Endocrine Pancreas Guerin Flashcards
how can the islets of langerhans cells be differentiated
ultrastucturally and by their hormone content
what do PP cells do
pancreatic polpeptide stimulates the secretion of gastric and intestinal enzymes
-inhibits intestinal motility
rare cell types in islets of langerhans
D1 cells: VIP
enterochromaffin cells: serotonin
-tumor of these can cause carcinoid syndrome
what does VIP do
induces glycogenolysis and hyperglycemia
stimulates GI fluid secretion and causes secretory diarrhea
what is fasting plasma glucose levels usually detemined by
hepatic glucose output
insulin action on adipose tissue
increase glucose uptake
increase lipogeneisis
decrease lipolysis
insulin action on liver
decreased clugoneogenesis
increased glycogen synthesis
increased lipogenesis
insulin action on striated muslce
increase glucose uptake
increase glycogen syn
increase protein syn
mitogenic effects of insulin
initiation of DNA synthesis in certain cells and stimulation of their growth and differentiation
what pathway intracellulary is responible for GLUT4 transport to the PM
PI3K/ATK
and CBL
In the US diabetes is the leading cause of what
ESRD
adult onset blindness
non traumatic LE amputations
populations at greatest risk for diabetes
NAH
native americans, africans, hispanics
diagnosis of diabtes with fasting glucose of
126 or greater
diagnosis of diabetes: random plasma glucose
200 or greater (in pts with clasic hyperglycemis signs)
diagnosis of diabetes: 2 hour plasma glucose at ___ or greater during an oral glucose tolerance test with load dose of __
200 mg/dL
75 gm
diagnosis of diabetes: HbA1C level at
6.5% or above
which of the diagnosis of diabetes does not need confirmation test on separate visit
random blood glucose test in pt with classic hyperglycemic signs
what can lead to transient hyperglycemia
acute stress
infections, trauma, burns
impaired glucose tolerance (prediabetes)
fasting plasma glucose ___
2 hour plasma glucose with 75 gm OGTT ____
HbA1C level ___
will they develop overt diabetes?
increased risk for what?
100-125 mg/dL
140-199 mg/dL
5.7-6.4%
1/4 will over 5 years
increased risk for cardiovascular complications
genetic susceptibility in DM1
main ones
HLA gene cluster on chrom 6p21
- 90-95% of caucasians with HLA-DR3 or DR4
- DR3 or DR4 plus DQ8 has highest risk
- DQA11301-DQB10302 alleles
genetic susceptibility in DM1 other genes
wasinsulin polymorphism in CTLA4 and PTPN22 VNTR in promoter region of insulin gene gene for immune regulators (AIRE) -cause autoimmune polyendocrinopathy syndrome, type 1
environmental factors for diabetes type 1
possible viral infection but unknown which one
autoantigen target in B cell destruction for DM1
insulin
GAD (glutamic acid decarboxylase)
islet cell autoantigen 512
how much of islet B cell needs to be loss before get hyperglycemia and ketosis
90%, long period btwn initiation of autoimmune process and appearance of diseas
inadequate insulin secretion (b cell dysfunction) in DM2
initially there is insulin hypersecretion to overcome resistance
- from a combo of excess FFA (lipotox)
- chronic hyperglycemia (glucotox)
- abnormal incretin effect
- amyloid deposition within islets, and genetics
insulin resistance in liver
failure to inhibit gluconeogenesis (endogenous glucose production)
contributes to high fasting blood glucose levels
insulin reseistance in fat
failure to inhibit activation of HSL–> excess TG breakdown and excess circulating FFA
which adipokines decrease blood glucose by increasing insulin sensitivity and how are they effected in obesity
leptin and adiponectin
adiponectin levels are reduced in obseity and contribute to insulin resistance
PEP C and gluconeogensisis in central obesity
central obesity increases lipolysis of adipose tissue = excess FFA, which has DAG intermediate, which canc stop insulin signaling
-insulin usually stops gluconeogensis by blocking PEP carboxykinase, so without insulin PEPC ramps up gluconeogeneisis
central obesity and inflammation
proinflammatory cytokines are secreted in response to excess nutrients like FFAs and glucose =
insulin resitance and b cell dysfunction
-excess FFas within macrophages and b cells can activate inflammasome = more proinflamm cytokines = insulin resitance
several mechanism for b cell dysfunction in overt diabetes in type 2
excess FFA compromise b cell function and attenuate insulin release (lipotox)
impact of chronic hyperglycemia (glucotox)
abnormal incretin effect = reduced GIP and GLP-1 that normally causes insulin release
amyloid deposition wihtin islets, in people with long standing DM2 in 90% of pts
monogenic forms of diabetes, genetic defect in b cell function
no b cell loss
b cell mass and or insulin production effecte4d
was called MODY bc like DM2 but earlier onset
gene mutation is in glucokinase, this is the RLS for oxidative glucose metabolism which in turn is coupled to insulin secretion within islet b cells
-can also have defect in genes for ATP/K+ channel
monogenic forms of diabetes, genetic defects that impair tissue response to insulin
2 types
-symptoms associated with each
insulin receptor mutations
- acanthosis nigricans
- women have polycysitic ovaries and elevated androgen levels
-lipoatrophic diabetes
:hyperglycemia with loss of adipose tissue in subcut fat
:also have hyperTGemia, acanthosis nigricans, and fat deposition in liver
pregestational diabetes and pregnancy increased risk for
stillbirth
congenital malformations
gestational diabetes
what is it
how to fix
what can develop
women develops impaired glucose tolerance and diabetes for first time during pregnancy
- typically resolves after delivery
- majority develop overt diabetes in next 10-20 yrs
poorly controlled diabetes later in pregnancy can cause
large for gestational age newborn
child at increased risk of developing obesity and diabetes later in life
classic triad in DM1
if severe get
also see
polyuria, polydipsia, polyphagia
when severe enough you get diabetic ketoacidosis too
-also see weight loss and muscle weakness
DM type 2 can present with
fatigue, dizziness, or blurred vision
diabetic ketoacidosis is typically triggered by
failure to take insulin (most common)
other stressors: infections, illness, trauma, drugs (epinephrine, blocks insulin action and stimulates glucagon secretion)
glucose level for diabetic ketoacidosis
250-600 mg/dL
how are ketone bodies formed
decreased insulin = increased HSL–>increased FFA–>in liver FA esteried to fatty acyl coA–>in liver mitochond oxidize this to produce acetoacetic acid and b-hydroxybutyric acid
clinical manifestations of diabeti ketoacidosis
fatigue nausea and vomiting ab pain fruity odor deep, labored breathing (kussmaul breathing) -can get CNS depression and coma
why is ketoacidosis less common in DM 2
bc of higher portal vein insulin levels that prevent unrestricted hepatic fatty acid oxidation and keeps formation of ketone bodies in check
what is this called when
severe dehydration from sustained osmotic diuresis
-in pts who don’t drink enough water to compensate for urinary loss
-what pts?
when usually seek medical attention?
hyperglycemia at what?
hyperosmolar hyperosmotic syndrome in type 2 DM
older pts and disabled pts by stroke or infection
seek attention when
- severe dehydration
- impaired mental status
hyperglycemia 600-1200 mg/dL
signs and symptoms of hypoglycemia
dizziness, confusion, sweating, palpitations, tachycardia
chronic complication of diabetes
-diabetic macrovascular disease
large and medium sized muscular arteries
- accelerated atherosclerosis (hallmark)
- increased risk of MI, stroke, LE ischemia
- HTN and dyslipidemia in type 2 DM
- diabetics have increased PAI-1 = procoag = formation of atherosclerotic plaques
chronic complications of diabetes
microvascular disease
small vessels
retina, kidneys, and peripheral nerves
diabetic microangiopathy
diffuse thickening of basement memrbanes
- capillaries are more leaky than normal to plasma proteins
- seen in skin, muscle, retina, renal glomeruli and medulla
- leads to diabetic nephropathy, retinopathy, and some neuropathy
diabetic neprhopathy first sign
- marker for what
- may develop
microalbuminuria over 30 mg/day but less than 300 mg/day
- also marker for greatly increased CV mobidity and mortality
- 80% of type 1 and 20-40% of type 2 over 10-15 yrs will develop overt nephropathy with macroalbuminuria and HTN
3 lesions in diabetic neprhopathy
glomerular lesions
-capillary BM thickening, diffuse mesangial sclerosis, and nodular glomerulosclerosis
renal vascular lesions, principally arteriolosclerosis
pyelonephritis, including necrotzing papillitis
capillary basement membrane thickening
- what % of pts
- seen how
- when begins
- what else occurs
in virtually all diabetic nephropathy, only seen by electron microscopy
begins 2 years after onset of type 1
also have thickening of tubular basement membranes
diffuse mesangial sclerosis
- depositions are positive for what
- progression of disese
PAS positive
as progresses, becomes nodular
nodular glomerulosclerosis
- name of disease
- where
- progression?
kimmelstiel-wilson disease
nodules of matrix (PAS positive) in periphery of glomerulus
progression: nodules enlarge and obliterate glomerular tuft
arterioles in and tubes in diabetic nephropathy
hyalinosis of both afferent and efferent glomerular hilar arterioles
glomerular and arteriolar lesions –> ischemia–>tubular atrophy and intersitital fibrosis
diabetic neuropathy
distribution
types
glove and stocking pattern (LE first)
sensory and motor
autonomic neuropathy: bowel, bladder, ED
mononeuopathy: sudden footdrop, wristdrop, or isolated cranial nerve palsies
diabetic retinopathy
other eye manifestations
from neovascularization from hypoxia induced overexpression of VEGF in the retina
glaucoma and cataracts
diabetics have increased susceptibility to infections of the
skin, TB, pneumonia, and pyelonephritis
criteria for malignancy in pancreatic neuroendocrine tumors
can’t predict behavior based on microscopic appearance bc bland
criteria is metastases, vascular invasion, local infiltration
90% of insulin producing tumors are benign or malignant?
benign
60-90% of non insulin functioning and nonfunctioning NETs are what
malignant
genetic alterations in sporadic pancreatic NETs
MEN1 LOF: PTEN and TSC2 inactivating mutations in -ATRX -DAXX
most common clinical syndromes in PanNETs
hyperinsulinism
hypergastrinemia
MEN
classic clinical picture of insulinoma
hypoglycemic episodes if blood gluose under 50 mg/dL
morphology of insulinoma
small (less than 2 cm diameter)
look like giant islets
deposition of amyloid
hyperinsulinism not from insulinoma
focal or diffuse hyperplasia of islets (use to be called nesidioblastosis)
- maternal diabetes
- beckwith-wiedemann syndrome
- rare mutations in B cell K+ channel protein or sulfonylurea receptor
- mor common in neonates and infants from congenital malformation
other causes of hypoglycemia
abnormal insulin sensitivity
diffuse liver disease
inherited glycogenoses
ectopic production of insulin by retroperitoneal fibromas and fibrosarcomas
-induced by self injection of insulin
zollinger-ellison syndrome oversecretion of what location metastases? syndrome involved histology
hypersecrtion of gastrin in duodenum or pancreas >50% are locally invasive or have already metastasized at time of diagnosis -25% arise as part of MEN? -histologically bland
multifocal gastrinoma vs sporadic
MEN-1 syndrome is multifocal
sporadic is single
if you have unusual location of ulcer in the jejunum think what
zollinger-ellison syndrome
clinical course of ZE
metastases?
peptic ulcers in duodenum and stomach
50% have diarrhea
pts with hepatic metastases–>eventual liver failure within 10 yrs
treatment of ZE
PPI
total resection
other rare pancreatic endocrine neoplasms
- mild diabetes, skin rash (necrolytic migratory erythema) and anemia
- in perimenopausal and postmenopausal women mostly
SAM is an a-cell tumor bc he is menospausal
other rare PanNETs
-diabetes mellitus, cholelithiasis, steatorrhea, hypochlorhydria
D-cell tumor (somatostatinomas)
-D High school class
watery diarrhea, hypokalemia, achlorhydria
syndrome?
VIPoma
WDHA syndrome
