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Path - Endocrine Pancreas
Pathology of the endocrine pancreas
61
Pathology
Professional
04/16/2011

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Term
Describe beta cell granules.
Definition
they have rectangular crystalline matrix surrounded by a halo
Term
Describe alpha cell granules.
Definition
they are round with closely applied membranes and a dense center
Term
Describe delta cell granules.
Definition
they are large and pale with with closely applied membranes
Term
What does PP cell secretion do?
Definition
Stimulates secretion of gastric and intestinal enzymes, inhibits motility.
Term
Describe PP cell locations in the pancreas and describe the cell granules.
Definition
In islets but also scattered, they have small dark granules.
Term
What do D1 cells do?
Definition
Elaborate VIP, which induces glycogenolysis and hyperglycemia, stimulates GI fluid secretion and causes secretory diarrhea.
Term
What do enterochromaffin cells do? They are the source of pancreatic tumors that cause which syndrome?
Definition
Synthesize serotonin, carcinoid syndrome
Term
What is the most important susceptibility locus for Type 1 Diabetes? What are the associated alleles?
Definition
HLA on 6p21. DR3 and DR4. DR3/4 with DR8 is especially high risk.
Term
What are some of the non-HLA susceptibility loci for Type 1 Diabetes?
Definition
insulin (with VNTRs in promotor region), CTLA4 and PTPN22 (which normally inhibit T cell responses), CD25 (a-chain of the IL-2 receptor which is important for maintaining regulatory T cells)
Term
What are the 3 proposed mechanisms for how viral infection might be involved in Type 1 Diabetes?
Definition
bystander damage, molecular mimicry, viral deja vu
Term
The islet auto-antigens that are the targets of immune attack in Type 1 Diabetes may include...
Definition
insulin itself, glutamic acid decarboxylase (GAD), islet cell autoantigen 512 (ICA512)
Term
What is the genetic factor most strongly associated with Type 2 Diabetes?
Definition
transcription factor 7-like-2 (TCF7L2) on 10q, encodes TF in WNT signaling pathway
Term
Loss of insulin sensitivity in which cells is likely to be that largest contributor to the pathogenesis of insulin resistance?
Definition
hepatocytes
Term
How are NEFAs involved in insulin resistance?
Definition
Excesses overwhelm FA oxidation pathways, intermediates accumulate (DAG and ceramide), they activate serine/threonine kinases, causes aberrant phosphorylation of the insulin receptor and IRS proteins. This attenuates the insulin signaling, and PEPCK can ramp up gluconeogenesis. Excess NEFAs also compete with glucose for oxidation.
Term
How do leptin and adiponectin improve insulin sensitivity?
Definition
They enhance the activity of AMP-activated protein kinase, which promotes FA oxidation in liver and skeletal muscle.
Term
What are some of the inflammatory CKs secreted by adipose tissue, and why do they matter?
Definition
IL-6, TNF, MCP-1, they increase cellular stress, which activates signaling cascades that antagonize insulin action on peripheral tissues
Term
What is PPARy?
Definition
nuclear receptor and TF in adipose tissue, promotes secretion of anti-hyperglycemic adipokines and shifts deposition of NEFAs toward adipose tissue and away from liver and skeletal muscle.
Term
What condition is characterized by 1) autosomal dominant inheritance, 2) early onset of diabetes, 3) absence of obesity, 4) absence of beta cell autoantibodies?
Definition
Genetic defects in beta cell function resulting in monogenic diabetes. Caused by a heterogeneous group of defects.
Term
What causes MODY?
Definition
Hemizygous LOF mutation in one of 6 genes. Glucokinase (GCK) mutation causes mild fasting hyperglycemia and 50% of carriers develop gestational diabetes. Other 5 are TFs that control insulin expression and beta cell mass (like IPF1)
Term
Mutations of KCNJ11 and ABCC8 genes results in which condition? What do these genes encode? GOF mutations cause what problem?
Definition
Permanent neonatal diabetes, Kir6.2 and SUR1 subunits of the ATP-sensitive K-channel on beta cells. GOF mutations cause constitutive activation and hypoinsulinemic diabetes. Severe hyperglycemia, ketoacidosis, 20% with neuro symptoms.
Term
What causes maternally-inherited diabetes and deafness?
Definition
mitochondrial DNA mutations, impairs ATP synthesis in beta cells, decreased insulin secretion.
Term
People with insulin receptor mutations have what type of insulin resistance? What other symptom is this associated with? In females, what is often found?
Definition
Type A insulin resistance, acanthosis nigricans, polycystic ovaries and increased androgen levels
Term
Which rare group of genetic disorders has in common insulin resistance, diabetes, hypertriglyceridemia, acanthosis nigricans, and hepatic steatosis?
Definition
Lipatrophic diabetes, which is hyperglycemia accompanied by loss of subcutaneous fat. There are multiple subtypes, with different causes. Dominant-neg mutations have been found in PPARG.
Term
What is the lifetime of the RBC?
Definition
about 120 days
Term
What are AGEs? What do they bind to? On what types of cells?
Definition
Advanced glycation end products, formed from glucose-derived dicarbonyl percursors interacting with amino groups of proteins. Bind to RAGE receptor on inflammatory cells, endothelium, vasc smooth muscle.
Term
What is the effect on AGE-RAGE signaling on intimal macrophages?
Definition
release of pro-inflammatory CKs and growth factors
Term
What is the effect of AGE-RAGE signaling on endothelial cells and macrophages?
Definition
increased procoagulant activity
Term
What is the effect of AGE-RAGE signaling on endothelial cells?
Definition
Generation of ROS
Term
What is the effect of AGE-RAGE signaling on vascular smooth muscle cells and ECM?
Definition
Enhanced proliferation and synthesis of ECM
Term
What can AGEs do to extracellular matrix proteins? What effects does this have?
Definition
cross linking, decreases elasticity, predispose to shear stress and injury, decreases endothelial cell adhesion and increases fluid extravasation, makes proteins resistant to degradation, traps nonglycated plasma or interstitial proteins
Term
Intracellular hyperglycemia stimulates synthesis of DAG from glycolytic intermediates, leading to activation of which enzyme?
Definition
PKC
Term
Activation of which enzyme is responsible for these effects: production of VEGF, elevated endothelin-1, decreased NO from decreased expression of endothelial nitric oxide synthase, production of profibrogenic factors like TGF-B, production of PAI-1 leading to reduced fibrinolysis, production of proinflammatory CKs in vascular endothelium
Definition
PKC
Term
How does intracellular hyperglycemia cause increased cellular susceptibility to oxidative stress?
Definition
excess glucose is metabolized by aldose reductase to sorbitol and eventually to fructuse, the reaction uses NADPH. NADPH is required by glutathione reductase to regenerate GSH. GSH is an important antioxidant.
Term
Reduction in number and size of islets is seen most often in Type __ DM. ____________ infiltrates may also be found at the time of clinical presentation.
Definition
1, leukocytic (principally T cells)
Term
In type 2 DM there may be a subtle ______ in islet cell mass, and deposition of _______ within islets.
Definition
decrease, amyloid
Term
An increase in the number and size of islets is characteristic of...
Definition
nondiabetic newborns of diabetic mothers.
Term
What is the hallmark of diabetic macrovascular disease? What distinguishes it from nondiabetics?
Definition
accelerated atherosclerosis, just the severity and earlier onset
Term
What is the most common cause of death in diabetics?
Definition
MI
Term
What is the vascular lesion associated with HTN that is more prevalent and severe in diabetics?
Definition
hyaline arteriolosclerosis, hyaline thickening of the wall causing narrowing of the lumen
Term
What is the diffuse thickening of basement membranes in diabetics called? What are the capillaries like?
Definition
Diabetic microangiopathy, caps are more leaky to plasma proteins
Term
What are the 3 main types of lesions in diabetic nephropathy?
Definition
glomerular lesions, renal vascular lesions, pyelonephritis
Term
What are the most important glomerular lesions in diabetic nephropathy?
Definition
GBM thickening, diffuse mesangial sclerosis, nodular gomerulosclerosis
Term
What is diffuse mesangial sclerosis?
Definition
a diffuse increase in mesangial matrix
Term
Nodular glomerulosclerosis is also known as..
Definition
intercapillary glomerulosclerosis or Kimmelsteil-Wilson disease
Term
Fibrin caps and capsular drops are associated with...
Definition
Nodular glomerulosclerosis
Term
In diabetics, hyaline arteriolosclerosis affects which arterioles of the glomerulus?
Definition
afferent AND efferent
Term
Where does pyelonephritis usually begin? Where does it spread? What special pattern is seen more often in diabetics?
Definition
interstitial tissue, to the tubules. Necrotizing papillitis.
Term
Diabetic ocular complications include...
Definition
cataracts, glaucoma, retinopathy
Term
What are islet cell tumors called? What do they resemble? They make up what percentage of pancreatic tumors?
Definition
pancreatic endocrine neoplasms, carcinoid tumors, 2%
Term
What percentage of insulinomas are benign?
Definition
90%
Term
What is the characteristic clinical picture of insulinomas?
Definition
hypoglycemic episodes, with confusion, stupor or LOC, precipitated by fasting or exercise
Term
10% of insulinomas are...
Definition
carcinomas
Term
Describe the appearance of solitary insulinomas.
Definition
Usually small, encapsulated, pale to red-brown. Look like giant islets. Usually have deposition of amyloid.
Term
What are some situations that result in focal or diffuse hyperplasia of the islets?
Definition
maternal diabetes, Beckwith-Wiedemann syndrome, K-channel protein/sulfonylurea recep mutations
Term
What type of tumor is found in Zollinger-Ellison syndrome? Where are they found? What are other features of this condition?
Definition
gastrinomas, duodenum, peripancreatic soft tissues, pancreas. Pancreatic islet cell lesions, hypersecretion of gastric acid, severe peptic ulcers. Over half are invasive at Dx. Can be part of MEN-1, have multifocal tumors. Also have diarrhea, ulcers in unusual locations like jejunum.
Term
Which condition is associated with mild DM, necrolytic migratory erythema and anemia? Who does it occur in most frequently?
Definition
alpha cell tumors, glucagonomas
Term
Which condition is associated with DM, cholelithiasis, steatorrhea, and hypochlorhydria?
Definition
delta cell tumors, somatostatinomas
Term
Which condition is associated with watery diarrhea, hypokalemia, and achlorhydria (WDKA syndrome)? What else can this be associated with?
Definition
VIPoma. Neural crest cell tumors.
Term
Which tumors produce serotonin?
Definition
Pancreatic carcinoid tumors
Term
Which pancreatic tumors are endocrinologically asymptomatic?
Definition
PP-secreting endocrine tumors
Term
In addition to insulin, glucagon, SS, VIP, PP and gastrin, pancreatic endocrine tumors may produce...
Definition
ACTH, MSH, ADH, serotonin and norepi. (multihormonal tumors)
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