROS and more ER stress further exacerbate insulin resistance
Describe the two main animal models of obesity and insulin resistance
- diet-induced obese (DIO) mouse: placed on HFD for weeks, mice devleop visceral adiposity, insulin resistance, glucose intolerance, and hyperglycemia
- ob/ob mouse (genetic mouse): leptin regulated food intake and enhances metabolism; leptin-deficient mice
Compared to lean individuals, what do obese individuals have?
- more circulating FAs and a.a.s
- hyperinsulinemia
- hyperglycemia
- alterations to some apidokine (e.g. more leptin)
- elevated pro-inflammatory cytokines (IL-1B, IL-6, TNFa) –> worsenes glucose tolerance
Describe how obesity-associated dysbiosis contributes to the activation of the IS?
- contributes to more gut permeability, facilitating the leakage of microbial products and oral Ags across the gut epithelium
- together with lipid excess and dying apidocytes, these serve as potential sources of Ags and co-stim molecules for the activation of VAT B and T cells, a process that can take place in draining LNs or locally in the VAT
Describe the role of macrophages in obesity-linked inflammation
- macrophages accumulate in both visceral and subcutaneous fat and are the major producers of TNFa in fat
- TNFa signaling in adipocytes causes them to become insulin resistant
- macrophage-derived IFNg and TNFa can stimualte adipocytes to secrete chemokines that help recruit T cells to the adipose tissue
Describe how two hormone’s levels change in obesity in the adipose tissue. How does each hormone contribute to inflammation (normally)?
- leptin increases – Th1 promoting
- adiponectin decreases – suppresses immune activation and promotes M2 polarization
Describe how T cells regulate VAT macropahge polarization
- obese adipose tissue in enriched for Th1 cells
- Th2 and Treg are decreased in obese adipose tissue
- Tregs and less functional in an obese environment
net result: more M1 polarization and more inflammation
Describe the role of B cells in the pathogensis of obesity-linked insulin resistance
- obese B(null) mice show improved metabolic function
- B cells can be pathogenic, but specific subsets (e.g. B1 cells) can have regulatory properties as well
