Guerin: Endocrine Pancreas Flashcards
What kinds of cells are int he Islets of Langerhans?
- B cells: Insulin
- a cells: glucagon
- d cells: somatostatin
- PP cells: pancreatic polypeptide
What is somatostatin’s effect on insulin and glucagon?
-suppresses both of them
What are the rare cell types of the Islets of Langerhans?
- D1 cells: Vasoactive intestinal polypeptide (VIP)
- Enterochromaffin cells: serotonin
what does VIP do?
- induces glycogenolysis and hyperglycemia
- stimulates GI fluid secretion and causes secretory diarrhea
What does serotonin cause when it presents as a tumor?
-carcinoid syndrome
If someone has a fasting glucose done, where is that glucose coming from?
the liver
After a meal, what happens to insulin and glucagon levels?
-insulin levels rise and glucagon levels fall
Insulin
- B cells
- Precursor ptn is cleaved in golgi
- C-peptide is secreted in equimolar amounts with it
- stored in secretory granules
what lab do we look at to see if the B cells are working in someone who is taking exogenous insulin?
C peptide
What does the sulfonylurea recptor blokc?
the K+ channel…. traps K+
What two things does insulin decrease?
- Lipolysis
- Gluconeogenesis
Diabetes Mellitus
- hyperglycemia
- defects in insulin secretion or action
- damages other things if chronic
In the US, what is DM the leading cause of ?
-renal disease, adult-onset blindness, and non-traumatic lower extremity amputations
What is a normal glucose leve?
70-120
What is the criteria for diagnosing Diabetes?
- fasting glc >126
- random glc >200
- 2 hour plasma glc >200 during and oral glucose tolerance test (OGTT) with a loading dose of 75 gm
- HbA1C (glycated hemoglobin) >6.5
- need to be repeated and confirmed on a separate visit
What can acute stresses like burns or trauma lead to?
- transient hyperglycemia
- so, dx of Diabetes requires hyperglycemia following resolution of the acute illness
Impaired glucose tolerance (Prediabetes)
- fasting plasma glc 100-125
- 2 hr glc 140-199
- HbA1C 57.-6.4%
- up to 1/4 will develop overt diabetes over 5 years
- also have a significant risk for CV complications
Which is more common, type 1 or type 2 diabetes?
Type 2 (90-95%)
Which one has the circulating islet autoantibodies?
DM 1
Which one has the diabetic ketoacidosis in absence of insulin therapy?
DM1
Which one has insulin resistance in peripheral tissues, failure of compensation by B cells?
-DM2
Which one is the one where they are fat?
DM2
Which one has insulitis (inflammatory infiltrate of T cells and macrophages)?
DM1
-DM2 has amyloid deposition in islets
Type 1 DM
Islet destruction is cause by immune effector cells reacting against endogenous B cell antigens
-Childhood
Genetic susceptibility with DM1
- HLA gene cluster on Chromosome 6p21
- White ppl have HLA-DR3 or HLA-DR4 haplotype
Which genes have the highest inherited risk for DM1?
-HLAD DR3 or 4 PLUES DQ8
How many B cells do we have to lose to get hyperglycemia?
90%
What things do the autoantigens in DM1 target?
- insulin
- B cell enzyme glutamic acid decarboxylase (GAD)
- Islet cell autoantigen 512 (ICA512)
What was the big environmental factor for DM2?
OBESITY!
Metabolic defects in DM2
- insulin resistance
- inadequate insulin secretion (B-cell dysfunction)
Example of insulin resistance in Liver, muscle, and fat?
- Liver: failure to inhibit gluconeogenesis
- Muscle: failure of glucose uptake and glycogen synthesis after a meal
- Fat: failure to inhibit activation of lipase…. excess triglyceride breakdown and excess circulating FFA’s
How are the B cells through the development of DM2?
- normal
- increased secretion of insulin
- decreased… get tired
Monogenic forms of diabetes
- Genetic Defects in B cell function
- Defects that impair tissue response to insulin (IR mutations): Acanthosis nigricans and polycystic ovaries and elevated androgen levels
- Lipatrophic diabetes: hyperglycemia with loss of adipose tissue in the subcutaneous fat
Pregestational diabetes
- when women with preexisting diabetes become preggo
- increaed risk of stillbirth and congenital malformations in the fetus if poorly controlled
Gestational diabetes
- woman develops impaired glucose tolerance and diabetes for the first time during preggo
- resolves following delivery
- if poorly controlled later in preggo, you get large newborn
Clinical presentation of DM1
- <18 y/o
- can occur at any age tho
- sometimes, the transition from impaired glc tolerance to overt diabetes can be abrupt…. often triggered by infection
What is the classic triad for DM1?
- polyuria, polydipsia, and polyphagia
- when severe: diabetic ketoacidosis
Clinical presentation of DM2?
- > 40 y/o
- obese
- noticed after routine blood testing
- fatigue, dizziness, or blurred vision
Diabetic Ketoacidosis
- type 1 usually
- failure to take insulin is most common trigger
- Glc 250-600
- hyperglycemia causes an osmotic diuresis and dehydration
How doe diabetic ketoacidosis come about?
- insulin deficiency… stimulates lipase… breakdown of adipose stores… increased FFAs
- in the liver: FAs are esterified to fatty acyl CoA
- in liver mitochondria: oxidatino of fatty acyl CoA molecules produces Ketone bodies!
What happens if we also have dehydration along with diabetic ketoacidosis?
- decreased urinary excretion of ketoones
- metabolic ketoacidosis
Clinical manifestations of diabetic ketoacidosis?
- Fatigue
- Nausea and vomiting
- Severe ab pain
- fruity breath
- CNS depression and coma if we don’t do anything about it
What does reversal of ketoacidosis require?
- administration of insulin
- correction of metabolic acidosis
- tx of the underlying precipitating factors such as infection
Hyperosmolar hyperosmotic Syndrome (HHS) in Type 2 DM
- severe dehydration resulting from sustained osmotic diuresis
- usually only seek medical attention when: severe dehydration, imparireed mental status
- hyperglymcemia typically 600-1200 mg/dL
What is the most common acute metabolic complication in either type of diabetes?
- Hypoglycemia
- from missing a meal or physical exertion or excess insulin administration
- dizziness, confusion, sweating, palpitations, and tachycardia…. loss of consciousness
How do you treat hypoglycemia?
-oral or IV glucose
How do we assess glycemic control?
- % of glycated hemoglobin (HbA1C)
- keep it at <7% is diabetics
Diabetic macrovascular disease
- larger to medium arteries
- accelerated atherosclerosis: increased risk of MI, stroke, and lower extremity ischemia
Diabetic microvascular disease
- small vessels
- retinal, kidneys, and peripheral nerves
What is the hallmark for diabetic macrovascular disease?
-accelerated atherosclerosis involving the aorta and large and medium-sized arteries
What is the most common cause of death in diabetics?
Myocardial infarction
What do diabetics have a lot of that is an inhibitor of fibrinolysis and thus acts as a procoagulant… formation of atherosclerotic plaques
-PAI-1
What is something involving the extremities that is 100 times more common in diabetics?
-gangrene of the lower extremities
What blood vessel problem is more prevalent and severe in diabetics?
-hyaline arteriolosclerosis
What is diabetic microangiopathy?
- diffuse thickening of basement membranes
- paradoxically, diabetic capillaries are more leaky than normal to plasma proteins
What does diabetic microangiopathy lead to ?
development of diabetic nephropathy, retiopathy, and some forms of neuropathy
What is the second most common cause of death in diabetics?
- Diabetic nephropathy
- Native americans, hispanics, and african americans with type 2 DM
What is the first sign of diabetic nephropathy?
- microalbuminuria… low amounts of albumin in the urine
- if untreated…. overt nephropathy with macroalbuminuria… usually accompanied by the appearance of htn
- end stage renal disease… dialysis or renal transplant…. more common with DM1
What are the three lesions in diabetic nephropathy?
- glomerular
- Renal vascular lesions, principally arteriolosclerosis
- Pyelonephritis, including necrotizing papillitis
What happens with diabetic nephropathy to the capillary basement membrane
- GBM thickening
- can only be seen by electron microscopy
Diffuse mesangial sclerosis
- mesangial increase due to thickening of GBM
- MAtrix depositions are PAS positive
Nodular glomerulosclerosis
- Kimmelstiel-Wilson disease
- Nodules of matrix (PAS positive) situated in the periphery of the glomerulus
- as it progresses: nodules enlarge and eventruallly obliterate the glomerular tuft
What is that special pattern of acute pyelonephritis that is much more common in diabetics?
Necrotizing papillitis
Diabetic Neuropathy
- distal symmetric polyneuropathy of lower extremities is the most frequent pattern
- upper extremities get there too…. gloce and stocking pattern of polyneuropathy
- Autonomic neuropathy: bowel, bladder, and sometimes erectile dysfunction
- Mononeuropathy: sudden footdrop, wristdrop, or isolated cranial nerve palsies
What are some diabetic ocular complications?
- visual impairment, sometimes even total blindness
- 60-80% of diabetics
- retinopathy… overexpression of VEGF in retina
- Cataract: opacification of the lens
- Glaucoma: increased intraocular pressure and resulting damage to the optic nerve
In a pt with diabetic neuropathy, what could a trivial infection in the toe lead to?
-gangrene, bacteremia, pneumonia, even death
If we have an insulin producing tumor in the pancreas, will it most likely be benign or malignant?
- benign
- 60-90% of other functioning and nonfunctioning NETs are malignant… so insulin=good
Genetic alterations in sporadic PanNets?
- MEN1
- LOF mutation in tumor suppressor genes: PTEN and TSC2
- Inactivating mutations in two genes:
- Alpha-thalassemia/mental retardation syndrome, W-linked (ATRX)
- Death-domain associated protein (DAXX)
What are the most common clinical syndromes in PanNETs?
- hyperinsulinism
- hypergastrinemia (ZE syndrome)
- MEN
Hyperinsulinism (Insulinoma)
- B cell tumors
- most common pancreatic endocrine neoplasms
- can secrete enough insulin to induce clinically significant hypoglycemia
- classic clinical picture: hypoglycemic episodes (if blood glucose level falls below 50 mg/dL)
- relieved by feeding or parenteral administration of glucose
Morphology of insulinoma
- small
- looks like giant islet cells
- typically have deposition of amyloid
- hyperinsulinism may also be cause by focal or diffuse hyperplasia of the islets
What are other situations in which there is hyperplasia of the islets?
- maternal diabetes (usually transient)
- Beckwith-Wiedemann syndrome
- Rare mutation in the B-cell K+ channel protein or sulfonylurea receptor
Lab findings for insulinoma
-high circulating levels of insulin and a high insulin:glucose ratio
Tx for insulinoma
surgical resection of the tumor
Zollinger-Ellison Syndrome (gastrinomas)
- marked hypersecretion of gastrin
- as likely to arise in the duodenum and peripancreatic soft tissues as in the pancreas
- > 50% are locally invasive or have already metastasized at the time of diagnosis
- ~25% of pts gastrinomas arise in as part of the MEN-1 syndrome
- histologically bland
Clinical course of ZE syndrome?
- hypergastrinemia gives rise to extreme gastric acid secretion…. peptic ulceration
- ulcers are often unresponsive to therapy
- can also get ulcers in unusual locations such as the jejunum
- > 50% have diarrhea
Tx of ZE syndrome
- control of gastric acid secretion with proton pump inhibitors
- total resection of the neoplasm, when possible, eliminates the syndrome
What happens with pts that have ZE with hepatic metastases?
-progressive tumor growth leading to liver failure usually within 10 years
alpha cell tumors (glucagonomas)
- rare
- mild DM
- characteristic skin rash (necrolytic migratory erythema) and anemia
- most frequently in perimenopausal and postmenopausal women
Delta cell tumors (somatostatinomas)
- DM, Cholelithiasis, steatorrhea, and hypochlorhydria
- difficult to localize preoperatively
- also rare
VIPoma (release of vasoactive intestinal peptide (VIP))
- rare
- watery diarrhea, hypokalemia, achlorhydria (WDHA syndrome)
Most common Pancreatic NET?
-insulinoma
