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Endocrine Two > Pancreas Pathology > Flashcards

Pancreas Pathology Flashcards

1
Q

How do you differentiate cell types in islets of langerhans?

A

ultrastructurally

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2
Q

D1 cells secrete ___? Fxn?

A

Vasoactive Intestinal Peptide (VIP)
• Induces glycogenolysis and hyperglycemia
• Stimulates gastrointestinal fluid secretion and causes
secretory diarrhea

WDHA Syndrome in VIPoma: Water Diarrhea, Hypokalemia, Achlorhydria

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3
Q

Enterochromaffin cells secrete ___? called what if present as a tumor?

A

Serotonin.

“carcinoid syndrome”

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4
Q
  • **Criteria for Dx of diabetes
  • which test does not need to be repeated for confirmation)

– A fasting plasma glucose
– Random plasma glucose
– 2-hour plasma glucose
– HbA1C (glycated hemoglobin) level

A

– A fasting plasma glucose ≥ 126 mg/dL
– Random plasma glucose ≥ 200 mg/dL (in a patient with classic
hyperglycemic signs) –> Does not need to be repeated
– 2-hour plasma glucose ≥ 200 mg/dL during an oral glucose tolerance test (OGTT) with a loading dose of 75 gm
– HbA1C (glycated hemoglobin) level ≥ 6.5%

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5
Q

Normal blood glucose

A

70-120

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6
Q

***Diagnostic criteria for imparied glucose tolerance (prediabetes)

– A fasting plasma glucose
– 2-hour plasma glucose
– HbA1C (glycated hemoglobin) level

A
  • Fasting plasma glucose 100-125 mg/dL
  • 2-hour plasma glucose 140-199 mg/dL following a 75-gm glucose Oral Glucose Tolerance Test
  • HbA1C level 5.7-6.4%
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7
Q

Prediabetics also have significant risk of what type of complications?

A

cardiac

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8
Q

Name the cell types in islets/exocrine pancreas and what they secrete.

A 
– β cells: insulin
– α cells: glucagon
– δ cells: somatostatin 
– PP cells: pancreatic polypeptide 
– D1 cells: vasoactive intestinal polypeptide (VIP)
– Enterochromaffin cells: serotonin
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9
Q

What does glycogen stimulate?

A

Glycogenolysis in the liver

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10
Q

What does pancreatic polypeptide stimulate?

A

Secretion of gastric and intestinal enzymes and inhibits intestinal motility

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11
Q

How are fasting plasma glucose levels determined?

A

Hepatic glucose output

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12
Q

By measuring the level of what peptide in a person taking exogenous insulin can determine how well B-cells are functioning. Why?

A

C-peptide because it is a mature hormone and a peptide byproduct of B-cells production.

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13
Q

Storage and secretion of B-cells and C-peptides.

A

Both are stored in secretory granules and secreted

after physiologic stimulation

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14
Q

What defines the “immediate release of insulin”.

A

The influx of intracellular Ca that occurs when membrane depolarizes dt ATP-inactivation of K+ channel (K stays in).

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15
Q

What is the most importan calss of hormones responsible for promotion of B-cell secretion following meals?

A

incretin

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16
Q

Name the most important types of incretins (dt pharmacologic importance).

A
  • GIP (secreted by K cells in small bowel)

- GLP-1 (secreted by L cells in distal ileum and colon)

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17
Q

Metabolic actions of insulin in striated muscle

A

Glycogen synthesis: increased
Protein synthesis: increased
Glucose uptake: increased

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18
Q

Metabolic actions of insulin in liver

A

Gluconeogenesis: decreased
Glycogen synthesis: increased
Lipogenesis: increased

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19
Q

Metabolic actions of insulin in adipose tissue

A

Glucose uptake: increase
Lipogenensis: increase
Lipolysis: decrease

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20
Q

Define type 1 DM

A

Islet destruction is caused primarily by immune effector cells reacting against endogenous β-cell antigens

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21
Q

Most important locus (~50% of genetic susceptibility) to Type 1

A

HLA gene cluster on ch6p21

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22
Q

95% of whites with DM1 have what one of what two haplotypes?

A

HLA-DR3 or HLA-DR4

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23
Q

HLA-DR3 or HLA-DR4 + ___ = highest inherited risk

A

DR8

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24
Q

Three other non-HLA genes that also confer susceptibility to DM1.

A
  • insulin with VNTRs in promoter region
  • CTLA4 and PTPN22
  • genes that code for immune regulators (AIRE)
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25
Q

Mechanism of B-cell destruction in DM1

A

Failure of self tolerance in autoreactive T cells specific for islet antigens.

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26
Q

Autoantigen targets in DM1

A

– anti-Insulin
– anti-GAD: β cell enzyme glutamic acid decarboxylase
– anti-ICA512: Islet cell autoantigen 512

27
Q

What two T cell populations are implicated in B-cell damage in DM1?

A
  1. Th1 (secrete cytokines, IFN-gamma and TNF, that injure B-cells)
  2. CD8 CTLs (kill B-cells directly)
28
Q

Loss of what % of B-cells necessary for hyperglycemia and ketosis to be evident in DM1?

A

90%

29
Q

Three overall reasons for pathogenesis of DM2

A
  1. Genetic
  2. Environmental - CENTRAL/VISCERAL OBSITY
  3. Metabolic Defects
30
Q

Describe the two realms of metabolic defects that implicate DM2.

A

a. Insulin resistance

b. inadequate insulin secretions

31
Q

Describe effects of insulin resistance in: liver,

A

– Failure to stop glucose production in presence of insulin

– Contributes to high fasting blood glucose levels

32
Q

Describe effects of insulin resistance in: skeletal muscle

A

– Failure of glucose uptake and glycogen synthesis after a meal
– Contributes to high post-prandial blood glucose level

33
Q

Describe effects of insulin resistance in: fat

A

Failure to inhibit activation of lipase → excess triglyceride breakdown and excess circulating free fatty acids (which amplifies insulin resistance)

34
Q

List three ways obesity can adversely impact insulin sensitivity.

A
  1. FFA - excess FFA leads to toxic intermediates (DAG), which attenuate insulin signaling, leading to INCREASED GLUCONEOGENESIS
  2. Adipokines - released by adipose and (1) promote hyperglycemia OR (2) result in insulin insensitivity
  3. Inflammation - excess FFA/glucose increase proinflammatory cytokine release (IL-8)
35
Q

Most common cause of monogenic diabetes and its MOA.

A

MODY - resembles DM2, results in mutations in glucokinase = decreased glucose metabolism, and decreased insulin release.

36
Q

Name the two genetic defects that impair tissue response to insulin

A
  1. Insulin receptor mutations

2. Lipoatrophic diabetes

37
Q

What is this? Hyperglycemia along with loss of adipose tissue in the subcutaneous fat
• Also have hypertriglyceridemia, acanthosis nigricans, and fat deposition in the liver

A

Lipoatrophic diabetes

38
Q

A person presents with:

  1. Acanthosis nigricans - velvety hyperpigmentation of the skin OR
  2. Women frequently have polycystic ovaries and elevated androgen levels
A

Insulin receptor mutations that impair tissue response to insulin –> Type A insulin receptor resistance.

39
Q

A women with preexisting diabetes become pregnant. What is this called and what are the risks?

A

Pregestational/Overt Diabetes: Increased risk of stillbirth and congenital malformations in the fetus if poorly controlled.

40
Q

A women develops impaired glucose tolerance and diabetes for the first time during pregnancy. What is this called and why does it occur?

A

Gestational Diabetes: Pregnancy is a “diabetogenic” state where the hormones favor a state of insulin resistance.

41
Q

What is the outlook for women with gestational diabetes?

A

– Typically resolves following delivery

– Majority develop overt diabetes over the next 10 to 20 years

42
Q

A pregnant woman does not realize that she had diabetes or poorly controls it. What are the consequences for her child?

A

– Large for gestational age newborn (Macrosomia)

– Child at an increased risk of developing obesity and diabetes later in life

43
Q

A YA presents with wt loss, mm weakness, and the sx of DM1. What is the classic triad of clinical symptoms for DM1? What can result when severe?

A

Polyuria, polydipsia, polyphagia.

Diabetic ketoacidosis if severe.

44
Q

An asx person presents is diagnosied with DM2 after a routine blood testing. If the person was sx, what are possibly s/s?

A

fatigue, dizziness, blurred vision

45
Q

A person presents with fruity odor breath, (Kussmaul breathing) deep/labored breathing, fatigue/N/V/abd pain. If severe, CNS depression and coma. What does this person have and DM1 or DM2 more likely - why?

A

Diabetic ketoacidosis, DM1 > DM2 because DM2 have higher portal vein insulin levels that prevent unrestricted hepatic fatty acid oxidation.

46
Q

What is the molecule/where is this molecule made that provokes diabetic keotacidosis.

A

Ketone bodies made from FA that are esterified in the liver, then oxidized in liver mitochondria.

47
Q

What condition will lead to the state of diabetic ketoacidosis?

A

Dehydration leads to decreased excretion of ketones, thus instigating metabolic ketoacidosis.

48
Q

An older diabetic disabled by stroke or infection is unable to maintain adequate water intake. Absence of ketoacidosis and sx, so delayed seeking medical attention until SEVERE DYHYDRATION and mental status impairment. What is this called and DM1 or DM2?

A

Hyperosmolar Hyperosmotic Syndrome (HHS) in DM2.

sustained osmotic diuresis causes severe dehydrations

49
Q

A DM presents with dizziness, confusion, sweating, palpitations, tachycardia. What does this person have?

A

Hypoglycemia - The most common acute metabolic complication in DM1 or DM2.

50
Q

In addition to failure to take insulin, what are other stressors that can cause diabetic ketoacidosos?

A

infections, trauma, drugs - many associated with EPINEPHRINE release, blocks insulin action and increases glucagon secretion

51
Q

Describe chronic complications from hyperglycemia/diabetes in relation to damage to large blood vessels.

A
  1. Diabetic macrovascular disease: HALLMARK = Accelerated atherosclerosis
52
Q

Describe chronic complications from hyperglycemia/diabetes in relation to damage to small blood vessels.

A
  1. Diabetic microvascular disease: retinopathy, nephropathy, neuropathy
53
Q

What is used for assessment of glycemic control in diabetics?

A 
Glycated hemoglobin (HbA1C)
– Provides a measure of glycemic control over the lifespan of a red cell (120 days)
– Recommended to be maintained
54
Q

What is HbA1C?

A

Formed by addition of glucose to hemoglobin in red cells. (4 mo hx of glucose control)
- More glucose = more HbA1C

55
Q

The rate of what nonenzymatic reactions between intracellular glucose-derived precursors with both intracellular and extracellular proteins is accelerated in presence of hyperglycemia?

A

Advanced Glycation End Products (AGEs)

56
Q

What do AGEs do?

A

Bind to specific receptor (RAGE) on inflammatory cells (macrophages and T cells), endothelium, and vascular smooth muscle = BM thickening/vascular damage!

57
Q

What are detrimental effects of AGEs when they bind to RAGE?

A

– Endothelial cells: Procoagulant activity, ROS, and cytokine/GF (TGFβ) → VEGF and BM material = Implicated in diabetic retinopathy
– Macrophages: Procoagulant activity
– Enhanced proliferation of vascular smooth muscle cells and synthesis of extracellular matrix

58
Q

What detrimental effects to AGEs have when they directly cross link ECM proteins?

A
  • Type I collagen in large vessels → ↓ elasticity (shearing and injury)
  • Type IV collagen in basement membrane → ↓ endothelial cell adhesion and ↑ extravasation of fluid
  • Trap LDL (lg vessels) and albumin (capillaries)
59
Q

What activates de novo synthesis of DAG and what does this result in?

A

Intracellular hyperglycemia stimulates DAG synthesis –> excessive PKC activation.

60
Q

List three downstream effects of PKC activation

A

Production of VEGF, TGF-B, PAI-1 = diabetic microangiopathy

61
Q

In nerves, lenses, kidneys, and blood vessels that DO NOT need insulin for glucose transport, how does hyperglycemia still affect them?

A

ultimately leads to increased susceptibility to ROS dt decreased glutathione

62
Q

Tx of ketoacidosis

A

insulin

63
Q

Pancreatic damage: type 1 v. type 2

A

type I = insulitis

type II = amyloid

Endocrine Two (16 decks)

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