Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
166 Cards in this Set
- Front
- Back
Somatotrophs?
|
Produce GH, half of all hormone producing cells in anterior pituitary.
Acidophilic |
|
Lactotrophs?
|
Produce pRL.
Acidophilic |
|
What anterior pituitary cells are basophils?
|
Corticotrophs - ACTH, POMC, MSH, Endorphins, lipotropin
THyrotrophs - TSH Gonadotrophs - FSH, LH |
|
What stimulates ADH release?
|
Decreased BP sensed by the baroreceptors in the cardiac atria and carotids
Increase in plasma osmotic pressure detected by osmoreceptors Increased atrial distention (hypervolemia) inhibits ADH secretion |
|
Causes of hyperpituitarism?
|
Adenoma
Hyperplasia Carcinomas Ectopic Hypothalamic disorders |
|
Causes of hypopituitarism?
|
Ischemic injury
Surgery Radiation Inflammatory reactions Nonfunctional pituitary adenomas |
|
what are the earliest changes referable to mass effect?
|
Radiographic abnormalities of sella turcica
Sellar expansion Bony erosion Disruption of the Diaphragma sella |
|
What is pituitary apoplexy?
|
Acute hemorrhage into an adenoma associated with clinical evidence of rapid enlargement of the lesion. This is a surgical emergency because it can cause sudden death.
|
|
What is the most common cause of hyperpituitarism?
|
Adenoma arising in the anterior lobe
functioning vs. nonfunctioning |
|
Who are pituitary adenomas found in?
|
Usually in adults with a peak incidence from 35-60 years of age.
14% prevalence in population. Microadenomas vs. macroadenomas (</> 1cm) |
|
What are the best characterized molecular abnormalities in pituitary adenomas?
|
G-protein mutations
40% somatotrops, minority corticotroph absent in thyrotroph, lactotroph and gonadotroph - not cAMP dependant The alpha subunit of Gs is encoded by the GNAS gene on chromosome 20. A mutation in this subunit interferes with intrinsic GTPase activity and results in constitutive activation and generation of cAMP => unchecked cellular proliferation (mitogenic stimulus) |
|
What genes have been identified as a cause of familial pituitary adenomas?
|
MEN1
CDKN1B (checkpoint regulator) PRKAR1a (Protein kinase A regulatory subunit) AIP only 5% of cases arising from these |
|
What is MEN1?
|
It is a tumor suppressor protein "menin"
Causes tumors in multiple endocrine organs. 1/3 develop pitiuitary adenomas (GH, PRL, ACTH) |
|
What gene is mutated in MEN-1 like syndrome?
What gene is mutated in Carney complex? |
CDDKN1B (ACTH adenomas)
PRKAR1A (autosomal dominant disorder/ GH and PRL adenomas) |
|
What gene is often mutated in agromegaly patients?
|
AIP (aryl hydrocarbon receptor interacting protein)
Typically younger (<35 years) |
|
What genes are mutated in aggressive adenomas?
|
Overexpression of cyclin D1
P53 mutation Silenced retinoblastoma RB1: methylation of RB gene HRAS oncogene: activating mutation - pituitary carcinomas |
|
What do pituitary adenomas normally look like?
|
Soft, well-circumscribed lesions that are confined to the sella turcica.
Larger extend into the suprasellar region. |
|
What is an invasive adenoma?
|
30% are not encapsulated and inflitrate tisseus like the cavernous and sphenoid sinuses, dura, and brain.
Can have foci of hemorrhage and necrosis |
|
What is the histology of a pituitary adenoma?
|
Uniform, polygonal cells arrayed in sheets or cords.
Reticulin is sparse, so they have a soft gelatinous consistency. Sparse mitotic activity, stains differently depending on the type of tumor (generally uniform) "cellular monomorphism" |
|
What immunoreactivity do pituitary adenomas present with?
|
p53
3% with proliferation marker Ki-67 Tumors with these markers are atypical adenomas. |
|
What are the general signs and symptoms of pituitary adenomas?
|
Radiographic abnormalities of sella turcica, visual field abnormalities, signs of elevated intracranial pressure, hypopituitarism.
|
|
What is the most frequent type of hyperfunctioning adenoma?
|
Prolactinomas (lactotroph adenomas) 30% of all clinically recognized cases.
Composed of weakly acidophilic or chromophobic cells Sparse or dense (color determination) |
|
What symptoms occur with a prolactinoma?
|
Amenorrhea (no FSH or LH from lack of GnRH)
Galactorrhea (lobular unit of breast makes milk) Loss of libido (lack of GnRH) Infertility Headaches |
|
What are the characteristics of prolactinoma?
|
Diagnosis is made more readily in women than men.
Ages 20-40 years, older people have subtle symptoms because of cessation of hormones 1/4 of amenorrhea cases = prolactinoma |
|
What other things cause hyperprolactinemia?
|
Pregnancy: serum levels peak at delivery
Nipple stimulation Stress Lactotroph hyperplasia: normal dopamine inhibition is blocked (damage to hypo or to stalk) Drugs blocking dopamine receptors on lactotroph cells Mass in suprasellar compartment Estrogens Renal failure Hypothyroidism |
|
How do you treat prolactinomas?
|
With bromocriptine: dopamine receptor agonist
Surgery to remove tumor. |
|
What are GH cell-containing adenomas classified into?
|
Densley granulated: Monomorphic and acidophilic cells. Demonstrate cytokeratin staining in perinuclear distribution.
Sparsely granulated: Chromophobe cells with nuclear and cytologic pleomorphism and focal, weak GH staining. Bihormonal mammosomatotorph adenomas (GH and PRL expression) - resemble densely granulated |
|
What happens if a somatotropic adenoma appears in a child before the epiphyses have closed?
|
Elevated GH and IGF-1 will cause gigantism
Increase in body size, disproportionately long arms and legs. |
|
What occurs if increased GH secretion is present after closure of hte epiphyses?
|
Acromegaly
Skin soft tissue growth Visceral growth: thyroid, heart, liver, adrenals Bones of face, hands and feet Bone density increased (hyperostosis) in spine nad hips Prognathism Changes can develop for decades without being noticed |
|
What other things can cause GH excess?
|
Gonadal dysfunction, DM, generalized muscle weakness, hypertension, arthritis, CHF, GI cancers
|
|
How do you diagnose pituitary excess?
|
Elevated serum GH and IGF-1 levels.
Failure to suppress GH production with an oral load of glucose |
|
How do you treat GH excess?
|
Somatostatin analogs
GH receptor antagonists |
|
What are the characteristics of ACTH cell adenomas?
|
Basophilic (densley granulated)
Sometimes they are chromophobic (sparsely granulated) Stain with PAS because POMC has carbohydrates in it. |
|
What occurs with an ACTH cell adenoma?
|
Adrenal hypersecretion of cortisol = development of hypercortisolism (Cushings syndrome/disease)
|
|
What is Nelson syndrome?
|
When large destructive adenomas develop in patients after surgical removal of adrenal glands for treatment of Cushing syndrome.
Loss of inhibitory effect of adrenal hormones on a preexisting corticotroph microadenoma. Present with mass effects of pituitary tumor but no hypercortisolism. Hyperpigmentation possible because of ACTH stimulation of melanocytes. |
|
What are the characteristics of a gonadotroph adenoma?
|
More frequently found in middle aged men and women
Impaired vision Headaches Diplopia Pituitary apoplexy Impaired LH = decreased libido, amenorrhea, secondary gonadal hypofunction Neoplastic cells: alpha subunit and specific B-FSH and B-LH subunits |
|
What is the prevalance of thyrotroph adenomas?
|
1%, rare cause of hyperthyroidism
|
|
What are nonfunctioning pituitary adenomas?
|
Heterogeneous group (25-30%) of all pituitary tumors.
Silent varients or null-cell adenomas Typical presentation is mass effects, can cause hypopituitarism from enlargement of the tumor or hemorrhage from enlargement. |
|
What kind of pituitary carcinomas are the most common?
|
These account for less than 1% of pituitary tumors.
Craniospinal/systematic metastases appear late in its course. PRL and ACTH are the most common functional neoplastic forms. |
|
When does hypofunction of the anterior pituitary?
|
When 75% of the parenchyme is lost or absent.
Congential or acquired Evidence is almost always accompanied by diabetes insipidus |
|
What are the causes of hypopituitarism?
|
Pituitary adenomas (adults)
Craniopharyngioma (kids) Metastatic malignancies Cysts Traumatic brain injury and subarachnoid hemorrhage (most common) Pituitary surgery or radiation Pituitary apoplexy Sheehan syndrome (ischemic injury) Rathke cleft cyst Empty sella syndrome Genetic defects Hypothalamic lesions Inflammatory disorders and infections (sarcoidosis, TB, meningitis) |
|
What is Sheehan syndrome?
|
Postpartum necrosis of anterior pituitary.
Pregnancy: pituitary doubles in size and does not have an increased blood supply, relative anoxia. Redction in blood supply following delivery, or shock can cause infarction and necrosis can occur. Posterior pituitary receives blood from direct arteries, not veins, so it is not affected. |
|
What other things can cause pituitary necrosis?
|
DIC
Sickle cell anemia Elevated intracranial pressure Traumatic injury Shock |
|
What is a Rathke cleft cyst?
|
Lined by ciliated cuboidal epithelium
Has occasional goblet cells and anterior pituitary cells => accumulate proteinaceous fluid and expand. |
|
What is empty sella syndrome?
|
Any condition that destroys part or all of the pit gland.
Ablation by surgery or radation The syndrome is an enlarged epty sella turcica. |
|
What are the two types of empty sella syndrome?
|
Primary= congenital defect in the diaphragma sella that allows the arachnoid mater and SCF to herniate into the sella which compresses and atrophies the gland.
Secondary = From trauma, where a mass is removed or necroses leading to loss of function. |
|
Who clasically gets primary empty sella?
|
Obese women with a hx of multiple pregancies.
Visual field defects, endocrine anomalies. |
|
Mutation of what gene causes combined pituitary hormone deficiency?
|
POU1F1= pituitary specific homeobox gene
Deficiencies in GH, pRL, and TSH |
|
What cause of hypopituitarism can affect the posterior pituitary?
|
Hypothalamic lesions.
Tumors, craniopharyngiomas, malignant tumors (breast and lung carcinomas) |
|
What are most prevalent signs of hypopituitarism?
|
Dwarfism
Amenorrhea Loss of pubic and armpit heair in men Infertility in women Decreased libido, impotence No lactation Pallor from loss of MSH on melanocytes |
|
Causes of diabetes insipidus?
|
Trauma
Tumors Inflammatory disorders Infection Surgical procedures Drugs: (nephrogenic) lithium, endomethlocycline |
|
What are the causes of SIADH?
|
Secretion of ectopic ADH by malignant neoplasms (small cell carcinomas of the lung)
Drugs that increase ADH secretion (cyclophosphamide) CNS disorders Infections and trauma |
|
What are the most common implicated lesions for hypothalamic suprasellar tumors?
|
Gliomas: arise in the chiasm
Craniopharyngiomas: Rathke pouch remnant (1-5% of intracranial tumors, slow growing) |
|
Characteristics of suprasellar tumors?
|
Bimodal age: 5-15 years or 65 and older
Headaches visual disturbances Children: growth retardation Abnormal WNT signaling pathway, activating B-catenin mutations |
|
What is the morphology of a craniopharyngioma?
|
3-4 cm in diameter
Encapsulated and solid, but more commonly cystic and multiloculated Can bulge into the floor of the third ventricle Rarely malignant and have a great survival if they are less than 5 cm. |
|
What are the two types of craniopharyngioma?
|
Adamantinomatous (kids): frequently is calcified
Papillary (adults) |
|
What is the morphology of adamantinomatous craniopharyngiomas?
|
Nests or cords of stratified squamous epithelium embedded in a spongy reticulum that is more prominent in the internal layers.
Palisading of the squamous epithelium is seen at the periphery Compact lamellar keratin formation (wet keratin) Dystrophic calcification Cyst formation = cholesterol rich brown-yellow fluid (looks like motor oil). Fibrosis, chronic inflammation Fingerlets of epithelium extend into adjacent brain where they elicit a brisk glial reaction. |
|
What is the morphology of papillary craniopharyngiomas?
|
Solid sheets and pipillae lined by well-differentiated squamous epithelium.
Lack keratin, calcification and cysts. Squamous cells of solid sections: lack peripheral palisading and do not have spongy reticulum |
|
What is the usual age of onset for DM 1?
|
14 years
5-10% of people with DM have type 1. Type 2 is much more common. |
|
What are the three principal sequelae that develop with DM 1?
|
1) Increased blood glucose
2) Increased utilization of fats for energy, cholesteral formation 3) Depletion of body proteins |
|
What is the threshold for appearance of glucose in the urine?
|
180 mg/100 mL glucose.
100 or more grams can be lost when glucose is in the 300-500 range. |
|
What is "asthenia"?
|
Lack of energy
|
|
What is "polyphagia"?
|
Eating large amounts of food.
|
|
When does type 2 DM occur?
|
After the age of 30, mostly between 50-60 years.
90-95% of DM cases. Related to obesity, which is the most important risk factor for developing type 2. |
|
What is the mechanism behind most of the insulin resistance that leads to DM2?
|
Abnormalities of the signaling pathways that link receptor activation with cellular effects.
Toxic effects of lipid accumulation in tissues like skeletal muscle and liver secondary to excess weight gain. |
|
What is metabolic syndrome?
|
1) Obesity = abdominal fat accumulation
2) Insulin resistance 3) Fasting hyperglycemia 4) Lipid abnormalities (increased TG's/ decreased HDL) 5) Hypertension |
|
What other things can cause DM2?
|
Polycystic ovary syndrome (PCOS)
Cushings syndrome/steroid therapy Agromegaly Pregnancy/gestational diabetes Genetic lipodystrophy Autoantibodies/mutations of insulin receptor Mutations of peroxisome proliferator's activator receptor (PPARY) Mutations in melanocortin receptors Hemachromatosis |
|
Why does PCOS affect insulin resistance?
|
Increases in ovarian androgen production causing insulin resistance.
6% of all women during reproductive life affected. Insulin resistance and hyperinsulinemia found in 80% of affected women. |
|
What drugs increase insulin sensitivity?
|
thiazolidinediones
|
|
What drugs suppress liver glucose production?
|
metaformin
|
|
What drugs cause additional release of insulin by pancreas?
|
Sulfonylureas
|
|
What occurs in DM patients after a load of glucose?
|
Rises above 140, and have a much greater than normal rise in blood glucose.
Normal patients will have the level fall back to the control value after 4-6hrs and falls BELOW control value. If it does not fall below the control value: 1) normal increase in insulin secretion after glucose ingestion is impaired 2) decreased sensitivity to insulin |
|
When does excessive insulin production occur?
|
Usually from an adenoma of an islet of Langerhans.
10-15% are malignant and can spread throughout body. |
|
What is a complication of having an insulinoma?
|
Hypoglycemic shock. "insulin shock"
Glucose of 50-70 = excitable CNS from sensitized neuronal activity. Nervousness, tremor, sweating. Glucose of 20-50 = Metabolism of CNS depressed. Clonic seizures, loss of conciousness. Glucose <20 = coma Administer glucose, glucagon, epinephrine. |
|
How do you differentiate between diabetic coma and hypoglycemic coma?
|
Presence of acetone breath, deep breathing = Diabetic
|
|
What do the B cells of the pancreas look like?
|
Granules contain a rectangular crystalline matrix surrounded by a halo.
|
|
What do the A cells of the pancreas look like?
|
Granules, are round, with closely applied membranes and a dense center.
|
|
What do the D cells of the pancrease look like?
|
Large, pale granules with closely applied membranes.
|
|
What do the PP cells look like?
|
Small, dark granules that are not only present in islets but also are scattered in the exocrine pancreas.
|
|
What are the two rare cell types in the pancreas?
|
D1 cells: VIP (induces glycogenolysis and hyperglycemia; stimulates GI fluid secretion, causes diarrhea)
Enterochromaffin cells: Synthesize serotonin => cause carcinoid syndrome (pancreatic tumors) |
|
What is "prediabetes"?
|
Elevated blood sugar that does not reach the criterion accepted for an outright diagnosis of DM
Elevated risk for developing frank diabetes. (5-10% developing DM per year) At risk for cardiovascular diseease Fasting glucose btwn 100-126 OGTT values btwn 140-200 |
|
What race is more at risk for developing diabetes over a lifetime?
|
Native Americans
African Americans Hispanics 1.5-2x more likely |
|
How is the diagnosis of DM made?
|
1) random glucose concentration >200
2) fasting glucose concentration >126 on more than one occasion 3) Abnormal glucose tolerance test, where glucose concentration is >200 two hours after a standard carb load |
|
What is Type 1 DM?
|
B-cell destruction usually leading to absolute insuline deficiency
(5-10% of DM cases) Usually diagnosed under 20 years Immune mediated type Idiopathic type |
|
What is Type II DM?
|
Combo of insulin resistance and B-cell dysfunction
(90-95% of DM cases) Adult onset => related to obesity |
|
What is maturity onset diabetes of the young (MODY)?
|
Type 1: HNF4A
Type 2: Glucokinase Type 3: HNF1A Type 4: Pancreatic & Duod homeobox 1 (PDX1) Type 5: HNF1B Type 6: Neurogenic differentiation factor 1 (NEUROD1) |
|
What is Neonatal diabetes?
|
Activating mutations in KCNJ11, ABCC8
These encode Kir6.2 (inward rectifying K channel) and SUR1 (sulfonylurea receptor, binding site for oral hypoglycemic agents) |
|
What is maternally inherited diabetes and deafness?
|
Due to mitochondrial DNA mutations
m.3243A --> G |
|
What are genetic defects of B-cell function?
|
MODY - mutations in glucokinase, and/or 5 genes that control transcription factors that control insulin expression in B-cells and B-cell mass. IPF1 (PDX1 develops pancreas).
Neonatal diabetes - activation mutations of KCN11 & ABCC8 genes encode subunits of K channel (hyperpolarized cell). Severe hyperglycemia, KA, and (1/5) have epilepsy MIDD - mitochondrial DNA mutations => impair ATP synthesis in islet cells => decreased insulin. Bilateral sensorineural deafness. Defects in proinsulin conversion Insulin gene mutations - presents in neonatal but also in childhood/adolescence |
|
What are genetic defects in insulin action?
|
Type A insulin resistance - velvity hyperpigmentation of skin (acanthosis nigricans). PCOS, elevated androgen levels.
Lipoatrophic diabetes = mutations in PPARG Hyperglycemia w/ loss of adipose tissue (subcutaneous). Insulin resistance, diabetes, hypertriglyceridemia, AN, hepatic steatosis. Dominant negative = DNA-binding domain of PPARG |
|
What are exocrine pancreas defects?
|
Chronic pancreatitis
Pancreatectomy/trauma Neoplasia CF Hemachromatosis Fibrocalculous pancreatopathy |
|
What are endocrinopathies that can give someone DM?
|
Acromegaly
Cushings sydrome Hyperthyroidism Pheochromocytoma Glucagonoma |
|
What are infections that can cause DM?
|
Cytomegalovirus
Coxsackie B virus Congenital rubella Mumps |
|
What are drugs that can cause DM?
|
Gulcocorticoids
Thyroid hormone Interferon-a Protease inhibitors B-adrenergic agonists Thiazides Nicotinic acid Phenytoin (dilantin) Vacor |
|
What are genetic syndromes associated with diabetes?
|
Down's syndrome
Klienfelter syndrome Turner syndrome Prader-Willi syndrome |
|
What glucose transporter facilitates glucose uptake into B-cells?
|
GLUT2
|
|
What is the structure of the insulin receptor?
|
Tetrameric protein which has two A and two B subunits.
The A subunit is anchored in the membrane The B subunit has TK activity |
|
How does the insulin receptor work?
|
The A subunit is activated by insulin binding and in turn activates the B-subunit TK => autophosphorylation of receptor => phosphorylation of IRS proteins & GAB1 =>
1)activate PI-3K => AKT => Docking of vesicles containing the GLUT-4 transporter 2) MEK/ERK => MAP kinase pathways => protein synthesis, cell growth and differentiation |
|
What mediates the GLUT-4 transporter vesicle docking?
|
PI-3K => AKT
CBL which is directly phosphorylated by the receptor |
|
What inhibits the insulin receptor?
|
Protein tyrosine phosphatase 1B = dephosphorylates the insulin receptor and inhibits signaling
PTEN => attenuates signaling by blocking AKT activation in the PI-3K pathway |
|
What is the most important susceptibility loci for Type 1 DM?
|
HLA locus on chromosome 6p21
50% contribution 90-95% of Caucasians with disease have HLA-DR3 or HLA-DR4 40-50% of ppl have DR3/DR4 combined 5% have a DQ8 with DR3 or DR4 (highest risk for DM in siblings) |
|
What mutations are non-MHC contributors to DM1?
|
VNTR (tandem repeats) => altered negative selection in thymus
CTLA4 PTPN22 (inhibit T cell responses, so excessive T cell activation occurs) CD25 = encodes A chain of IL-2 receptor |
|
What three mechanisms are proposed to explain the role of viruses in the induction of autoimmunity for DM?
|
1) Bystander damage = viral infections induce islet injury/inflammation causing B-cell antigens to build up and activate T cells
2) Molecular mimicry = viral proteins mimic B-cell antigens and there is cross reactions with self tissue 3) Viral deja vu = early predisposing virus stays in tissue of interest and when the person is infected with a related virus (precipitating) that shares the epitopes leads to the immune response. (this might explain the latency between infections and onset of diabetes) |
|
When do the manifestations of DM 1 appear?
|
After more than 90% of the B-cells have been destroyed
Failure of self-tolerance = combo of defective clonal deletion of self-reactive T cells and/or defects in functions of regulatory T-cells and/or resistance of effector T-cells to suppression |
|
How does Tcell injury to B-cells occur?
|
Activation in the peripancreatic lymph nodes in response to antigens [insulin itself and/or gultamic acid decarboxylase and/or autoantigen 512 (ICA512)]
Tcells then traffic to the pancreas to cause damage Th1 cells (release IFNgamma and TNF) CD8 + CTLs (direct kill) |
|
What genetic loci make someone susceptible to DM 2?
|
Transcription factor 7-like-2 (TCF7L2) => WNT pathway
|
|
What are the two metabolic defects that characterize DM2?
|
1) decreased response to insulin
2) B-cell dysfunction manifested as inadequate insulin secretion in the face of insulin resistance/ hyperglycemia More than double risk if both parents affected. 35-60% concordance in monozygotic twins |
|
What is the largest contributor of insulin resistance?
|
Loss of sensitivity in the hepatocytes
|
|
What functional defects have been reported in the insulin signaling pathway in states of insulin resistance?
|
Reduced tyrosine phosphorylation
Increased serine phosphorylation (attenuates signal transduction) |
|
How can obesity adversely impact insulin sensitivity?
|
Obesity => >80% in patients with DM2
1) Nonesterified fatty acids 2) Adipokines 3) Inflammatoin 4) Peroxisome proliferator-activated receptor gamma |
|
What is the effect of NEFA's?
|
Excess amounts in muscle and liver tissues => overwhelm FA oxidation => accumulation of DAG and ceramide => activate serine/threonine kinases => aberrant serine phosphorylatoin of insulin receptor and IRS => weakens insulin signaling => allows PEPCK to work and start gluconeogenesis
Also compete with glucose for substrate oxidation => feedback inhibition of glycolytic enzymes => worsening glucose imbalance |
|
What are adipokines?
|
Hormones secreted by adipose tissue. Reduced in obesity.
Pro-hyperglycemic Resistin Retinol binding protein 4 Anti-hyperglycemic: enhance the activity of AMPK (target for metaformin) that promotes FA oxidation and improves insulin sensitivity. Leptin Adiponectin |
|
How does adipose tissue contribute to the inflammatory process?
|
Release pro-inflammatory cytokines that increase stress => activates signaling cascades => antagonize insulin action on peripheral tissues
TNF IL-6 Macrophage chemoattractant protein-1 |
|
What is the PPARy's role in obesity?
|
Receptor & TF expressed in adipose tissue => adipocyte differentiation
Activation promotes secretion of anti-hyperglycemic addipokines => shifts deposition of NEFAs towards adipose tissue and away from liver/muscle Mutations cause obesity |
|
What do the thiazolidinediones do?
|
Act as agonist ligants for PPARy and improve insulin sensitivity.
|
|
Obese people with insulin resistance must also have what other factor in order to develop DM2?
|
Intrinsic predisposition to B-cell failure
TCF7L2 = reduced insulin secretion |
|
What does metaformin do?
|
Enhance FA oxidation through AMPK activation and improve B-cell function.
|
|
What is a characteristic finding in DM2?
|
Amyloid replacement of islets in people with long-standing DM2 and is present in 90% of cases.
|
|
How are monogenic forms of diabetes characterized?
|
1) Primary defect in B-cell function (1-2%)
2) Defect in insulin-insulin receptor signaling |
|
How are primary defects in B-cell function characterized?
|
1) autosomal dominant inheritance
2) early onset before 25 years 3) absence of obesity 4) absence of B-cell autoantibodies |
|
What does macrovascular damage cause? Microvascular?
|
Macro: accelerated artherosclerosis: MI, stroke, gangrene
Micro: retina, kidney, perhipheral nerve damage. |
|
What three pathways have been implicated in causing damage from persistent hyperglycemia?
|
1) Formation of advanced glycation end products
2) Activation of protein kinase C 3) Intracellular hyperglycemia/disturbed polyol pathways |
|
What are AGEs?
|
Advanced glycation end prodcuts: nonenzymatic reactions between intracellular glucose-derived dicarbonyl precursors (glyoxal, methylyoxal, 3-deoxygucosone) with amino groups of intra/extracellular proteins.
|
|
How do AGEs cause damage?
|
Bind to RAGE receptor on inflammatory cells, endothelium and vascular smooth muscle.
1) releases pro-inflammatory cytokines and growth factors from macrophages 2) generates ROS in endothelial cells 3) increases procoagulant activity on endothelial cells and macrophages 4) enhanced proliferation of BV smooth muscle cells and synthesis of ECM Can also cross-link ECM proteins => decreasing elasticity which makes them susceptable to stress => cannot be destroyed by digestion => decreases protein removal and enhances protein deposition 1) Collagen I = endothelial injury 2) Collage IV = decreases endothelial adhesion and increases extravation for fluid Modified proteins bind plasma, LDL, albumin (proteins) and thicken arteries. |
|
How does PKC get activated?
|
By Ca ions and DAG(de novo synthesis from hyperglycemia)
|
|
What are the downstream effects of PKC?
|
1) Production of proangiogenic VEGF => neovascularization in retina
2) Elevated vasoconstrictor endothelin-1. Decreased NO (vasodilator) from decreased expression of endothelial NO synthase. 3) production of profibrogenic factors = TGF-B Increased deposition of ECM and BM material 4) Production of PAI-1 leading to reduced fibrinolysis and vascular occlusion (pro-coag) 5) Production of pro-inflammatory cytokines by vascular endothelium |
|
What is ruboxistaurin?
|
PKC inhibitor
|
|
What happens to tissues that are not insulin dependent when there is chronic hyperglycemia?
|
Nerves, lenses, kidneys, BV's
Excess intracellular glucose => metabolized by aldose reductase => sorbitol (polyol) => fructose (uses NADPH) Using up NADPH compromises the regeneration of GSH by glutathionine reductase => increases susceptibility to oxidative stress This is especially true in nerves/neurons and gives rise to neuropathy (glucose neurotoxicity) |
|
What changes occur in the pancrease with DM?
|
1) Reduction in number/size of islets (DM 1)
2) Leucocytic infiltrates in islets = Tcells, and eosinophilia (infants) (DM1) 3) Reduction in islet cell mass (DM 2) 4) Amyloid deposition in islets (DM2) - around capillaries and between cells, fibrosis (can also be from normal aging) 5) Increase in number and size of islets (gestational DM) = fetal islets undergo hyperplasia |
|
What is the hallmark of DM macrovascular disease?
|
Accelerated atherosclerosis: aorta & large/medium sized arteries
|
|
What is the most common cause of death in diebetics?
|
MI caused by artherosclerosis of coronaries
|
|
What symptoms are more prevalent in diabetics?
|
Cardiovascular disease
Gangrene (100 times ) Renal sclerosis Hyaline arteriolosclerosis Microangiopathy = thickening of BM Nephropathy (2nd to MI as COD) |
|
Where is microangiopathy seen in DM?
|
Skin
Skeletal muscle Retina Renal glomeruli Renal medulla Renal tubules Bowman capsule Peripheral nerves Placenta Capillaries are more leaky than normal to plasma proteins |
|
What are the three lesions encountered in DM Nephropathy?
|
1) glomerular
2) renal vascular (arteriolosclerosis) 3) pyelonephritis - necrotizing papillitis Three most important: Capillary BM thickening, mesangial sclerosis, nodular glomerulosclerosis |
|
What does GBM thickening cause?
|
Occurs in all DM nephropathy cases
Thickening begins as early as 2 years after onset of type 1 DM and by 5 years 30% increase. Mesangial widening Thickening of tubular BMs |
|
What does diffuse mesangial sclerosis look like?
|
Diffuse increase in mesangial matrix.
Some cell proliferation early on, but associated with thickening of the GBM. Depositions are PAS positive. Expansion extends to nodular configurations => increase proteinuria |
|
What is nodular glomerulosclerosis?
|
Intercapillary glomerulosclerosis
Kimmelsteil-wilson disease 15-30% of DM develop this. Lesions are ovoid/spherical often laminated nodules of matrix situated in the periphery of the glomerulus. PAS positive Lie within mesangial core of lobules and surrounded by patent/dilated peripheral capillary loops Mesangiolysis features: fraying of mesangial/capillary lumen interface, disruption where capillaries are anchored into mesangial stalks, capillary microaneurysms as capillaries distend outward. Even uninvolved nodules show sclerosis. Advanced = enlargement of nodues, compression of capillaries, obliteration of glomerular tuft. Fibrin caps = hyaline accumulations Capsular drops = adherent to B capsule Hyalinosis = afferent/efferent Kidney suffers from ischemia, atrophies, fibroses, contracts in size. |
|
What is pyelonephritis?
|
acute/chronic inflammation of kidneys.
Begins at interstitial tissue and spreads to affect tubules. Necortizing papillitis = more prevalent in DM |
|
What is the "honeymoon period" in DM1?
|
Time following onset where exogenous insulin requirements are minimal because there is still some endogenous insulin secretion going on.
Transition to overt DM is triggered by an event (infection) that increases the need for insulin. |
|
What are the symptoms of the onset of overt DM?
|
Classic triad:
Polyuria Polydipsia Polyphagia (coupled w/ weight loss = DM indicator) KA Catabolic state - proteolysis for gluconeogenesis Weight loss, muscle weakness Glycosuria = osmotic diuresis - loss of water/electrolytes |
|
What are the plasma glucose levels in KA?
|
500-700
1) osmotic diuresis = dehydration 2) lipoprotein lipase stimulated => breakdown of adipose stores => increase in FFA => esterified to fatty acyl CoA => oxidation => ketone bodies => utilized by perhipheral tissues => excess => ketonemia/ketonuria Dehydration => no elimination of ketones in urine => metabolic KA release of KA amino acids => makes it worse |
|
Symptoms of DM2?
|
Polyuria
Polydipsia Older/obese patients (over 40 yrs) = diagnosis made through blood/urine testing as most are asymptomatic |
|
Why do DM2 not get KA?
|
Higher portal vein insulin levels prevents unrestricted hepatic FA oxidation and keeps the formation of ketones in check
|
|
What do DM2 develop in a decompensated state?
|
Hyperosmolar nonketotic coma
Severe dehydration from osmotic diuresis . Absent KA symptoms (nausea, vomiting, respiratory difficulties) |
|
What are the complications of both types of DM?
|
1)Macrovascular - 2-4x coronary artery disease, 4x cardiovascular complications, 75% have HTN, dyslipidemia, elevated PAI-1
2) Nephropathy - 30-40% develop, higher in DM2, 50% of people on dialysis are DM2, NA & AA & hispanics develop end stage renal disease 3) Visual impairment - 60-80% develop some retinopathy 15-20 years after diagnosis, glaucoma, cataract formation 4) Neuropathy - distal symmetric polyneuropathy of LEs involving both motor & sensory function. Can progress to "glove and stocking" pattern. Autonomic - disturbances in bowel/bladder fxn, sexual impotence, Mononeuropathy - (footdrop, wristdrop, cranial nerve palsies) 5) Infections - TB, pneumonia, pyelonephritis, death of 5%. Brings on gangrene, bacteremia, pneumonia. Decreased neutrophil functions (chemotaxis, adherence, phagocytosis, microbicidal), impaired cytokene production by macrophages, impaired vasculature - reduces delivery of cells. |
|
What does the dyslipidemia in DM incluse?
|
Increased TG and LDL levels
Decreased HDL Insulin resistance contributes to dlipidemia favoring hepatic production of artherogenic lipoproteins and suppresses the uptake of circulating lipids in the peripheral tissues |
|
What is the earliest manifestation of nephropathy?
|
Low amounts of albumin in urine (>30-300 mg/day) = microalbuminuria
Mortality marker for CVdisease as well. 80% DM1, 20-4-% DM2 will develop with macroalbuminuria >300 mg/day with HTN 20 yrs 75% DM1, 20% DM2 will develop end stage renal disease |
|
What is metabolic syndrome?
|
Abdominal obesity
Insulin resistance Abnormal lipid profiles (other CVD risks) |
|
What are pancreatic endocrine neoplasms?
|
Tumors of pancreatic islet cells.
2% of neoplasms. Most common in adults Can occur anywhere along pancreas, within or around. Resemble carcinoid tumors Can be single/multiple benign/malignant, functional/nonfunctional. Malignancy: metastases, vascular invasion, local infiltration |
|
What types of pancreatic neoplasms are there?
|
Insulinomas (90% benign)
Others (60-90% malignant) Gastrinomas Glucagonomas Somatostatinomas VIPoma Carcinoid tumors PP secreting endocrine tumors Bihormonal tumors |
|
What are the most common/distinct clinical syndromes with pancreatic neoplasms?
|
1) hyperinsulinism
2) hypergastremia & zollinger-ellison syndrome 3) MEN |
|
What clinical manifestations does insulinoma present with?
|
Hypoglycemic episodes occurring with
1) Blood glucose levels below 50 2) CNS symptoms: confusion, stupor, loss of concious 3) Precipitation with fasting, exercise Relief with eating, administration of glucose parenterally 80% secrete excessive insulin 20% of people never have symptoms |
|
What is the morphology of an insulinoma?
|
Most are solitary
o usually <2cm diameter o encapsulated, pale-red-brown nodules o look like giant islets o have cords of monotonous cells and preservation of vasculature o not much anaplasia (even with malignancy) o deposition of amyloid in ECM If invasion is present (10%) = Bona fide carcinomas Can be ectopic |
|
What is the morphology of hyperinsulinism?
|
Focal/diffuse hyperplasia of islets
In adults, but more common in neonates/infants Cause: Maternal diabetes Beckwith-Wiedemann syndrome Mutations in B-cell K channel sulfonylurea receptor |
|
What else causes hypoglycemia?
|
Abnromal insulin sensitivity
Diffuse liver disease Inhereited glycogenoses Ectopic tumor (retroperitoneal fibromas/fibrosarcomas) Self induced from over-injection of insulin |
|
What is a gastrinoma?
|
Tumor that oversecretes gastrin.
Arise in wall duodenum and peripancreatic soft tissues and pancreas (triangle) ZE syndrome: islet lesions, hypersecretion of gastric acid, severe peptic ulceration = 90-95% of patients |
|
What is the morphology of a gastrinoma?
|
Arise in gastrinoma triangle areas.
50% invasive, or have already metastasized when diagnosed 25% arise with other tumors in MEN-1 syndrome = multifocal tumors Histologically bland, rare anaplasia |
|
What is Zollinger-Ellison syndrome?
|
Hypergastrinemia gives rise to extreme gastric acid secretion which causes peptic ulceration.
Ulcers are multiple, and identical to normal ulcers. However, UNRESPONSIVE to therapy, and can occur in unusual locations like the jejunum (always a key for ZE diagnosis) |
|
What are the presentations of gastrinoma?
|
50% have diarrhea
30% present with diarrhea at first. Treat: control gastric acid secreation with H/K ATPase inhibitors and surgery. Hepatic metastases = liver failure in 10 years |
|
What is a glucagonoma?
|
A-cell tumor.
Increased levels of glucagon causing mild DM Skin rash = necrolytic migratory erythma Anemia Occur in perimenopausal/postmenopausal women Extremely high glucagon levels |
|
What is a somatostatinoma?
|
Delta cell tumor
Assoicated with DM, cholelithiasis, steatorrhea, hypochloryhydria Difficult to localize |
|
What is a VIPoma?
|
Endocrine tumor with characteristic syndrome = VIP release
Watery diarrhea = VIP assay with this symptom ALWAYS Hypokalemia Achlorhydria WDHA syndrome |
|
What other tumors can be associated with VIP syndrome?
|
Neural crest tumors:
Neuroblastomas Ganglioneuroblastomas Ganglioneuromas Pheochromocytomas |
|
What do pancreatic carcinoid tumors secrete?
|
Serotonin
|
|
What are the signs of PP-secreting endocrine tumors?
|
Usually none
|
|
What else can pancreatic tumors secrete?
|
ACTH
MSH ADH Serotonin Norep (multihormonal tumors) Must be distinguished from MEN syndromes! |