13. Pathology of Diabetes Flashcards
Where does gluconeogenesis (GNG) occur in the body?
Liver
Pro-insulin is cleaved into which two things?
Insulin and C-peptide
How do you tell if someone was given exogenous insulin or if it were endogenous?
Exogenous wouldn’t have C peptide levels because it is secreted together with insulin
What are the three lab tests for glucose. Note special characteristic mentioned for each lab test
Urine glucose - colorimetric indicators
Finger stick glucose - gives instantaneous glucose levels
Serum glucose - best checked during fasting state
How do we identify glucose in a post-mortem state?
Measure in vitreous humor of eye, does degrade though.
Normal values tell you nothing
Very high values tell you patient might have been hyperglycemic
How are glycated proteins formed, and what is an example of one that is used in labs?
Glucose attaches to circulating proteins. Initially is reversible; becomes irreversible with long-lasting hyperglycemia
HbA1C = measures glucose levels for past three months
Type 1 diabetes pathogenesis
Autoimmune destruction of pancreatic beta cells (they secrete insulin) –> severe lack of insulin
Destruction begins years before symptoms arise at which point 90% of beta cells have been destroyed
CD 4 T cells activate macrophaghes
CD 8 T cells directly kill beta cells
In Type 1 DM, beta cell destruction causes what? Describe it
Insulinitis
Autoantibodies against target islet cells, insulin, beta cell antigens i.e. GAD (glutamine acd decarboxylase)
Cytokines IFN, TNF, IL-1 –> apoptosis
See significant infiltration of T lymphocytes
Amyloid depositions are more common in which type of DM? Where do they occur? Congo red stain shows what?
Type 2 DM. In and around capillaries and between cells
Green birefringence
Differentiate Type I and Type II DM
Type I = autoimmune, insulinitis, marked atrophy and fibrosis, beta cell depletion, and HLA gene linkage
Type 2 = amyloid deposition
Also, Type I usually discovered in younger people; Type 2 is older but now is becoming more prevalent in younger populations as well
Macrovascular disease caused by DM involve which arteries and lead to what?
Large and medium sized arteries
Atherosclerosis, MI, strokes, gangrene of lower extremities
Microvascular disease caused by DM involves which structures and lead to what?
May effect retina, kidney, peripheral nerves
Numbness in extremities –> foot care is especially important in DM patients
What are the three metabolic pathways that are altered in DM?
AGE, activation of PKC pathway (production of DAG), disturbance in polyol pathways
AGE pathway involvement in DM
AGE formed from reaction between intracellular glucose and proteins (either intracellular or extracellular)
Results in cross linking –> abnormal matrix-cell or matrix-matrix interactions
Cross-linking AGE to collage type I
Decreases elastin and contributes to endothelial cell injury
Cross-linking AGE to collagen type IV
Occurs in BM and increases fluid filtration –> fluid leakage
AGE cross linked proteins are resistant to _________
proteolytic degradation –> increased protein deposition
Cross-linking AGE effect on LDL
AGE modified matrix components trap LDL –> contribute to atherosclerosis
Diabetic should have less LDL (normal person diet not healthy for diabetic)
Cross-linking AGE and albumin interaction
Albumin may bind to glycated BM causing thickening of the BM –> microangiopathy
Cross-linking AGE has six effects
- abnormal cell-matrix, matrix-matrix interactions
- Collagen type I –> Dec elastin, endothelial injury
- Collage type IV –> Bind BM, increase fluid leakage
- Resistant to proteolytic degradation
- LDL trapped, atherosclerosis
- Albumin binds to glycated BM –> thickening of BM –> microangiopathy
Effects of circulating plasma proteins modified by AGEs
Protein with AGE bind to AGE-R –> generate cytokines, growth factors, and pro-inflammatory molecules
Increased synth of ECM, endo permeability, inc ro-coagulant activity
Narrowed blood vesssels (MI, stroke, gangrene chances)
Polyol pathway disturbance in DM
Polyol pathway uses NADPH to produce fructos from glucose –> dec glutathione (antioxidant) –> susceptible to ROS damage
Microscopic changes in DM
Dec in number and size of islets
T cell infiltration (esp in DM1)
Beta cell degranulation (depletion of stored insulin)
Amyloid deposition esp in DM2 in and around blood vessels
What is the most common cause of death in DM
MI from atherosclerosis
