Pathology Ch. 24: Endocrine Pancreas

Front 1

Supresses both insulin and glucagon release

Back 1

Somatostatin: Delta cells

Front 2

Histological features of Beta cells. Alpha cells?

Back 2

Membrane bound granules with a dense rectangular core and halo
Round with closely applied membranes and a dense center

Front 3

Three criteria for establishing diabetes:

Back 3

1. Random glucose above 200 w/ symptoms
2. fasting BG level greater than 126
3. Abnormal OGTT with glucose greater than 200, 2 hrs after.

Front 4

Most important anabolic hormone known

Back 4

insulin

Front 5

Secreted by enterochromafinn cells

Back 5

Serotonin

Front 6

Prediabetic levels

Back 6

Fasting: 100-126
OGTT: 140-200

Front 7

Automimmune disease characterized by pancreatic B-cell destruction and absolute insulin deficiency

Back 7

Type I diabetes

Front 8

A combination of peripheral resistance and an inadequate secretory response by B-cells.

Back 8

Type II diabetes

Front 9

Facilitates hepatic gluconeogenesis and glycogenolysis

Back 9

Glucagon

Front 10

Primary determinant of fasting glucose levels

Back 10

Hepatic glucose output

Front 11

Major insulin receptor site for post-prandial glucose uptake and utilization.

Back 11

Skeletal muscle

Front 12

Serves as a surrogate for B cell function, decreasing with loss of B-cell mass in type I diabetes

Back 12

C-peptide

Front 13

Most important stimulus for insulin synthesis and release

Back 13

glucose

Front 14

Glucose receptor on pancreatic B-cells

Back 14

Glut-2

Front 15

Binding site for oral hypoglycemic agents such as sulfonylureas

Back 15

SUR-1

Front 16

How does binding of glucose to the Glut 2 cell receptor cause insulin release?

Back 16

Binding of Glut-2 receptor causes its uptake into the cell, where it is metabolized through glycolysis. This generates ATP, which shuts down the Na/K ATP-sensitive channel, and the membrane is depolarized. Ca influx stimulates release of insulin

Front 17

Insulin increases the rate of glucose uptake mainly where? What is it stored as?

Back 17

striated muscle: stored as glycogen
adipose tissue (small amount): lipid

Front 18

Glucose uptake in the brain

Back 18

insulin independant

Front 19

Insulin receptor

Back 19

Tetrameric protein composed of two alpha and two beta subunits

Front 20

Which inuslin receptor subunit has tyrosine kinase activity? Is this intra or extra-cellular. Action?

Back 20

B subunit: this is intracellular
Autophosphorylation of the IRS proteins, which activate PI3-Kinase and MAP kinase

Front 21

Insulin binding subunit. Intra or extracellular

Back 21

Alpha subunit: transcellular

Front 22

Insulin signaling facilitates the synthesis and transportation of vesicles containing what glucose transporter? Via what enzymes?

Back 22

GLUT-4: PI-3 Kinase activates AKT (protein kinase B), which mediates GLUT-4 synthesis and transport.

Front 23

Type I pathogenesis

Back 23

Autoimmune disease in which islet destruction is caused primarily by immune effector cells reacting against endogenous B-cell antigens

Front 24

Genetic haplotype consistent with diabetes

Back 24

HLA-DR3 or HLA-DR4

Front 25

Major environmental factor leading to Type-I diabetes

Back 25

Viral infections:
1. Bystander damage: viral infection induces islet injury and inflammation leading to B-cell activation and autoreactive T cell destruction.
2. Mimicry: Virus mimics B-cell antigens and immune response cross reacts with self-tissue
3. Viral deja vu: Predisposing virus is reactivated in the tissue with re-exposure, leading to an immune response.

Front 26

When do classical clinical manifestations present?

Back 26

Occur late in the course, when 90% of islet cells are destroyed.

Front 27

Fundamental immune abnormality in type I diabetes. Where does initial activation of these cells occur?

Back 27

Failure of self-tolerance in T cells
Peripancreatic lymph nodes, in response to antigens released from damaged islets

Front 28

Largest contributor to the pathogenesis of insulin resistance

Back 28

Decreased insulin sensitivity in hepatocytes

Front 29

Relationship of NEFA's and insulin sensitivity. Mechanism of decreased insulin sensitivity?

Back 29

Inverse: NEFA's cause accumulation of DAG and Ceramide, which activate serine/threonine kinases, which phophorylate the insulin receptor and IRS proteins at serine residues, thereby inactivating them.

Front 30

Phosphorylation attenuates insulin signaling

Back 30

Serine residues; tyrosine residues activates insulin signaling.

Front 31

Insulin inhibits what enzyme that is key for gluconeogenesis?

Back 31

PEPCK- the first enzyme

Front 32

Why is central adipose deposition associated with more deleterious effects than peripheral fat deposition

Back 32

Its more lipolytic, leading to increased amounts of plasma fatty acids.

Front 33

Anti-hyperglycemic adipokines. Mechanism of action

Back 33

Leptin and adiponectin:
Increase insulin sensitivity by activating AMPK, an enzyme that promotes fatty acid oxidation in liver and skeletal muscle

Front 34

Levels of what are reduced in obesity

Back 34

adiponectin

Front 35

Target of metformin

Back 35

AMPK, which increases fatty acid oxidation in skeletal muscle and liver

Front 36

How does inflammation affect insulin sensitivity?

Back 36

Decreases it by activating TNF, IL-1, IL-6, which induce cellular stress, and activate insulin counter-regulatory hormones.

Front 37

Characteristic finding of long-standing type II diabetics

Back 37

amyloid replacement of islets

Front 38

What other factor must be present besides insulin resistance, to lead to over diabetes?

Back 38

Beta-cell failure. Without this, many insulin resistant obese people will continue to secrete elevated levels of insulin, making up for receptor dysfunction.

Front 39

PPAR-Gamma is a receptor and transcription factor expressed where? Function? What line of medications act as agonists?

Back 39

Adipocytes: Promotes secretion of adiponectin and shifts deposition of NEFA's away from skeletal and muscle tissue and towards adipose tissue.
Thiazolidinediones

Front 40

Monogenic diabetes. What is its inheritance pattern? What form is most common?

Back 40

Primary defect in Beta-cell function or insulin receptor signaling.
Autosomal dominant with high penetrance.
MODY2 with enzyme dysfunction of glucokinase (GCK gene)

Front 41

Permanent neonatal diabetes

Back 41

Caused by a gain-of-function mutation of the ATPase K channel, leading to membrane hyperpolarization, and hypoinsulinemic diabetes.

Front 42

Characteristic finding of genetic defects of insulin receptor or action

Back 42

Hyperpigmentation of skin known as acanthosis nigrans

Front 43

Enzyme dysfunction associated with gestational diabetes

Back 43

Glucokinase gene

Front 44

The effects of microvascular disease are most profound in what organs?

Back 44

Capillary dysfunction of Retina, Kidney, and peripheral nerves

Front 45

Mcarovascular disease causes what

Back 45

Accelerated atherosclerosis

Front 46

What is the key mediator of long-term complications of diabetes

Back 46

Persistent hyperglycemia

Front 47

HB1ac

Back 47

non-enzymatic glycosylation of glucose to Hb

Front 48

AGE cross linking with what protein, decreases large vessel elasticity, and predisposes them to shear stress and endothelial injury

Back 48

Collagen type I

Front 49

Decreases endothelial cell adhesion and increases extravasation of fluid from basement membrane

Back 49

AGE induced crosslinking to type IV collagen

Front 50

RAGE

Back 50

Receptor that binds AGE's on inflammatory cells, vascular smooth muscle, and enodthelium

Front 51

What pathology occurs in the kidneys due to AGE's?

Back 51

AGE-crosslinked matrix in the glomerular capillary basement membrane bind and trap albumin, causing basement membrane thickening

Front 52

Deliterious effects of AGE-RAGE signaling

Back 52

1. Release of pro-inflammatory cytokines and growth factors from intimal macrophages
2. Generation of ROS from endothelium
3. Increased procoagulation activity
4. Proliferation of vascular smooth muscle and extracellular matrix

Front 53

Intracellular synthesis of DAG from glycolytic intermediates activates what enzyme that leads to many pathogenic effects

Back 53

Protein Kinase C

Front 54

Neovascularization characterizing diabetic retinopathy is caused by what?

Back 54

Increase in protein Kinase C which increases VEGF

Front 55

How does protein kinase C influence a thrombotic state

Back 55

1. Decreased levels of NO and increased levels of endothelin-1
2. Production of profibrogenic TGF-B, leading to an increased deposition of matrix and basement membrane material.
3. Production of PAI-1: Leading to reduced fibrinolysis
4. Pro-inflammatory cytokines

Front 56

In what tissues is the polyol pathway influential

Back 56

those that do not require insulin for uptake: nerves, lenses, kidneys, blood vessels

Front 57

Polyol Pathway

Back 57

Excess glucose is metabolized by aldose reductase to sorbitol and then to fructose. This rxn uses NADPH, which is also needed for glutathione reductase to reduced glutathione. Without glutathione, the cell becomes susceptible to ROS

Front 58

Major underlying cause of diabetic neuropathy

Back 58

hyperglycemia

Front 59

pancreatic finding in newborns, whose mother has diabetes

Back 59

Increase in the number and size of islets

Front 60

Histological findings of the Pancreas in type I diabetes

Back 60

1. reduction in the number and size of islets
2. Leukocytic infiltration (T cells) of the islets

Front 61

Histological presentation of the pancreas in type II diabetes

Back 61

1. Subtle reduction in islet cell mass
2. Amyloid deposition within islets in type 2 diabetes begins in and around capillaries

Front 62

Hallmark of diabetic macrovascular disease? Most common cause of death in diabetics?

Back 62

Accelerated atherosclerosis in the aorta and arteries.
Myocardial Infarction

Front 63

What diabetic pathology is 100x more common than the general population

Back 63

Gangrene of the lower extremities

Front 64

What vascular change is seen hypertensive diabetics?

Back 64

Hyaline arteriosclerosis

Front 65

Most consistent morphologic feature of diabetes. Despite this, what feature do they still show?

Back 65

Diffuse thickening of the basement membrane. Despite this, they are more leaky to plasma proteins.

Front 66

Glomerular sclerosis

Back 66

Spherical nodular lesions of matrix situated in the periphery of the glomerulus. Nodules show features of mesangiolysis with disruption of the mesangial-capillary interface, and resultant capillary microaneurysms. These lesions advance, the nodules enlarge and engulf the capillaries, destroying the glomerular tuft.

Front 67

Glomerular sclerosis lesions are accompanied by?

Back 67

Fibrin caps and capsular drops: prominent accumulations of hyaline material in capillary loops or adherent to Bowman's capsule.

Front 68

Most cases of kidney failure occur as a result of what pathological change in diabetics

Back 68

nodular glomerulosclerosis

Front 69

End result of glomerular arteriosclerosis

Back 69

Ishemia and tubular atrophy of the kidney, with interstitial fibrosis, and decreases in size.

Front 70

What feature of hyaline arteriosclerosis in diabetics is different from all other cases

Back 70

It also affects the efferent arterioles

Front 71

Form of pyelonephritis that is common in . Why is there increased susceptability?

Back 71

Necrotizing pappillitis: There is reduced neutrophil function (chemotaxis, endothelial adherence, phagocytosis, and microbicidal activity), impaired cytokine production, and vascular compromise

Front 72

Honeymoon period

Back 72

In initial 1-2 yrs after over type I diabetes, there may still lie a residual amount of minimal endogenous insulin secretion. thereafter, the insulin supply is exhausted and exogenous supply increases dramatically.

Front 73

Presentation of overt type I diabetes

Back 73

It may abrupt and precipitated by a stressful event or infection that increases the requirement for insulin

Front 74

Onset is marked by what clinical features

Back 74

PPP

Front 75

Glycosuria causes what?

Back 75

Osmotic diuresis and polyuria, this causes polydipsia, and may lead to hyperosmotic coma

Front 76

Decompensated Type II diabetics are at increased risk for?

Back 76

Hyperosmolar nonketotic coma

Front 77

The catabolism of proteins and fats tends to induce a negative energy balance, resulting in what symptom

Back 77

polyphagia

Front 78

Where are ketone bodies produced. What symptom may produce metabolic ketoacidosis?

Back 78

From oxidation of fatty acyl coenzyme A molecules within the hepatic mitochondria
During dehydration

Front 79

Earliest manifestations of diabetic nephropathy

Back 79

Microalbuminuria

Front 80

All patients with microalbuminuria should be screened for?

Back 80

Macrovascular disease

Front 81

Fundamental lesion of retinopathy. how is this induced

Back 81

Neovascularization: Induced by hypoxic conditions that overexpress VEGF in the retina