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Flashcards in Pancreas Deck (20):
1

Diabetes Mellitus criteria
Random
Fasting

1. Random glucose>200 mg/dL
+ classical signs and symptoms
-polyuria, polydipsia, unexplained weight loss

2. 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

2

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

3

Type 1 DM pathogenesis

Autoimmune
-pancreatic B-cell dysfunction
-usually less than

4

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

1. insulin resistance
2. beta cell compensation(hyperplasia)
3. beta cell failure

Genetics:
No HLA linkage; candidate diabetogenic and obesity related genes

5

What is deposited in DM2 islets?

amyloid
=amylin

6

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

7

Glucotoxicity can be caused by Formation of advanced glycation end products, how?

1. 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

1. Initial glycation products (aka Schiff bases) are labile and can dissociate
2. 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

8

What does advanced glycation end products lead to?

1. crosslinking colagen
-deposition of extracellular matrix
-increased vascular stiffness
-increased vascular permeability

2. binding lipoproteins
-trap LDL, foam cell formation

3. RAGE--Nuclear transcription factors
-lead to Reduction in NO, oxidative stress, chemokines cytokines
-endothelial dysfunction


Results:
1. thickening of basement membrane
2. microangiopathy
3. large vessel injury-atherosclerosis

9

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:
1. Production of VEGF (abnormal blood vessels in the eye =blindness)
2. Decreased Expression of endothelial NO synthase
-elevated endothelin-a (vasoconstrictor) and decreased NO (vasodilator)
3. Production of profibrogenic factors (TGF-B)
-increased deposition of extracellular matrix and basement membrane material
4. Increased PAI-1
-reduced fibrinolysis and possible vascular occlusive episodes
5. Production of proinflammatory cytokines by vascular endothelium

Results in:
Changes in retinal and renal blood flow, contractility, permeability
-Retinopathy, Nephropathy
-promotes hypertension and atherogenesis

10

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:
1. intracellular oxidative stress
-neuronal affect=peripheral neuropathy
2. Increased sorbitol may create osmotic gradient
-ocular lens swelling

11

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

12

Diabetic Retinopathy

1. Preproliferative-microvascular changes lead to increased production of VEGF and retinal angiogenesis
2. 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)

13

Diabetic nephropathy

Renal vascular lesions
-hyaline arteriosclerosis
Glomerular lesions
-capillary basement membrane thickening
-diffuse mesangial sclerosis
-nodular glomerulosclerosis (kimmelstiel-wilson lesions)
Pyelonephritis

14

Peripheral Neuropathy

Prevalent with increasing time of disease
-pain, weakness, functional disability
-predisposition to ulcer formation; increased risk of infection and gangrene

15

Insulinomas

most solitary
90% benign
-arise in B-cells

Symptoms:
typically mild hypoglycemia
Clinical triad
1. glucose

16

Gastrinomas

Gastrin producing cells found in pancreas, duodenum and in peripancreatic tissue

EX:
Zollinger-Ellison Syndrome
-Hypergastrinemia stimulates gastric acid secretion
-peptic ulceration
-ulcers in 90-95% of patients
-duodenal: gastric 6: 1
-multiple-unusual places-jejunum
-diarrhea frequently part of ZE

Treatment:
-control of gastric acid secretion
-excision of neoplasm
-tumors often locally invasive
-total resection eliminates ZE syndrom

-Hepatic metastasis= shortened life expectancy

17

Glcuomas

alpha-cell tumors presenting with diabetes, a skin rash, often middle aged and older women, anemia, high glucagon levels

18

Somatostatinomas

diabetes and malabsorption associated with d-cell tumor, very hard to lacalize preop

19

VIPoma

severe secretory diarrhea--can be associated with neural crest tumors

20

PP-secreting tuors

silent endocrinologicaly