Endocrine Pancreas Flashcards
What is the #1 cause of new cases of blindness in the US?
Diabetes
What is the #1 cause of kidney failure?
Diabetes
Random glucose test above what level indicates diabetes?
> 200 mg/dL
Fasting glucose levels above what indicates diabetes?
> 126 mg/dL
How is an abnormal glucose tolerance test performed?
Someone is given a carbohydrate load (75gm glucose dissolved in water) and their blood sugar is tested 2 hours later. If blood glucose >200 mg/dL , they are positive for diabetes
Hbg A1C above what level is considered diabetic?
> 6.5%
Which tests for diabetes must be confirmed by a repeat test before a diagnosis can be made?
Fasting blood glucose, abnormal glucose tolerance test, and Hbg A1C
What is the pathogenesis of DM type I?
Autoimmune destruction of pancreatic beta cells leads to an insulin deficiency
There is linkage of DM type I to which HLA haplotypes?
HLA- DR3 and HLA-DR4
What is the mechanism of autoimmune destruction of the pancreatic beta cells?
Lack of self-tolerance –> direct attack by T-cells
There is also Th1 cell injury by cytokines, and antibodies directed against islet cell antigens
Name 3 islet cell antigens
Insulin
Beta-cell glutamic acid decarboxylase (GAD)
Islet cell autoantigen 512
Why is it important to differentiate type 1 from type II diabetics?
Type I MUST be treated with insulin
What causes DM type 2?
Insulin resistance
There is also a relative insulin secretion deficiency –> absolute deficiency at later stages
What is the prevalence of type 1 vs type 2 diabetes
Type 1: 5-10%
Type 2: 90-95%
Describe the genetic predisposition for DM type II?
Not clearly defined
There are known polymorphisms in genes associated with insulin secretion
Name two adipokines responsible for keeping tissues sensitive to insulin
Leptin
Adiponectin
What is the affect of obesity on adipokines?
Adipokine production is lowered in obese patients
Obesity leads to the increase in FFAs. How do FFAs contribute to the pathogenesis of diabetes?
Increase in FFAs overwhelm the intracellular fatty oxidation pathways –> build up of toxic intermediates that attenuate the signaling of the insulin receptor pathway
An increase in what two factors can cause inflammation (in the pathogenesis of diabetes)?
Increased FFAs and glucose leads to the secretion of pro-inflammatory cytokines
They act at the major sites of insulin action
What is the protein that is deposited as amyloid in the islets of a diabetic person?
Amylin
What is the life-threatening state seen in Type I diabetics vs Type II diabetics?
Type I: DKA
Type II: Nonketotic hyperosmolar Coma
Describe the pathogenesis of Nonketotic hyperosmolar comas
Extreme hyperglycemia (>600) –> Serum hyperosmolality and dehydration, –> somnolence, coma, seizure
Old people with decreased thirst mechanisms, poor access to water, in nursing homes etc are at risk
What are the three macrovascular diseases that arise as a complication of long term diabetes?
MI
Stroke
LE ischemia
What are the three microvascular diseases that arise as a complication of long term diabetes?
Retinopathy
Nephropathy
Neuropathy
What is glycation?
Nonenzymatic glycosylation of proteins
Glucose covalently attaches to multiple intra and extracellular proteins. This process of glycation is proportional to the severity of the hyperglycemia
What is an advanced glycosylation end product (AGEs)?”
Over-time, the labile glycation products undergo complex chemical rearrangements that form stable AGEs.
The formation of AGEs permanently alters the protein structure/function
What are Schiff bases?
The intermediate labile NEG’d proteins
What are the cellular consequences of AGE formation?
Deposition of extracellular matrix Increased vascular stiffness Increased vascular permeability Trapping of LDL and foam cell formation Endothelial dysfunction
What is the more large scale results of AGEs formation/
Thickening of basement membranes
Microangiopathy
Large vessel injury –> athersclerosis
Describe the glycation of Hb
Glucose freely enters RBCs
Glycation of Hb is irreversible
How does diabetes lead to the activation of Protein Kinase C?
Intracellular hyperglycemia
How is VEGF affected by PK C?
Increased production of VEGF –> angiogenesis
How does activation of PK C affect endothelial NO synthase?
Decreased –> increased vasoconstriction
How is TGF beta affected by activated PK C?
Increased –> increased deposition of extracellular matrix and basement membrane material
Protein Kinase C can induce PAI-I. What are the effects?
Plasminogen activator inhibitor- 1 reduces fibrinolysis increases the risk of vascular occlusion events
Overall, what are the effects of activation of protein kinase C?
Changes in retinal and renal blood flow –> retinopathy and nephropathy
Promotes hypertension and atherogenesis
What’s the trouble with NADPH and diabetes?
Excess glucose is metabolized to sorbitol using NADPH as a cofactor. This can deplete the NADPH levels needed for the regeneration of glutathione (and leads to oxidative damage)
Which three tissue types do not require insulin for the uptake of glucose?
Nerves
lenses
blood vessels
What is the cellular mechanism behind peripheral neuropathy seen in DM?
Intracellular oxidative stress (following free flow of glucose into the cells)
What is the cause of ocular lens swelling in DM?
Increased sorbitol is thought to create an osmotic gradient that leads to swelling
Describe preproliferative angiogenesis in the retina
Hypoxia –> increased production of VEGF and retinal angiogenesis
These are poorly constructed/leaky and can lead to blood in the retina
Describe proliferative retinopathy
Retinopathy caused by new vessel formation on the disc, retina and elsewhere –> hemorrhage and vitreous detachment
Name two ocular complications of diabetes
Cataracts
Glaucoma
How can diabetes cause glomerular hyperfiltration?
Dilation of the afferents –> hyperfiltration
What complication of diabetes is prevented by ranibizumab?
Diabetic retinopathy (it is a VEGF inhibitor)
What is the risk to the fetus in a mother with preconception diabetes?
Low birth weight, congenital malformations
What is the risk to a fetus if the mother develops hyperglycemia during pregnancy?
High birth weight, obesity, DM later in life
Are insulinomas benign or malignant?
90% benign
How do people with insulinomas present?
Signs of hypoglycemia
Glucose <50
high insulin (and high insulin:glucose ratio)
