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BMS 460 > Endocrine Pancreas: Islet Cell Tumors > Flashcards

Endocrine Pancreas: Islet Cell Tumors Flashcards

1
Q

where are NETs derived from?

A
  • first of all, these are islet cell tumors, aka pancreatic neuroendocrine tumors
  • they arise from neuroendocrine cells in the islets of langerhans
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2
Q

other note about carcinoid tumors

A
  • can also develop in the pancreas
  • they behave similarly to other carcinoid tumors of the gi tract
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3
Q

tumors with hormonal syndrome that present with hyperglycemia

A

due to glucagon-secreting tumors

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4
Q

tumors with hormonal syndrome that present with hypoglycemia

A

due to insulin-secreting tumors

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5
Q

tumors with hormonal syndrome that present with achlorhydria

A

due to somatostatin-secreting tumors

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6
Q

tumors with hormonal syndrome that present with peptic ulcers

A

due to gastrin-secreting tumors (could be part of zoellinger-ellison syndrome)

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7
Q

tumors with hormonal syndrome that present with secretory diarrhea (pancreatic diarrhea)

A
  • due to malignant VIPoma (secretes vasoactive intestinal polypeptide)
  • induces glycogenolysis and hyperglycemia, which stimulates GI fluid secretion
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8
Q

are NET’s benign or malignant?

A
  • can be both
  • malignant ones are called pancreatic endocrine cancer, or islet cell carcinoma
  • they often present with multiple metastatic tumor deposits in the liver
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9
Q

some details on pancreatic endocrine cancer (aka islet cell carcinoma)

A
  • remember, these are tumors from neuroendocrine cells in islets of langerhans
  • removal of localized tumors is usually curative
  • most islet cell tumors are nonfunctional and often reach a large size before being discovered
  • most islet cell tumors grow in the tail of the pancreas. this means they do not cause common bile duct obstruction and jaundice (unlike ductal pancreatic adenocarcinomas)
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10
Q

treatment of metastatic tumors with octreotide?

A
  • octreotide is a somatostatin analog
  • this will inhibit secretions that tumors may be exacerbating
  • this may alleviate hormonal symptoms, but does not cure because the actual tumors are still there
  • somatostatin inhibits glucagon, insulin, and HCl secretion, which many tumors exacerbate. however, some tumors themselves secrete somatostatin, so I don’t think octreotide would alleviate hormonal symptoms for these tumors
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11
Q

histology of neuroendocrine cells in islet cell tumors

A

tend to grow in ribbon-like patterns

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12
Q

compare islet cell tumors with pancreatic exocrine tumors

A
  • islet cell tumors are much less common than pancreatic exocrine tumors and have a better prognosis
  • insulinomas are the most common functioning pancreatic endocrine tumors
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13
Q

describe synthesis of insulin

A
  • insulin gene transcripts code for pre-proinsulin, which is a precursor protein
  • removing the signal peptide from this precursor in the ER of pancreatic B cells converts it to proinsulin
  • then, proinsulin gets cleaved by two endopeptidases that remove the C peptide that links the alpha and beta chains (these endopeptidases are proprotein convertases 1 and 2)
  • the C peptide and insulin are stored in secretory granules of B cells
  • they both get released to portal circulation (when blood glucose rises)
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14
Q

ratio of insulin to C peptide?

A

insulin and C peptide are stored and released in equimolar amounts

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15
Q

how can C peptide be used in a diagnostic context?

A
  • in type 1 diabetes, pancreas can’t make insulin, so there will be decreased C peptide
  • in type 2 diabetes, C peptide is normal or even higher because the pancreas does secrete insulin; it is the response that is impaired
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16
Q

describe secretion of insulin

A
  • plasma glucose concentration is the major stimulus for insulin release
  • glucose enters b cells via facilitated diffusion through GLUT2
  • increasing intracellular glucose increases the ATP/ADP ratio
  • increasing this ratio blocks the ATP-sensitive K+ channel, so K+ can’t leave the cell
  • this makes the inside more positive, therefore depolarizing the cell
  • depolarization opens v-gated calcium channels and increases cytosolic calcium levels
  • increased intracellular calcium triggers docking and fusion of neurosecretory granules with the plasma membrane. these granules are the ones that store insulin and C peptide, waiting to be released
  • insulin gets exocytosed
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17
Q

what precedes calcium-regulated neuroendocrine secretion of insulin?

A
  • ATP-dependent priming of the secretory granules
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18
Q

neonatal DM

A
  • mutations of the ATP-sensitive K+ channel
  • if this channel can’t get blocked response, intracellular K+ can’t increase, so the cell cannot depolarize, so vesicles containing insulin (and C-peptide) can’t be released
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19
Q

describe the effect of insulin on glucose uptake and metabolism

A
  • insulin binds to its receptor, which is a tyrosine kinase
  • this starts protein activation cascades
  • these cascades result in GLUT4 transporter getting put into the membrane
  • also influx of glucose, glycogen synthesis, glycolysis, and fatty acid synthesis
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20
Q

GLUT4

A
  • insulin-regulated glucose transporter
  • does facilitated diffusion
  • mostly found in adipose tissues and striated muscle
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21
Q

two types of glucose transporters

A
  1. GLUT (glucose transporter proteins): transport glucose via facilitative diffusion
  2. SGLT (sodium-dependent glucose transporters) use an energy coupled mechanism (active transport (secondary), sodium comes down its gradient and takes glucose in with it)
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22
Q

how many glut proteins are expressed in humans?

A
  • 14
  • they include transporters for things other than glucose, like fructose, etc.
  • some are insulin-regulated, some are not
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23
Q

describe fed-state metabolism

A
  • under the influence of insulin
  • promotes glucose metabolism by cells
  • overall, goal is to decrease plasma glucose, which as risen after a meal
  • slide 95!!!
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24
Q

describe fasted-state metabolism

A
  • under the influence of glucagon and insulin
  • this is the response to hypoglycemia
  • goal is to increase plasma glucose
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25
Q

big difference between insulin and glucagon

A
  • insulin acts on liver, mucle, adipose tissue, and other cells
  • glucagon only acts on the liver!!
26
Q

describe type 1 diabetes

A
  • IDDM, or insulin-dependent diabetes mellitus
  • caused by viral infection, autoimmunity (most common), or chemical toxins that affect B cells
  • overall, there is a lack of insulin because B cells get destroyed
  • these people need exogenous insulin because their pancreas doesn’t make any
  • B cells get damaged by cytokine action and autoantibodies from inflammatory cells
  • these people are susceptible to ketosis
  • most cases begin in childhood, but can develop at any age
27
Q

example of a type 1 diabetes lesion

A

insulitis - inflammation of the islet

28
Q

describe type 2 diabetes

A
  • NIDDM, or non-insulin-dependent diabetes mellitus
  • not enough insulin is secreted to combat glucose levels
  • can be caused by a genetic predisposition
  • these people do not need exogenous insulin
  • usually there is a decrease in tissue response to insulin
  • issue could be with insulin receptor or glut 2 transporter - it is something other than actual production of insulin
29
Q

example of a type 2 diabetes lesion

A

amyloidosis (accumulation affects function of normal islets)

30
Q

CF and cancer risk

A
  • CF patients have 5-10x higher risk of colorectal cancer
  • patients who have had a solid organ transplant have an even higher risk of colorectal cancer
31
Q

CF-related diabetes

A
  • about 30% of CF patients get CFRD
  • thick mucus in the pancreas prevents enough insulin (and other pancreatic enzymes) coming out of it
  • these patients can have their blood glucose monitored, eat a proper diet, and receive insulin injections
32
Q

go over CF-related diabetes pathophys on slide 97

A

DON’T BE LAZY

33
Q

go over the chart on slide 98

A

YOU NEED TO

34
Q

what is a manifestation that should raise suspicions about diabetes?

A

polyphagia (eating too much food) and weight loss at the same time

35
Q

is ADH effective in a diabetic state?

A
  • increased glucose in the renal tubes (because can’t all get filtered out) acts as an osmole, meaning it would pull water into the tubes and not as much will get reabsorbed
  • even when ADH is working to increase water reabsorption, it is not as effective when this intratubular glucose is elevated
36
Q

diabetic ketoacidosis

A
  • serious complication of type 1 diabetes, but can happen in type 2
  • release of epinephrine blocks any residual insulin action and stimulates glucagon release
  • excess glucagon alongside deficient insulin decreases peripheral utilization of glucose while at the same time increasing gluconeogenesis
  • glucose is being synthesized, but also can’t get into cells!
  • this exacerbates ketoacidosis and hyperglycemia
37
Q

what type of hormone is insulin?

A
  • an anabolic hormone
  • insulin deficiency puts the body in a catabolic state
  • this affects metabolism of glucose, fat, and proteins
38
Q

how does insulin deficiency lead to metabolic ketoacidosis?

A
  • insulin deficiency stimulates lipoprotein lipase
  • this breaks down adipose stores (because no glucose in the cell to get energy from)
  • which increases free fatty acids
  • free fatty acids get esterified to fatty acetyl CoA in the liver
  • acetyl CoA gets oxidized in the hepatic mitochondria to make ketone bodies
  • ketones are acidic
  • this leads to ketonemia (ketones in blood) and ketonuria (ketones in urine)
  • this leads to metabolic ketoacidosis
39
Q

we looked at ketoacidosis, but how does insulin deficiency cause regular metabolic acidosis?

A
  • blood glucose exceeds renal threshold for glucose, causing glucosuria
  • this causes osmotic diuresis/polyuria (too much pee)
  • this causes dehydration, decreasing blood pressure and blood volume
  • this causes circulatory failure, so tissues don’t have enough oxygen and need to resort to anaerobic metabolism
  • anaerobic metabolism produces lactic acid as a byproduct
  • this leads to metabolic acidosis
  • this will also increase ventilation (try to remove CO2 to increase pH) and cause urine acidification and hyperkalemia
40
Q

go over DM chart on slide 98

A

PLZ

41
Q

discuss counter-regulatory hormones in metabolic ketoacidosis

A
  • secretion of glucagon, growth hormone, and epinephrine is unopposed
  • epinephrine gets released due to the stress, blocks any residual insulin action, and stimulates glucagon
  • now, there is too little insulin but too much glucagon
  • this decreases peripheral utilization of glucose (because it can’t get into cells)
  • gluconeogenesis increases (because cells think there is no glucose)
  • this makes hyperglycemia that much worse
42
Q

what is another major effect of this change in the insulin:glucagon ratio, other than exacerbation of hyperglycemia?

A
  • this ratio activates ketogenic machinery
  • so, ketogenic amino acids will be released in order to produce ketones (causing ketoacidosis)
  • this happens by protein catabolism
43
Q

review/draw chart on slide 99

A

yesyesyesyesyesyes

44
Q

untreated absolute insulin deficiency

A
  • catabolic state
  • ketoacidosis and severe volume depletion
  • this impairs the CNS so much that coma and death can occur
45
Q

associations in type 1 vs. type 2

A
  • type 1: associated with other autoimmune diseases
  • type 2: no autoimmune associations
46
Q

difference in pathogenesis between type 1 and type 2

A
  • type 1: lack of insulin, pancreas does not have beta islet cells
  • type 2: relative insulin deficiency, though early stages might have hyperinsulinemia
47
Q

clinical findings in type 1 vs. type 2

A
  • type 1: polyuria, polydipsia, polyphagia, weight loss. also can have ketoacidosis or lactic acidosis from shock
  • type 2: insidious onset of symptoms, recurrent blurry vision is common. HNKC: hyperosmolar nonketonic coma: enough insulin to not have ketoacidosis, but not enough to stop hyperglycemia
48
Q

what is a major target of diabetes?

A
  • the vascular system
  • atherosclerosis of the aorta and large/medium blood vessels leads to myocardial and brain infarctions, as well as gangrene of the lower extremeties
  • this is a late complication of DM
  • arteriolosclerosis (thickening of arteriole walls) can cause HTN
49
Q

what does elevated serum glucose do?

A
  • causes nonenzymatic glycosylation
  • these abnormally glycosylated proteins can resist degredation and result in organ dysfunction
  • for example, elevated HbA1C is results from elevated glucose glycosylating hemoglobin
50
Q

loss of B cells as a late complication of DM causes

A
  • insulitis (type 1)
  • amyloid (type 2)
51
Q

eye complications and DM

A
  • DM can cause total blindness
  • retinopathy, cataracts, or glaucoma are common
52
Q

DM and kidneys

A
  • glomerulosclerosis (scarring), arteriosclerosis, and pyelonephritis (kidney infection) are common
53
Q

most significant damage to kidney caused by DM

A
  • thickening of basal lamina of glomerular capillaries and proliferation of mesangial cells within kidney
  • this is called the kimmelstiel-wilson lesion
54
Q

DM and gangrene

A
  • gangrene can be caused by blood vessel obstruction due to vascular arteriosclerosis
55
Q

four main types of neuropathy

A
  • peripheral
  • autonomic
  • radiculoplexus (diabetic amyotrophy)
  • mononeuropathy (focal neuropathy)
56
Q

peripheral neuropathy

A
  • most common types of diabetic neuropathy
  • starts with very ends of longest nerves
  • feet and legs affected first, then hands and arms
57
Q

autonomic neuropathy

A
  • ANS controls heart, bladder, lungs, stomach, intestines, sex organs, and eyes
  • this means that autonomic neuropathy can adversely affect any of these tissues
58
Q

radiculoplexus neuropathy (diabetic amyotrophy)

A
  • this does not affect the ends of nerves like peripheral neuropathy
  • instead, it affects nerves close to the hips or shoulders
  • typically at the root of long bones
  • this is more common in older adults and people with type 2 DM
59
Q

mononeuropathy (focal neuropathy)

A
  • only affects one nerve
  • sudden onset
  • a common type of compression neuropathy in people with DM is carpal tunnel syndrome
60
Q

how does diabetic neuropathy work overall?

A
  • loss of myelinated fibers
  • only thinly myelinated fibers
  • thickening of endoneurial vessel wall
  • remember endoneurium is CT layer covering each fiber

BMS 460 (28 decks)

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