Pancreas Flashcards
Diabetes Mellitus criteria
Random
Fasting
- Random glucose>200 mg/dL
+ classical signs and symptoms
-polyuria, polydipsia, unexplained weight loss - Fasting glucose>126 mg/dL
a. abnormal glucose tolerance test
- carb load
- 2 hours later blood glucose >200mg/dl
b. HgbA1C greater than or equal to 6.5
What levels of impaired fasting glucose, impaired glucose tolerance and HgbA1C put you at risk for DM?
Fasting: 100-125 after overnight fast
Glucose tolerance: 140-199 postprandial glucose
HgbA1C 5.7 to 6.4
Type 1 DM pathogenesis
Autoimmune
- pancreatic B-cell dysfunction
- usually less than
Diabetes Mellitus Type 2
Pathogenesis
Peripheral insulin resistance inadequate secretory response of insulin "relative insulin deficiency" 90-95% of cases overweight-metabolic syndrome "adult onset" -no islet cell autoantibodies
Pathogenesis: multifactorial environment -sed life, obesity strong genetic predisposition
- insulin resistance
- beta cell compensation(hyperplasia)
- beta cell failure
Genetics:
No HLA linkage; candidate diabetogenic and obesity related genes
What is deposited in DM2 islets?
amyloid
=amylin
What is a nonketotic hyperosmolar coma?
Rare Type 2 Extreme Hyperglycemia Serum hyperosmolarity Dehydration, free water deficit Somnolence, confusion, coma, seizure
Prototypic patient: NH residents, impaired thirst mech, decreased water access
Glucotoxicity can be caused by Formation of advanced glycation end products, how?
- Formation of Advanced glycation End products
- Non enzymatic glycosylation(glycation)
- glucose covalently attaches to multiple proteins non enzymatically
- ie cellular basement membrane proteins, ocular lense
- glycosylation~ proportion of severity of hyperglycemia - Initial glycation products (aka Schiff bases) are labile and can dissociate
- over time labile products undergo complex chemical rearrangements to form stable advanced glycosylation end products
- glucose derives bound covalently to protein amino groups
- AGE formation permanently alters protein structure, possibly function
What does advanced glycation end products lead to?
- crosslinking colagen
- deposition of extracellular matrix
- increased vascular stiffness
- increased vascular permeability - binding lipoproteins
- trap LDL, foam cell formation - RAGE–Nuclear transcription factors
- lead to Reduction in NO, oxidative stress, chemokines cytokines
- endothelial dysfunction
Results:
- thickening of basement membrane
- microangiopathy
- large vessel injury-atherosclerosis
Glucotoxicity can be caused by Modification of protein kinase c activity, how?
Enzyme influencing multiple cellular processes
-intracellular (why is it intracellular?) hyperglycemia results in activation of protein kinase C
Leads to:
- Production of VEGF (abnormal blood vessels in the eye =blindness)
- Decreased Expression of endothelial NO synthase
- elevated endothelin-a (vasoconstrictor) and decreased NO (vasodilator) - Production of profibrogenic factors (TGF-B)
- increased deposition of extracellular matrix and basement membrane material - Increased PAI-1
- reduced fibrinolysis and possible vascular occlusive episodes - Production of proinflammatory cytokines by vascular endothelium
Results in:
Changes in retinal and renal blood flow, contractility, permeability
-Retinopathy, Nephropathy
-promotes hypertension and atherogenesis
Glucotoxicity can be caused by Increase in intracellular glucose, how?
GLucose+NADPH–Sorbitol + NADP
- excess glucose metabolized by aldose reductase to sorbitol via NADPH cofactor
- Depletion of intracellular NADPH, glutathione
- key in antioxidant mechanisms
(hyperglycemia induces glucose uptake into tissues that do not depend on insulin)
Results:
- intracellular oxidative stress
- neuronal affect=peripheral neuropathy - Increased sorbitol may create osmotic gradient
- ocular lens swelling
What is Hemoglobin A1C used for?
serve as a marker for glycemic control
- hemoglobin formed in new RBC enters circulation with minimal glucose attached
- RBC freely permeable to glucose
- glycation of hemoglobin irreversible
Diabetic Retinopathy
- Preproliferative-microvascular changes lead to increased production of VEGF and retinal angiogenesis
- Proliferative-retinopathy caused by new vessel formation on disc, retina and elsewhere
- can lead to hemorrhage and vitreous detachment
-diabetes can also impact lense (cataracts), iris (glaucoma)
Diabetic nephropathy
Renal vascular lesions -hyaline arteriosclerosis Glomerular lesions -capillary basement membrane thickening -diffuse mesangial sclerosis -nodular glomerulosclerosis (kimmelstiel-wilson lesions) Pyelonephritis
Peripheral Neuropathy
Prevalent with increasing time of disease
- pain, weakness, functional disability
- predisposition to ulcer formation; increased risk of infection and gangrene
Insulinomas
most solitary
90% benign
-arise in B-cells
Symptoms:
typically mild hypoglycemia
Clinical triad
1. glucose
