Endocrine pancreas Flashcards
What are the main cell types in the islets and scattered in the exocrine pancreas and what do they secrete?
- Beta: insulin
- Alpha: glucagon
- delta: somatostatin
- PP: pancreatic polypeptide
What does glucagon do?
stimulates glycogenolysis in liver
What does somatostatin do?
suppresses both insulin and glucagon
What does pancreatic polypeptide do?
Stimulates secretion of gastric and intestinal enzymes and inhibits intestinal motility
What are the Rare cell types in the islets of Langerhans and what do they secrete
- D1 cells: VIP
- Enterochromaffin cells: serotonin
What does VIP do?
- induces glycogenolysis and hyperglycemia
- stimulates GI fluid secretion and causes secretory diarrhea
What is it called when there is a tumor of enterochromaffin cells secreting serotonin
carcinoid syndrome
during fasting you should have _____ levels of insulin and ______ levels of glucagon
- low
- high
Fasting plasma glucose levels are determined primarily by what?
hepatic glucose output
-Hepatic gluconeogenesis and glycogenolysis
the insulin precursor protein is proteolytically cleaved by what?
gives what and what?
- Golgi complex
- mature hormone and C-peptide
What can you measure in someone receiving exogenous insulin to determine how well B cells are functioning
C peptide levels
Describe the steps of insulin synthesis and secretion
- Glucose comes in through GLUT-2
- goes to mitochondria to produce ATP
- This ATP inhibits a K+ channel on the beta cells
- leads to membrane depolarization and influx of Ca
- this leads to secretion of insulin
effects of insulin on adipose tissue
- increase glucose uptake
- increase lipogenesis
- decrease lipolysis
effects of insulin on Striated muscle
-increase in glucose uptake, glycogen synthesis, and protein synthesis
effects of insulin on Liver
- decrease gluconeogenesis
- increase in glycogen synthesis
- increase in lipogenesis
A group of metabolic disorders with hyperglycemia from defects in insulin secretion and/or insulin action
Diabetes Mellitus
in Diabetes mellitus, chronic hyperglycemia and metabolic dysregulation is associated with secondary damage to what?
- kidneys
- eyes
- nerves
- blood vessels
In the US, what is the leading cause of end-stage renal disease, adult-onset blindness, and non traumatic lower extremity amputations
Diabetes mellitus
What ethnic groups are more likely to develop diabetes
- native americans
- african american
- Hispanics
What is normal blood glucose lever
70-120
- Diabetes: fasting plasma glucose >/= what?
- Random glucose level of what (in a patient with classic hyperglycemic signs)?
- 2 hour plasma glucose of what during an oral glucose tolerance test (OGTT) with loading dose of 75 gm?
- HbA1C (glycated hemoglobin) >/= what?
- 126
- greater than/equal to 200
- greater than/equal to 200
- > /= 6.5%
the tests for diagnosis of diabetes need to be repeated and confirmed on a separate visit except for which one?
the random blood glucose level in a patient with classic hyperglycemic signs
What acute stresses can lead to transient hyperglycemia?
-Severe infections, burns, trauma
What are the glucose levels for impaired glucose tolerance (Prediabetes)
- Fasting: 100-125
- 2 hour plasma glucose following 75 gm OGTT: 140-199
- HbA1C: 5.7-6.4%
describe the progression from prediabetes to diabetes and also the cardiovascular risk
- up to 1/4 of prediabetes pts will develop overt diabetes over 5 years
- they also have significant risk for cardiovascular complications
2 classifications of diabetes and %’s
- Type 1: 5-10%
- Type 2: 90-95%
This type of DM is caused by islet destruction caused primarily by immune effector cells reacting against endogenous Beta-cell antigens
type 1
Age for type 1 DM
- most commonly develops in childhood and becomes manifest at puberty and progresses with age
- can occur at any age
What is the MOST important locus for genetic susceptibility of type 1 DM
HLA gene on chromosome 6p21
- 90-95% of caucasians with DM1 have either HLA-DR3 or DR4 haplotype
- if DR3 or DR4 PLUS DQ8 . . . highest inherited risk
What are the other less important genes associated with susceptibility to DM1
- Wasinsulin
- CTLA4 and PTPN22
- AIRE: autoimmune polyendocrine syndrome, type 1
clinical onset of DM1 is what?
abrupt
what % of beta cells must be lost to get hyperglycemia and ketosis
90%
What do the autoantigens target in DM1
- insulin
- Beta cell enzyme glutamic acid decarboxylase (GAD)
- Islet cell autoantigen 512 (ICA512)
DM1 is failure of self tolerance in what cells?
T cells specific for islet antigens
What is the big environmental factor associated with DM2?
-Obesity: especially central/visceral obesity
What are the metabolic defects of DM2
- Insulin resistance: decreased response of peripheral tissues (esp. skeletal muscle, adipose tissue, and liver) to insulin
- Inadequate insulin secretion (Beta-cell dysfunction)
Inadequate insulin secretion is due to a combination of what things?
- excess free fatty acids: “lipotoxicity”
- chronic hyperglycemia: “glucotoxicity”
- abnormal “incretin effect”
- amyloid deposition within islets
- genetics
What does insulin resistance do to liver
- Failure to inhibit gluconeogenesis
- Contributes to high fasting blood glucose levels
What does insulin resistance do to skeletal muscles
- Failure of glucose uptake and glycogen synthesis after a meal
- contributes to high post-prandial blood glucose levels
What does insulin resistance do to fat
failure to inhibit activation of lipase –>excess triglyceride breakdown and excess circulating free fatty acids
What are the 2 broad categories of monogenic forms of diabetes
- Genetic defects in beta cell function
- Genetic defects that impair Tissue response to insulin
What are the 2 monogenic forms of diabetes that impair Tissue response to Insulin?
- Insulin receptor mutations: Acanthosis nigricans. Also Women frequently have polycystic ovaries and elevated androgen levels
- Lipoatrophic diabetes: hyperglycemia along with LOSS of adipose tissue and subcutaneous fat . . also have hypertriglyceridemia, aconathosis nigricans, and fat deposition in the liver
Describe pregestational diabetes
What are risks
- Women with preexisting diabetes become pregnant
- increased risk of stillbirth and congenital malformations in the fetus if poorly controlled
Describe gestational diabetes
what are risks
- women develops impaired glucose tolerance and diabetes for the first time during pregnancy
- Pregnancy is a “diabetogenic” state where the hormones favor a state of insulin resistance
- typically resolves following delivery
- Majority develop overt diabetes over next 10-20 years
What are the consequences of poorly controlled diabetes later in pregnancy
- Large for gestational age newborn (macrosomia)
- child at an increased risk of developing obesity and diabetes later in life
DM1 classically present when?
<18
the first 1 or 2 after the onset of DM1 can be a “honeymoon period” .. describe what this is
-exogenous insulin requirements may be minimal because of ongoing endogenous insulin secretion
Sometimes, in DM1, the transition from impaired glucose tolerance to overt diabetes can be abrupt and often triggered by what?
an infection
What is the classic triad in DM1?
if severe?
also see what?
- polyuria, polydipsia, and polyphagia
- Diabetic ketoacidosis
- weight loss and muscle weakness
typical age for DM2
> 40
how is DM2 usually diagnosed
after routine blood testing in asymptomatic persons
- screening recommended for >45 years
- Can present with fatigue, dizziness, or blurred vision
Which type of DM does diabetic ketoacidosis occur with
classically type 1, but can occur with type 2
What is diabetic ketoacidosis typically triggered by
- Failure to take insulin (most common)
- Other stressor: infections, illness, trauma and some drugs . . associated with release of epinephrine which blocks residual insulin actions and stimulates secretion of glucagon
What are glucose levels usually in diabetic ketoacidosis
usually 250 to 600
The hyperglycemia in diabetic ketoacidosis causes what?
-an osmotic diuresis and dehydration
Describe the mechanism of what happens to the body in diabetic ketoacidosis?
- insulin deficiency leads to activation of the ketogenic machinery
- insulin deficiency –> stimulates lipase –> breakdown of adipose stores –> increase in free fatty acids
- In liver: fatty acids are esterified to fatty acyl coenzyme A
- In liver mitochondria: oxidation of fatty acyl coenzyme A molecules produces KETONE BODIES (acetoacetic acid and Beta-hydroxybutyric acid)
When the rate of ketone body formation is greater than peripheral tissue use
- ketonemia
- ketonuria
If you get ketone body formation and also dehydration?
-decrease in urinary excretions of ketones –> metabolic acidosis
Clinical manifestations of diabetic ketoacidosis
- Fatigue
- Nausea and vomiting
- Severe abdominal pain
- Characteristic fruity odor
- deep, labored breathing (aka Kussmaul breathing)
- If persists, can get CNS depression and coma (and even death)
Reversal of Ketoacidosis requires what?
- Administration of insulin
- correction of metabolic acidosis
- Treatment of underlying precipitating factors such as infection
Why is it thought that ketoacidosis is lower incidence in DM2 than DM1?
higher portal vein insulin levels that prevent unrestricted hepatic fatty acid oxidation and keeps the formation of ketone bodies in check
What is it called when you get severe dehydration resulting from sustained osmotic diuresis
Hyperosmolar hyperosmotic syndrome (HHS)
What causes HHS and what type of DM?
- in patients who do not drunk enough water to compensate for urinary losses
- classically, pts are older and disables by a stroke or an infection
- DM2
HHS patients usually only seek medical attention when?
- severe dehydration
- Impaired mental status
what is the typical glucose level in HHS
600-1200
What is the most common acute metabolic complication in either type of diabetes
Hypoglycemia
Hypoglycemia in diabetes results from what?
- missing a meal
- excessive physical exertion
- excess insulin administration
- While trying to find appropriate dose of antidiabetic agents
Signs and symptoms of hypoglycemia
- Dizziness
- confusion
- sweating
- palpitations
- tachycardia
- Eventually loss of consciousness
What is the treatment for hypoglycemia
oral of IV glucose
overwhelming majority of the morbidity and mortality of diabetes is due to what?
chronic complications
Chronic diabetes takes how many years to develop
15-20 years after the onset of hyperglycemia
Severity of complication of chronic diabetes is related to what
both degree and duration of hyperglycemia
What are the 4 mechanisms proposed that contribute to the pathogenesis of hyperglycemia leading to chronic complications of DM
- formation of advanced glycation end products (AGEs)
- Activation of protein kinase C: vascular endothelium
- Oxidative stress and Disturbances in polyol pathways
- Hexosamine pathways and generation of Fructose-6-phosphate
What provides a measure of glycemic control over the lifespan of a red cell
percentage of glycated hemoglobin: HbA1C
What is the HbA1C recommended to be maintained at in diabetics
-<7% or even <6.5%
normal HbA1C
<5.7
What are the 2 broad categories of Chronic complications of diabetes from damage to blood vessels?
give the examples of each also
- Diabetic MACROvascular disease: Large and medium sized muscular arteries. Accelerated atherosclerosis . . increased risk of MI, stroke, and lower extremity ischemia
- Diabetic MICROvascular disease: small vessels. Retina, kidneys, and peripheral nerves
What is the hallmark of diabetic macrovascular disease
Accelerated atherosclerosis involving the aorta and large and medium sized arteries
-Greater severity and earlier age of onset than non-diabetic pts
What is the most common cause of death in diabetics
MI from coronary artery atherosclerosis
-followed by renal insufficiency and cerebrovascular accidents
give me the increased risks in diabetics for macrovascular complications
- 2-4 greater risk of coronary artery disease
- 4 fold greater risk of dying from cardiovacular complication
- increased risk also of CV in prediabetics
- Greater risk of HTN and dyslipidemia
Diabetics have and increase in PAI-1 . . explain what this means
This is an inhibitor of fibrinolysis and thus the increase acts as a procoagulant leading to formation of atherosclerotic plaques
Gangrene of lower extremity is 100x more common in diabetics . .this is from what?
vascular disease
Are larger renal arteries affected by diabetes
yes but microvascular damage is worse
Describe the hyaline arteriolosclerosis associated with HTN in diabetics
More prevalent and more severe
Describe diabetic microangiopathy
- DIFFUSE THICKENING OF BASEMENT MEMBREANES: paradoxically the capillaries are more leaky than normal to plasma proteins
- Most evident in capillaries of skin, skeletal muscle, retina, renal glomeruli, and renal medulla
- Leads to development of diabetic nephropathy, retinopathy, and some forms of neuropathy
What is the second most common cause of death in diabetics
diabetic nephropathy
what is the leading caused of end stage renal disease in the US
diabetes
What is he first sign of diabetic nephropathy
microalbuminuria: low amount of albumin in the urine (30-300 mg/day)
Microalbuminuria is a marker for greatly increased risk for what in diabetics
CV morbidity and mortality
All patients with microalbuminuria should be what?
screened for macrovascular disease and aggressively treated
If untreated, 80% of type 1 and 20-40% of type 2 diabetics with microalbuminuria will develop what over 10-15 years?
overt nephropathy with macroalbuminuria (>300 mg of urinary albumin/day)
-usually accompanied by appearance of HTN
> 75% of type 1 and 20% of type 2 diabetics with overt nephropathy will develops what over 20 years?
end stage renal disease requiring dialysis or renal transplantation
What are the 3 lesions in Diabetic nephropathy
- Glomerular lesions
- Renal vascular lesions, principally arteriolosclerosis
- Pyelonephritis, including necrotizing papillitis
What are the 3 glomerular lesions in Diabetic nephropathy?
- Capillary basement membrane thickening
- diffuse mesangial sclerosis
- nodular glomerulosclerosis
Capillary basement membrane thickening occurs in virtually all diabetic nephropathy and can only be seen how?
begins when?
what else thickens?
- electron microscopy
- as early as 2 years after the onset of type 1 diabetes and progresses
- tubular basement membranes
Describe the diffuse mesangial sclerosis of diabetic nephropathy
- Mesangial increase is typically associated with the overall thickening of the GBM
- Matrix depositions are PAS positive
- As the disease progresses it becomes nodular
- Progresssive expansion of the mesangium correlates with measures of deteriorating renal function (e.g. proteinuria)
Nodular glomerulosclerosis in diabetes is also called what?
Kemmelstiel Wilson disease
Describe the nodular glomerulosclerosis in diabetic nephropathy
- Nodules of matrix (PAS-positive) situated in the periphery of the glomerulus
- lesions can be patchy
- as it progresses: nodules enlarge and eventually obliterate the glomerular tuft
In Diabetic nephropathy, you get hyalinosis of what
both afferent and efferent glomerular hilar arterioles
In Diabetic nephropathy, the glomerular and arteriolar lesions lead to ischemia which then causes what?
tubular atrophy and interstitial fibrosis
this is a special pattern of acute pyelonephritis that is much more common in diabetics
Necrotizing papillitis or papillary necrosis
what % of diabetics have peripheral neuropathy
- up to 50%
- 80% with diabetes for >15 years
What is the most frequent pattern of involvement of diabetic neuropathy?
-distal symmetric polyneuropathy of lower extremity . . both motor and sensory function . .eventually upper extremities may be involved . . (“glove and stocking”)
describe the autonomic neuropathy in diabetics
bowel, bladder, and sometimes erectile dysfunction
What is the mononeuropathy in diabetics
sudden footdrop, wristdrop, or isolated cranial nerve palsies
What % of diabetics have visual impairment and sometimes even total blindness
-60-80% 15-20 years after diagnosis
What are the 3 visual impairments listed in diabetics?
- Retinopathy from neovascularization from hypoxia-induced overexpression of VEGF in the retina
- Cataract: opacification of the lens
- Glaucoma: increased intraocular pressure and resulting damage to optic nerve
Diabetics and infections
- increased susceptibility to infections of the skin, tuberculosis, pneumonia, and pyelonephritis
- Pt with diabetic neuropathy: trival infections in a toe may lead to gangrene, bacteremia, pneumonia, even death
Pancreatic neuroendocrine tumors are tumors of what
pancreatic islet cells
What is the unequivocal criteria for malignancy of pancreatic neuroendocrine tumors
- metastases
- vascular invasion
- local infiltration
Describe the functional status of pancreatic neuroendocrine tumors
- 90% of insulin producing tumors are benign
- 60-90% of other functioning and nonfunctioning NETs are malignant
What are the genetic alterations found in SPORADIC PanNETs
- MEN1
- loss of function: PTEN and TSC2
- inactivationg mutations in 2 genes: Alpha-thalassemia/mental retardation syndrome, X-linked (ATRX) and Death Domain associated protein (DAXX)
What are the most common clinical syndromes in PanNETs?
- Hyperinsulinism
- Hypergastrinemia (Zollinger-Ellison syndrome)
- Multiple endocrine neoplasia (MEN)
What is the momst common pancreatic endocrine neoplasm?
Insulinoma . . Beta cells
-Can secrete enough insulin to induce clinically significant hypoglycemia
What is the classic clinical picture of an insulinoma
- hypoglycemia episodes (if blood glucose level falls below 50)
- confusion, stupor, and loss of consciousness
- Precipitated by fasting or exercise
- Relieved by feeding or parenteral administration of glucose
Morphology of an insulinoma
- usually small (often < 2 cm)
- Histologically looks like giant islets
- Typically have deposition of amyloid
Besides an insulinoma, what else can cause hyperinsulinism
-focal or diffuse hyperplasia of the islets (previously known as nesidioblastosis)
hyperplasia of the islets can be seen in what situations?
- Maternal diabetes (usually transient)
- Beckwith-Wiedemann syndrome
- Rare mutations in the beta cell K+ channel protein or sulfonylurea receptor
What % of insulinomas are symptomatic
20%
lab finding in an insulinoma
- high circulating levels of insulin
- high insulin to glucose ratio
treatment of insulinoma
-surgical removal
What are the other random causes of hypoglycemia mentioned
- Abnormal insulin sensitivity
- diffuse liver disease
- inherited glycogenoses
- ectopic production of insulin by certain retroperitoneal fibromas and fibrosarcomas
- Induced by self injection of insulin
What gives marked hypersecretion of gastin
-Gastrinomas (Zollinger-Ellison syndrome)
Where are gastrinomas likely to arise
as likely to arise in the duodenum and peripancreatic soft tissues as in the pancreas
What % of Gastrinomas are locally invasive or have already metastasized at the time of diagnosis
> 50%
What % of patients with gastrinomas arise as part of MEN-1 syndrome
25%
Clincal course of Zollinger-Ellison syndrome
- Hypergastrinemia–>extreme gastric acid secretion –> peptic ulceration (in duodenum and stomach) . . ulcers are often unresponsive to therapy . . can also get them in jejunum
- > 50% have diarrhea
Treatment of Zollinger Ellison syndrome
- control of gastric acid with PPI
- Total resection of neoplasm, when possible, eliminates the syndrome
Describe the clinical course of Zollinger Ellison syndrome in those with hepatic metastases
progressive tumor growth leading to liver failure usually within 10 years
Describe an alpha-cell tumor
- glucagonoma
- mild DM
- characteristic skin rash (necrolytic migratory erythema)
- anemia
- Most frequently in perimenopausal and postmenopausal women
Describe a delta cell tumor
- somatostatinoma
- DM
- cholelithiasis
- steatorrhea
- hypochlorhydria
- Difficult to localize preoperatively
Describe a VIPoma
- watery diarrhea
- hypokalemia
- achlorhydria (WDHA syndrome)
