complications of DM Flashcards
pathology of hyperglycemia?
-hyperglycemia causes excess glucose to be stuck to everything (glycosylation) esp basement membranes. - excess intracellular glucose can go through SORBITOL pathway to fructose which is a never more potent glycosylator than glucose.
what are three mechanisms by which long term complications of DM arise?
1) formation of advanced glycation end products (AGEs)
2) activation of Protein kinase C (PKC)
3) disturbance of polyol pathway with glucose converted to sorbitol.
pathology of AGE mechanism
- AGE products are peptides with glucose IRREVERSIBLY stuck on them which cross-links with collagen trapping albumin in basement membrane and LDL in arterial atheromas.
- It also binds pro-inflammatory cell surface receptors which cause endothelial generation of ROS like superoxide
- cause pro-coagulant state
- cause pro-fibrogenic state
pathology of PKC mechanism
- activation of PKC cause production of pro-fibrogenic cytokines such as TGF-beta, which cause BM thickening.
- pro-angiogenic cytokines sych as VEGF which cause neovascularization in retinopathy
Pathology of polyol pathway mechanism
- disturbance of polyol pathway, with glucose converted to sorbitol (a polyol) by aldose reductase, and then fructose
- Uses NADPH as cofactor which keeps it from reducing glutathione which is needed to catabolize ROS causing injury by ROS.
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What is this? Describe and diagnose
Type 1 diabetes mellitus is associated with insulitis with T lymphocytes
What is this? Describe and diagnose.
What is the pathophysiology of T1DM?
- Destruction of beta cells rendenring these patients dependent on exogenous insuling—> sustained hyperglycemia
What is the pathophysiology of T2DM?
- Insulin resistance*** –> sustained hyperglycemia
- amyloidosis of islets render some of the patients dependedn on exogenous insulin.
How does hyperglycemia impair innate immunity?
- impairs neutrophil function
- upregulates CD11b on neutrophils and upregulates ICAM-1, VCAM-1, and E-selectin on endothelial cells, creating an adhesive phenotype keeping neutrophils from leaving blood vessels to sites of infection.
- hyperglycemia causes unactivated C3 complement to bind to Staph aureus which inhibits the activation of the functionally active forms (c3b/ic3b) on the bacterial surface –> decreased c5a generation –> **decreased phagocytosis. **
**- **consitutive activation of NET formation
- malfunction of monocytes and natural killer cells –> impairing back-up first responders in the innate immune response to infection
How does hyperglycemia impair bacterial killing?
- via oxidative burst
- hyperlgycemia saturates the kexokinase pathway which results in formation of sorbitol via aldose reductase
- hgih sorbitol = decreased NADPH => reduced production of superoxide in phagosomes whichi s needed to kill bacteria.
** too much superoxide/ROS -> diabetic triopathy
and
too little superoxide/ROS = diabetic infections
What is resisitin? where is it produced? what does it do?
- peptide hormone that renders cells resistant to insulin
- produced by monocytes as well as other cell types and is present at high levels in DM…duh.
- resistin inhibits neutrophil chemotaxis and oxidative burst via phosphatidyl-inositol-3-kinase pathways
how is NET and hyperglycemia related?
- hyperglycemia causes CONSTITUTIVE ACTIVATION of neutrophil extracellular trap (NET) formation –> decreased response to subsequent pathogens normally mediated by IL-6
what are the most common sites of infections in d/t diabetes impaired neutrophil function?
1) skin
2) feet (bone, soft tissue)
3) lungs
4) urinary tract
which pathogens cause the most infections in diabetes-impaired neutrophil function?
1) staph aureus
2) pseudomonas aeruginosa
3) candida species
4) zygomycetes (mucor)
5) many other bugs