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352 Cards in this Set

  • Front
  • Back
Normal blood glucose
90-180 mg/dl
Normal plasma Ca2+
9-11 mg/dl
Na+/K+ homeostasis
Calcium homeostasis
Water homeostasis
Blood glucose control
Basal metabolic rate
Growth control
Thyroid hormones
Gonadal function
GI function control
Pepsin and acid
Bile and pancreatic enzymes
Peptide hormones
Amino acid derivative hormones
Without iodine - DA, NE, E
With iodine - T4, T3
Steroid hormones
Thyroid hormone biosynthesis
Iodide (TPO) --> iodine (TPO) --> iodination of tyrosine residues of thyroglobulin (TPO) --> coupling of MIT and DIT

Occurs at the apical membrane of the cell

Iodine salvage -> thyroidal dehalogenase
Epinephrine synthesis
Occurs due to the presence of PNMT in the adrenal medulla

PNMT induced by high concentrations of glucocorticoids

Stored complexed to ATP in chromaffin cells
Steroid hormone sythesis
C27 -> C21 -> C19 -> C18

Pregnenolone (C21) precursor of all the steroid hormones

C21 - progesterone, corticosteroids
C19 - androgens
C18 - estrogens

Added oxygen from CYP450s
Permissive interaction
Hormone A has a robust action, whereas hormone B has little or no action, but w/o hormone B, hormone A has only weak action

Ex: Thyroid hormone and IGF-1 on bone growth
Synergistic interaction
Effect of hormone A and B together is greater than the additive effect of either alone
Inhibitory interaction
Hormone B opposes the action of hormone A

Action is at physiologic receptor B

Ex: insulin and glucagon or GHRH and somatostatin
Diabetes insipidus
Low gonadotropins
Low GH
Cushing's disease
Excess ACTH
Increased GH in childhood
Increased GH in adulthood
Primary hyperaldosteronism
Adrenal tumor or bilateral adrenal hyperplasia
Tumor or hyperplasia
Rickets and osteomalacia
25-hydroxycholecalciferol-1alpha-hydroxylase deficiency
Nephrogenic diabetes insipidus
Defective ADH receptor system
G alpha s
Stimulatory to adenylate cyclase to synthesize cAMP which stimulates PKA

Ex: beta receptors, calcitonin, PTH, ADH, ACTH, FSH, LH, TSH, glucagon
G alpha i
Inhibitory to adenylate cyclase which inhibits PKA

Ex: alpha 2 receptors
G alpha q
Stimulates activity of phospholipase C which leads to DAG and IP3 production

Ex: alpha 1 receptors, oxytocin, hypothalamic hormones, several eicosanoids
GEF vs. GAP vs. GDI
GEF - guanine nucleotide exchange factor

GAP - GTPase accelerating protein

GDI - guanine nucleotide dissociation inhibitor
Signal termination
Degradation of messenger - PDE
Receptor inactivation
G protein diseases
Highly specific (mutation) to widespread effects (subunits)
Hereditary defects
Acquired diseases (cholera, whooping cough)
Tumor formation
Receptor tyrosine kinases
EGF receptors, PDGF receptors, insulin receptors
Phosphorylation of MAPK and of transcription factors

Grb2 -> Ras-GEF -> RAS -> MAPKKK -> MAPKK -> MAPK
Tyrosine kinase associated receptors
Do not possess intrinsic enzymatic activity but are associated with intracellular proteins that have tyrosine kinase activity

JAK-STAT pathway
JAK - Janus kinases
STAT - signal transducers and activators of transcription

Also activate RAS pathway

Ex: cytokine receptors, GH, prolactin
Nuclear hormone receptors
Thyroid hormone
FA derived (linolenic, AA)

Regulate rate of transcription
Function as hormone regulating trans-acting TFs
Interaction sites called HREs
Nucleosome rearrangement is catalyzed by acetylation of histones by the coactivator proteins
Corepressor proteins deacetylate histones thereby compacting nucleosomes and making the TATA box inaccessible

Type 1 - requires ligand binding for DNA binding
Type 2 - requires ligand binding for activation
Domains of nuclear hormone receptors
LBD - hormone specific binding domain (C terminal)
-TAF2 - activation function domain - hormone dependent
DBD - DNA binding domain - Zinc finger domains binds to HREs
N-terminal domains (TAF1) transcriptional activation function - hormone independent
Excessive production of prolactin
Amenorrhea/oligomenorrhea w/ or w/o galactorrhea in women
Hypogonadism in men

Other causes of increased prolactin - pregnancy, hypothyroidism, breast or chest wall disease
GH excess in adults
Insidious onset
Pulsatile nature of GH secretion complicates Dx
Slow proliferation of soft tissue and cartilage
Bone growth of hands, feet, skull
Visceral and cutaneous growth
HTN, insulin resistance
Dx - increased basal fasting GH, failure of GH to suppress to <2 following 100 g glucose, elevated IGF-1
In acromegaly - L-dopa suppresses GH (normally increases)
Tx - surgery, radiation, octreotide, DA agonists
Cushing's disease vs. Cushing's syndrome
Disease - excess production of glucocortcoids due to increased ACTH from the AP
Syndrome - any excess of glucorticoids from any source
Thinning of the skin
Easy bruiseability
Proximal muscle weakness
Mood changes

Testing - urinary free cortisol, DST, ACTH, CRH
Tx - TS resection, radiation, inhibitors of synthesis
Ectopic ACTH
Usually secreted by fairly aggressive tumor
Most commonly Oat's cell carcinoma of the lung
Diabetes insipidus
Central or nephrogenic
Polyuria usually accompanied by polydipsia
Hypernatremia and dilute urine
Tx - water deprivation with monitoring of urine volume and osmolality; response to AVP or DDAVP
Diseases of the pituitary
Genetic, hypophysitis, surgery
Infiltrative - HX, sarcoidosis, hemochromatosis
Infectious - TB, fungal, treponemal
Euvolemic hyponatremia w/dilute urine and normal thyroid and adrenal function
Bronchogenic carcinoma
CNS trauma, malignancy, infection, inflammation
Always consider adrenal and thyroid status and drugs
Intrauterine growth
Mean birth length - 50 cm
Mean birth weight - 3.5 kg
Independent of GH
IGF-2 thought to play a role
High insulin -> increased BW
Growth plate
Proliferation (germinal) zone
Flattened cell zone
Hypertrophic cell zone
BMI > 85% = obesity
BMI = weight(kg)/height(m^2)
High BMI associated with CV and DM risk and advanced bone age/precocious puberty
ACTH (Cortrosyn) stimulation test
Measures the ability of the adrenal cortex to respond to ACTH by producing cortisol appropriately
Normal infancy growth
Growth rate - 3-5 inches/year
Rate declines from neonatal period
Pattern/velocity determined by 36 months of age
Neonatal period growth (birth - 12 months)
Normal rate - 9-11 inches/year
Rapid, highly variable rate
Childhood (3 years to puberty)
Normal rate - 2-2.5 inches/year
Linear growth stabilizes
Changes in growth velocity indicates potential growth or health disorder
Growth rate is rapid and highly variable - increased production of adrenal and gonadal hormones
Onset of pubertal growth spurt - often preceded by measurable decline in growth rate
Average age in girls - 10
Average age in boys - 12.5
Late adolescence/early adulthood
Growth rate declines markedly after puberty
Bone growth ceases
Epiphyseal plates fuse
Height is stable
Calculated midparental height
Average +/- 2.5
Girls = (FH+MH)/2 - 2.5
Boys = (FH+MH)/2 + 2.5
Target height = Midparental height +/- 4 inches
Clues to recognizing growth failure
Height >2-2.5 SD below mean
Abnormal growth rate for age
-<3 years - <7 cm
-3-puberty - <4.5-5 cm
-during puberty - <6 cm
Height crossing 2 centiles after 3 years
Obese short child
Puberty w/o growth spurt
Extremely delayed bone age
Bone age
BA (years) measures growth potential
Estimated from x-ray of LT hand and wrist - correlate well with tibial growth plate
Males grow until BA = 16
Females grow until BA = 14
BA>CA -> less time to grow
BA<CA -> more time to grow
Short stature normal variants
Genetic short stature - r/o GH deficiency
-Final height short but appropriate for FH
Constitutional delay - males >>>> females
Endocrine causes of short stature
Primary hypothyroidism
Glucocorticoid excess
Isolated GH deficiency
GH resistance
Biologically inactive GH
IGF-1 deficiency
Hypercortisolism - abnormal growth
Decreased secretion of GH
Counteracts local effects of GH, IGF-1
Increases somatostatin tone
Congenital GH deficiency
Normal birth weight and height
Midline defects
Often associated with other pituitary deficits
Statural growth decelerates while ponderal growth continues
GH deficiency: phenotype
Truncal obesity
Face appears younger than CA
Crowding of facial features to the center of the face (maxillary hypoplasia)
Small genitalia in boys
GH provocative tests
Needed since GH is mainly secreted at night
Insulin hypoglycemia, arginine, L-dopa, clonidine, GHRH
GH peak <10ng/ml is indicative of GHD
Low IGF-1 may reflect GH def.
May not reflect physiologic GH production during sleep
Injected SC to optimize IGF-1
SE - increased ICP, allergic skin reaction, slipped capital femoral epiphysis, scoliosis
Iodide uptake
Energy requiring
Inhibited by hypoxia, CN, 2,4-DNP
Competitively inhibited by monovalent ions of the same size (thiocyanate, perchlorate)
Thioureas (PTU) inhibit iodination
Controlled by TSH - cAMP dependent kinase
Involves NADP
TRH pathway
Arcuate nucleus and median eminence secrete
Acts on thyrotrophs of AP
Gprotein -> PLC -> DAG, IP3
Thyoid hormone transport
Thyroid binding globulin TBG
Transthyretin TBP A
Free hormone - T4 (0.03%), T3 (0.3%)
Estrogen - increased TBG
Testosterone, cortisol - decreased TBG
1/2 life of T3 = 1 day
1/2 life of T4 = 7 days
Type 1 5'-deiodinase
Kidney, liver, thyroid - high Km, depends on selenium, stress results in decreased type 1 activity, inhibited by PTU and propanolol, low in geriatric patients
Type 2 5'-deiodinase
Brain and pituitary
Low Km
High levels of serum T4 reduces type 2 enzyme
Increased in conditions of hypothyroidism
Type 3 5'-deiodinase
Placenta, glial cells, fetal liver
Inactivates T4 and T3 by conversion to rT3
Elevated in hyperthyroidism and decreased in hypothyroidism
Thyroid hormone action
Increase BMR
Necessary for normal fetal neonatal brain development
Stimulate protein synthesis but also breakdown
Stimulate lipogenesis but are also lipolytic
Increased HSL activity
Increased LPL activity
SNS-like actions - increased receptors and affinity
Inhibits fibroblast function
Protein levels affected by thyroid hormone
Through THR, RAR, TRE
Na-K pump
Gluconeogenic enzymes
Respiratory enzymes
Myosin heavy chain
Beta adrenergic receptors
Many others
Hormones secreted by the thyroid gland
Follicular cells - T4, T3, rT3
Parafollicular C cells - calcitonin
Half life of 50-60 minutes
Circulates unbound
Normal range 0.5-5.0
Thyroid hormones in blood
Total serum T4 - 5-12 ug/dL
Total serum T3 - 95-190 ng/dL
Free thyroxine index (FT4I)
Total T4 x T4RU
Normal resin T4 uptake is 25-35%
High resin uptake = high T4 or low TBG
Low resin uptake = low T4 or high TBG
Acute thyroiditis
Infection - associated with malnutrition, trauma to neck, IS pts. - pyogenic organisms, fungi, TB, syphilis, PC (HIV)
Radiation induced
Subacute thyroiditis (Granulomatous or De Quervain's)
Key - painful thyroid
Viral etiology?
Hyper -> hypo -> euthyroid
Subacute painless thyroiditis
High levels of thyroid hormone
Anti-thyroid Abs present
Likely autoimmune in nature
Subacute post-partum thyroiditis
Occurs within 6 months after childbirth
Overactive immune system
Chronic autoimmune thyroiditis
Most common form of thyroiditis
Atrophic form - idiopathic
Goitrous form - Hashimoto's
F>M peak at 30-50
Anti-microsomal, anti-TPO
Also TSH blocking Abs
Hurthle cells - large, eosinophilic epithelial cells
Lymphoma rare complication
Riedel's struma
Invasive fibrous thyroiditis
Unknown etiology
"Woody thyroid" - extensive fibrosis extending into adjacent tissue
Major symptoms are from tracheal compression
Enlargement of thyroid
Normal weight - 15-35 grams
Iodine deficiency, goitrogens in diet, Hashimoto's, SAT, neoplasms, congenital defects, resistance to hormone
Graves disease
Toxic multinodular goiter
Toxic adenoma
Iatrogenic or factitious
Pituitary, trophoblastic tumors (hCG has intrinsic TSH activity)
Ectopic hormone - struma ovarii
Graves disease
MCC of hyperthyroidism
TSH stimulating Abs
Exophthalmos - deposition of GAG in extraocular muscles leading to proptosis
Pretibial myxedema - accumulation of GAG
Thinning of lateral edge of the eyebrows
Cretinism - birth
Myxedema - late childhood or adulthood
Primary - TSH elevated
Secondary - TSH low
Benign thyroid tumors
Usually single, complete fibrous capsule, adjacent tissue normal
Adenomas - almost always follicular
Teratomas - rare usually children
Therapeutic indications for anti-thyroidal agents
Graves' disease
Thyroid storm
Pre-operatively for thyroidectomy
Iodine induced thyrotoxicosis
Propanolol in thyroid disease
Adjunct in hyperthyroidism
Block adrenergic effects
In high doses can also inhibit T4 to T3 conversion
Competitive anions of iodide
Thiocyanate - toxic
Perchlorate - may cause fatal aplastic anemia
PTU and methimazole
Inhibit peroxidases and prevent oxidation of iodide
Takes a few days to weeks to see effect
Cross the placenta - less risk with PTU
Can be found in breast milk
SE - agranulocytosis, urticaria, arthralgia
Propylthiouracil (PTU)
Also interferes with peripheral 5'-deiodinase conversion of T4 to T3 in addition to inhibiting iodination
Drug of chioce in thyroid storm
Longer acting/more potent than PTU
Iodine (I27 - non-RA)
Paradoxical inhibitor of formation and secretion of thyroid hormone in high doses
Cause goiter and hypothyroidism in high concentrations
Effect is prompt, but short lived
Can decrease vascularity pre-op
Can be used to reduce radioactive iodine uptake
SE - angioedema, hemorrhages, serum sickness, brassy taste, oral burning, enlarged glands
Radioactive Iodide (I31)
Half life 8 days
Beta emissions act almost exclusively on the follicular cells
Treatment of choice for hyperthyroidism and carcinoma of thyroid
Symptoms abate over months
Delayed hypothyroidism
CI in pregnancy
Diagnostic uses
Thyroid replacement therapy
Levothyroxine (T4) - drug of choice - incremental dosing
Liothyronine (T3) - rapid onset
Liotrix - 4:1 T4:T3
Aggressive therapy in cretinism and myxedema coma
Drug interactions of thyroid hormones
Competition for binding sites
Thyroxine binding increased
Drugs containing iodine
Cholestyramine - inhibits absorption
Increased clearance of digoxin
Oral anticoagulant effects
Insulin less effective in hyperthyroidism
Glucocorticoids reduce peripheral deiodination and thyroid hormone activity
Anterior pituitary blood supply
Superior hypophyseal artery
Just proximal to carotid entrance into cavernous sinus
Posterior pituitary blood supply
Inferior hypophyseal artery
Branch of meningohypophyseal trunk of ICA in cavernous sinus
Complications of pituitary surgery
Microadenoma >60% 5 year
Macroadenoma <50% 5 year
Diabetes insipidus
CSF leak
Carotid artery injury
Visual loss
Symptoms of hyperthyroidism DDx
Illicit drug use
GI disorder causing malabsorption
TSH or TSH-like thyrotoxicosis
Trophoblastic tumors (high levels of hCG)
Pituitary TSH
TRH secreting tumors
Apathetic thyrotoxicosis
Elderly patients with oligosymptomatic or atypical features of hyperthyroidism
Lack of eye findings or even ptosis
Variable cardiac features
Weight loss is the most reliable feature
Metabolic functions of calcium
Cellular adhesion
2nd messenger
Enzymatic activity
Muscle contraction
Platelet aggregation
Blood coagulation
Compounds that complex calcium
Phytic acid (cereal)
Fatty acids (fal malabsorption)
Oxalic acid (rhubarb)
Caused by deficiency of Ca2+
Due to lack of vitamin D in the diet or insufficient production in the skin (lack of sunlight)
Phosphate function
Buffering - in. and ex.
Energy metabolism
Nucleic acids
Signal molecules
Serum calcium
9-11 mg/dL
Low - convulsions (tetany)
High - neurologic damage and soft tissue calcifications
Parathyroid hormone
preproPTH -> proPTH -> PTH
N-terminal 33-36 contain biologic activity
Made in chief cells
Secretion triggered by low plasma Ca2+ - Ca sensor Gq
Action on the kidney - increases calcium reabsorption and phosphate excretion
Increases calcitriol production
Increases bone resorption - indirect via effect on osteoblasts which then stimulate osteoclasts
Vitamin D obtained from the diet but also in the skin
7-DHC -> CCFol -> 25-OHD3 -> 1,25-DiOHD3
Skin -> liver -> kidney (proximal tubule)
Calcitriol action on the gut is to increase synthesis of a calcium binding protein and to increase phosphate absorption
Synergizes with PTH to turn on bone resorption
Vitamin D stimulates all three steps of transcellular absorption of Ca2+ (duodenum)
Promotes the laying down of calcium into bone and the inhibition of bone resorption via osteoclast receptors
Inhibits Ca+ reabsorption by the kidney
Made in parafollicular cells of thyroid gland
Secreted in response to high Ca2+
Neuromuscular irritability
Dental abnormalities
Mental abnormalities
Type I - def. of Galpha s or abnormalities in the PTH receptors decreased cAMP response - short stature, round facies, short metacarpal and metatarsal bones
Type II - normal PTH induced cAMP but with blunted 2nd messenger response
Primary hyperparathyroidism
Hypercalcemia and hypophosphatemia
Adenomas - MCC - usually monoclonal
Hyperplasia - usually chief cell - MEN association
Carcinoma - uncommon
Secondary hyperparathyroidism
Hypocalcemia and hyperphosphatemia
Parathyroid glands become hyperplastic
Tertiary hyperparathyroidism
Parathyroid hyperplasia becomes autonomous
Hypercalcemia of malignancy
PTH-related hormone (PTHrP)
Non-parathyroid source
Squamous carcinoma of lung
Adenocarcinoma of kidney
Hepatocellular carcinoma
Metastatic calcification
Increased CaxP results in deposition of CaPO4
Kidney tubules
Stomach - ulcers
Lung alveoli
Skin, tendon, blood vessels
CRF where localized areas of skin become necrotic secondary to associated vascular calcification
Responsive to parathyroidectomy
Osteitis fibrosa cystica
Osteoclastic resorption
Osteoblastic activity but little actual bone formation
Cortical erosions - phalanges
Cystic tumors - hemorrhage
May form cytic "tumors" - Brown tumor due to hemorrhage - these tumors fill in once hyperparathyroid is treated
Distinguish from giant cell
Pancreatic islets
Parathyroid hyperplasia
Parathyroid hyperplasia
Medullary thyroid carcinoma
Medullary thyroid carcinoma
Mucosal neuromas
Hypercalcemic hormones - increase serum calcium
Hypocalcemic hormone - decrease serum calcium
Ca2+ <7 mg/dL
Muscle cramps
May cause death due to laryngospasms
Ca2+ >12 mg/dL
Lethargy, drowsiness, coma
Neuromuscular fatigue and weakness
N&V, constipation
Soft tissue calcification
X-linked hypophosphatemia rickets
Severe bone demineralization and hypophosphatemia due to impaired renal phosphate transport rather than a primary abnormality in vitamin D metabolism
Paget's disease
Chronic localized areas of bone destruction, coupled to accelerated bone repair
Single or multiple foci of disordered bone remodeling
Vitamin D
Oral and IV
Bile is essential for absorption
Circulates in plasma bound to vitamin D binding protiein
Major circulating form is 25(OH)D3
Clinical uses of calcitriol
Fast acting
Renal osteodystrophy
Vitamin D dependent rickets
X-linked HP rickets
In patients on phenytoin when there is inhibition of 1-hydroxylation
Vitamin D analogues - DHT
Does not require 1-hydroxylation
Faster onset and greater effect on mobilization of bone salts
Vitamin D analogues - doxercalciferol , paricalcitol
Used to suppress the secondary hyperparathyroidism seen in CRF
Able to suppress PTH secretion w/o an excessive hypercalcemic response
Clinical uses of PTH
Diagnostic drug - confirm the diagnosis of pseudohypoparathyroidism
Patient will fail to show an increase in serum calcium concentration after PTH injection and will also fail to show an increased excretion of phosphate and cAMP in the urine
Teriparatide - osteoporosis
Clinical uses of calcitonin
Half life in plasma - 40 min
Paget's disease
Hypercalcemia of various cause
Post-menopausal osteoporosis
SE - urticaria, swelling, GI upset
Resistance to chronic use is common
Ab production to calcitonin occurs with chronic use
Structurally related to pyrophosphate
Anti-bone resorptive
Paget's - TAPER
Hypercalcemia of malignancy - PZ
Osteoporosis - AIR
SE - esophagitis, E-osteomalacia, Z-renal
Calcium salts
Carbonate, lactate, gluconate, phosphate - oral
Gluconate, chloride, gluceptate - IV
CaCO3 use in long term prophylaxis of osteoporosis
Calcium gluconate (IV) treatment of choice for hypocalcemic tetany
Calcium and aluminum free phosphate binding resin
Used in hyperphosphatemia (CRF)
Phosphate salts
Used in treatment of hypercalcemia and forms of hypophosphatemia
Treatment of hypercalcemia
Glucocortioid - particularly due to sarcoidosis
Gallium nitrate
IV furosemide - acute calciuresis - use w/IV saline
EDTA - chelation (nephrotoxic)
Inorganic phosphates
Treatment of osteoporosis
Ralofoxine - SERM
Vitamin D/calcium
Drugs accelerating metabolism of 25(OH)D
Inhibitors of bone mineralization
Phosphate disorders
Osteomalacia - causes
Vitamin D metabolism disorders
Cirrhosis and other chronic hepatic disorders
Renal disease
Vitamin D dependent Type I
Rapid acting insulins
ONSET - most <15 minutes; R+S -> 0.5-1.5 hours
DURATION - various 3-10 hours
Intermediate acting insulins
DURATION - 18-24 hours
Long acting insulins
Ultralente - >36 hours
Glargine - 24 hours - *Glargine cannot be mixed due to acid pH
Zinc and protamine
Stabilizing agents
Prolong the absorption of insulin
Increased Zn => absorption rate decreases => duration of activity increases
Modified human insulin solution - rapid acting - shorter duration
Advantages - Improves quality of life due to flexible injection times, less frequent hypoglycemic reactions, can be used in pumps
Glargine insulin
Long lasting basal insulin levels - need rapid acting insulin at meal times
Powdered human insulin
Rapidly absorbed
Not for anyone <18
May be adjuvant in type I or II
Adverse reaction of insulin preparations
Immune/allergic response
Atrophy of fat at injection site
Powdered form - coughing, SOB, dry mouth, sore throat
Dosing of insulin
Morning glycosuria - need fast acting insulin in AM
Night glycosuria - need long acting insulin
Insulin resistant - much higher doses
Symlin (pramlintide acetate)
Synthetic analog of amylin
Achieve lower blood glucose after meals
Helps suppress glucagon secretion
AE - severe hypoglycemia, nausea
Substances that may increase the blood glucose control lowering effect of insulin
ACE inhibitors
Somatostatin analog (octreotide)
Sulfonamide antibiotics
Substances that may decrease the blood glucose control lowering effect of insulin
Phenothiazine derivatives
Somatropin (GH analog)
Mechanism of action - blocks ATP sensitive K+ channel -> insulin release; inhibit glucose release from liver; enhance IR number
CATT - 1st generation
GGG - 2nd generation
2nd more potent
Problems with 1st generation - hyponatremia, prolonged hypoglycemia, alcohol flush, interactions
Advantages of 2nd generation - high potency, free water diuresis, inactive metabolites, non-ionic binding, no alcohol flushing
Cardiovascular effects and antidiuretic effect
Adverse effects of sulfonylureas
Leukopenia, hemolytic anemia
Rashes, photosensitivity
Nausea, vomiting, jaundice
CI in pregnancy
Drugs impairing sulfonylureas
Thiazide and furosemide diuretics
Oral contraceptives
Drugs which potentiate hypoglycemic therapy
Phenylbutazone and clofibrate
Beta blockers
Meglitinides: Repaglinide, glyburide, glipizide, glimepiride
Oral hypoglycemic agent
Binding site on ATP sensitive K+ channel - different site from sulfonylureas
Rapid onset, short duration
Insulin secretion response mainly confined to prandial glucose load
Synergistic with metformin
Low rate of hypoglycemia
CI - hypersensitivity, Type I DM, DKA, liver function decline, serious CV events
Nateglinide: starlix
D-phenylalanine class of hypoglycemic agents
Inhibits K+ channel
Fast on fast off
Low incidence of hypoglycemia
Can be combined w/metformin or alpha-glucosidase inhibitors
Less likely to causes CV effects
CI - pregnancy, lactation, type I DM, DKA
Potentiates insulin action
Does not act on beta cells
Anti-hyperglycemic not hypoglycemic
Favorably affects lipids
Does not cause hyperinsulinemia
Inhibits intestinal absorption of AA's
Anti-inflammatory actions
Renal effects - decrease acid excretion
Increases blood pressure
Toxicity - lactic acidosis, ketonuria, GI effects, acute pancreatitis
Thiazolidinediones - rosiglitazone, pioglitazone
Act only in the presence of insulin and enhance insulin target response in target tissues thereby reducing insulin resistance
Binds to and activates PPAR-gamma - gene transcription
Increases GLUT1 synthesis, increases glucose uptake
Increases differentiation of pre-adipocyte to adipocyte
Possible loss of contraception
CI - pregnancy, breast feeding, active liver disease
AE - hypoglycemia, edema, anemia, ovulation, weight gain
Hypoglycemic glitazars
Target the alpha and gamma families of PPAR
PPAR-alpha - reductions in plasma TG level, increased HDL
PPAR-gamma - decreased plasma glucose
Alpha glucosidase inhibitors
Delay and reduce uptake of carbohydrates across the intestine
Competitive inhibition of the enzymatic digestion of carbohydrates in the intestinal lumen
Acarbose - non-absorbable
-SE - flatulence, pain, diarrhea
Glyset - absorbable
-CI in kidney dysfunction
Incretin mimetics
Similar sequence to GLP-1
Stimulates insulin secretion, inhibits glucagon secretion and slows gastric emptying and increases weight loss
Increases cAMP in the beta cell -> increases insulin
Reduces HbA1C
Emergency treatment of hypoglycemia
Relaxes intestinal smooth muscle; radiography
(+) inotropy, can be used in propanolol poisoning
Lowers blood glucose in type I DM
May suppress glucagon secretion
Insulin like activity in vivo
Phosphatase inhibitor that augments insulin receptor activation
Hyperglycemic agent
Inhibits glucose interaction with beta cell - produces diabetic state
Non-diuretic thiazide suppresses insulin secretion and peripheral utilization of glucose
Selectively destroys beta cells by alkylating bases of DNA and generating free radicals
Effects of sorbitol accumulation
Osmotic swelling
Decreased nerve conduction velocity
Cataract formation
Inhibits aldose reductase
Improves Na/K ATPase activity
Prevents cataracts
Appears to relieve some of the pathologies of DM - neuropathy
Renal effects of mineralocorticoids
Rapidly stimulate expression of sgk - enhanced Na+ channel surface expression
Promotes resorption of NaCl and secretion of K+ in cortical collecting tubule
Increases number of NaCl cotransporters in the distal tubule
Increased H+ excretion
Aldosterone escape phenomenon
Release of natriuretic factor from the hypothalamus
Increase in glomerular filtration due to ANP
Suppressed RAAS due to rise in systemic BP, renal perfusion pressure, and sodium content in the macula densa
K+ excretion continues
Mineralocorticoid receptor
Roughly equal affinities for cortisol and aldosterone
Renal concentration of cortisol is 1,000 fold higher than aldosterone
11-beta-HSDH2 converts cortisol to cortisone
Cardiovascular effects of aldosterone
Upregulates AT1 receptors - blocked by spironolactone and losartan
Cardiac myocytes, endothelial cells, and VSMC's contain high affinity MR's - 11-beta-HSDH2 present
In patients with CHF, spironolactone may improve outcome by reducing levels of procollagen
Primary hyperaldosteronism
Increased aldosterone secretion by ZG
Adenoma > idiopathic > micronodular hyperplasia
volume expansion, HTN, low PRA
11-beta hydroxylase form of CAH
More common in Jews of Moroccan ancestors
AR - chromosome 8
Virilization w/HTN
Decreased cortisol levels, increased androgens, increased 11-deoxycortisol
17-alpha hydroxylase form of CAH
AR - chromosome 10
Cortisol and androgen are decreased
DOC and corticosterone will be increased
HTN due to glucocorticoids
Increases the number of alpha-adrenergic, AII, and ADH receptors
Increase AII production and upregulate ACE expression
Increase GFR
Downregulates the expression of Na-Ca exchanger - increased cytosolic calcium and vasoconstriction
Cushing's syndrome
HTN and hypokalemia
High level of cortisol exceeds 11betaHSD2 capacity
HTN due to pheochromocytoma
About 20% familial
Monitor urinary catecholamine products - metanephrine
Histone interaction w/hormone response
(+) hormone -> coactivator complex containing HAT
(-) hormone -> corepressors containing histone deacetylase
GR-mediated transcriptional modulation
Antagonizes AP-1, STATs, CREB, NF-kB
Inhibits NF-kB by increasing IkB
Target genes for GCs
Beta-adrenergic receptor
IkB - sequesters NF-kB
Increased mRNA 1/2 life - collagenase
Decreased mRNA 1/2 life - COX-2
Decreased gene transcription - TNF-a, GM-CSF, iNOS, COX-2, adhesion molecules
Hypothalamus-anterior pituitary relationship
Portal blood supply from the hypothalamic veins to the organ capillaries of the anterior pituitary - regulates hormone release
Removal of the pituitary
Atrophy of gonads
Atrophy of adrenal cortex
Atrophy of thyroid
Interruption of the ovarian cycle
Decreased ability to respond to stress
Inhibition of growth and development in young animals
3 groups of anterior pituitary hormones
Large glycoproteins - TSH, LH, FSH
Large straight-chain polypeptides - GH, prolactin
Small peptides - ACTH, a-MSH, b-lipotropin, b-endorphin
Sertolli cell is the major source in the testis
Ovarian granulosa cell is the major source in the female
Inhibits FSH release
Hypersecretion of GH
Acidophilic or chromophobic adenoma
Anti-reproductive or anti-gonadal effects
Prolactin can suppress LH and lead to anovulation
TRH can stimulate prolactin secretion
Prolactinoma - chromophobe
Increases the rate of cholesterol side-chain cleavage - the rate-limiting step
Direct lipotrophic effect on adipose tissue
Diurnal release rhythm
Common characteristics of endocrine organs
Possess no ducts
Secrete directly into vascular system
Rich blood supply - fenestrated endothelium
Reacts to suppression or stimulation
Steroid secreting cells
Abundant SER
Large mitochondria w/extensive cristae
Lipid droplets with free cholesterol, esters, no limiting membrane
Enzymes for steps are present in distinct organelles
No stored hormone
Adrenal cortex - organization
ZG - cords in ball shape, few lipid droplets, shelf-like cristae
ZF - straight cords, tubular-vesicular cristae
ZR - branching, few lipid droplets, tubular-vesicular
Adrenal development
Fetal (80%)/Permanent (20%) -> after birth permanent cortex 100%
Testis, Leydig cells
Light staining vacuolated cytoplasm
Contain lipochrome pigment granules, crystals of Reinke
Theca interna cells - respond to LH by producing ASDione and testosterone
Granulosa cells - synthesize aromatase in response to FSH (can make estrogen)
Progesterone produced by corpus luteum
Modified myoepithelial cells in wall of afferent arteriole and a few in efferent
Cytoplasmic granules with PAS or Bowie's ethyl violet
Secretes renin
Angiotensin II
Potent vasoconstrictor
Simulates aldosterone
Polypeptide, AA organs
RER, small golgi
Hormone stored
Role of microtubules
Anterior pituitary - acidophil
Anterior pituitary - basophil
Pars intermedia
Produces MSH
Herring bodies
Local accumulations of neurosecretory material in axoplasm of fibers of hypothalamo-hypophyseal tract
Contains hormones produced in hypothalamic nuclei
Neurophysin - large carrier protein to which oxytocin and ADH are bound
Islets of Langerhans - structure
Spheroid structures
Pale staining cells
More numerous in tail and body than head
Alpha cell - insoluble in alcohol, periphery, highly opaque granules
Beta cell - soluble in alcohol, interior of islet, less electron opaque, more numerous, alloxan injures
Delta cell - Masson's triple stain, few
F cell - pancreatic polypeptide
Parathyroid glands - structure
Chief cells - glycogen
Oxyphil cells - larger cells
Adrenal medulla - structure
E secretory granules - homogeneous, less electron opaque
NE - secretory granules - very electron opaque
Pineal gland - structure
Pinealocytes - large nuclei, SER
Astroglial cells - IFs
Corpora arenacea - brain sand
Post-ganglionic SNS
Arginine vasotocin - anti-gonadotroph
-Pineal tumor - precocious puberty
ADH control
Controlled by plasma osmolality
High osmolality increased ADH
Increased in severe blood loss, nicotine, saline loading, dehydation
Decreased by ethanol, emotional stress, cold
Osmoreceptors- hypothalamus Stretch receptors - heart, aorta are inhibitory
Actions of ADH
Increased permeability of distal nephron
High doses - vasoconstriction
Stimulates renal mesangial cell contraction
Inhibits renin
Stimulates ACTH secretion
Increase in plasma ADH is dramatic above osmolality of 290
Suspect SIADH
Low serum Na+ with high urine Na+
Diabetes insipidus
Neurogenic (hypothalamic)
Nephrogenic (normal or high ADH)
Dilutional hyponatremia with high urinary sodium
Small cell lung carcinoma
Primary congenital adenohypophysis malformation
Complete absence
Ectopia - improper migration of Rathke's pouch
Secondary congenital malformation of adenohypophysis
Holoprosencephaly - affects olfactory, impaired midline cleavage of forebrain, midline dysplasia of face
Kallmann syndrome - X-linked - hypogonadotropic hypogonadism
Cleft lip and palate - selective GH deficiency
Hereditary dyfunction of adenohypophysis
Isolated GH deficiency - AD
Panhypopituitary dwarfism - sporadic - deficiency of GH and others (most frequently gonadotrophins)
Sheehan's syndrome
Severe anterior pituitary insufficiency following severe intrapartum or post-partum hemorrhage
Chronic inflammatory disease affecting the AP
TB, sarcoid, syphilis, rarely mycotic
Lymphoid hypophysitis
Autoimmune, rare
Immunologic attack on prolactin cells
Following pregancy
Hunter-Hurler disease
AP - Foamy cells and distended due to accumulation of mucopolysaccharides
Hemochromatosis - AP
Iron deposited in AP as in other organs - AR
Hypogonadotropic hypogonadism is most common manifestation
Pituitary adenomas
Microadenoma - <1 cm
Macroadenoma - >1 cm
Optic nerve, chiasm compression - BTH
Pituitary carcinoma - rare
In men - hypogonadism
Tumor of maldevelopmental origin - stratified squamous and ameloblastic epithelium
Epithelia displaced from oral cavity
Cause visual symptoms
Frequently calcify
Cystic containing turbid yellow fluid
Morphologically identical to seminomas
Usually involve posterior lobe and tuber cinereum and cause DI
Primary adrenal hyperplasia -influence on AP
Crooke's hyaline change occurs in ACTH producing cells
Empty Sella Syndrome
Diaphragm of the sella turcica has an opening much wider than necessary for passage of the pituitary stalk
Downward herniation of the subarachnoid space compressing the stalk and the gland
Secondary causes of elevated prolactin
Breast or chest wall disease
Suprasellar disease
Drugs - anti-psychotics
Acromegaly - clinical features
Slow proliferation of soft tissue and cartilage
Acral bone growth
Visceral and cutaneous growth
HTN and insulin resistance
Acromegaly diagnosis
Basal fasting GH is elevated - >10
Failure of GH to suppress following glucose load
Elevated IGF-1
L-dopa suppresses GH (normal is increased GH)
Acromegaly - treatment
Surgery - larger = poorer outcome
Radiation - adjuvant, GH levels decline over years
Medical - octreotide (somatostatin), DA agonists
Cushing's syndrome
Thinning of the skin
Easy bruiseability
Muscular weakness (proximal)
Mood changes
Ectopic ACTH
Usually a fairly aggressive tumor
Most commonly an Oat's cell carcinoma of the lung, but many others
Cushing's syndrome diagnosis
Urinary free cortisol
DST - low and high dose
Cushing's disease (pituitary) treatment
Trans-sphenoidal resection
Radiation may have fairly quick impact (contrast to GH)
Inhibitors of synthesis
Nelson's syndrome
Clinical appearance of an ACTH secreting tumor following bilateral adrenalectomy
Suppressive effect of cortisol is no longer present
Central causes of DI
Head trauma
Mass effect on the hypothalamus by craniopharyngioma
Local growths
Tumors or infarctions causing edema
Diabetes insipidus - clinical and diagnosis
Dilute urine
Use water deprivation with hourly monitoring of urine volume and osmolality
Response to AVP or DDAVP
Hypopituitarism - causes
Iatrogenic - surgery, radiation
Injury related
Histiocytosis X, sarcoidosis, hemochromatosis
Sheehan's syndrome
TB, fungal, treponemal
Hypopituitarism - testing
Serum cortisol +/- ACTH, CRH
Short loop testing - cosyntropin
Long loop testing - metyrapone, insulin hypoglycemia
Prolactin, FSH, LH, clomiphene, GnRH
TSH, T4, T3, TRH
GH - L-dopa test, arginine infusion test, insulin hypoglycemia
SIADH - causes and clincal picture
Bronchogenic carcinoma, other malignancies
CNS trauma, malignancy, infection, inflammation

Euvolemic hyponatremia with dilute urine and normal thyroid and adrenal function
Diagnostic work up for suspected growth abnormality
History - pregnancy, general, growth, family
Chemistry panel
Bone age
Skull x-ray films
Chromosomal karyotyping
Anti-gliadin Ab
RBC folate and carotene
24 hour urinary cortisol
GH stimulation test
CT or MRI of the skull
Non-endocrine causes of growth disorders
Renal disease
Cardiac disease
Chronic anemias
GI disorders
Congenital disorders
Laron-type dwarfism
GH resistance
Abnormality of GH receptor
Oriental Jews
High GH, low IGF-1
Rx: IGF-1
Anterior pituitary - cellular breakdown
GH secreting - 50%
Prolactin secreting - 20%
ACTH secreting - 20%
TSH secreting - 5%
FSH, LH secreting - 5%

Acidophils - PRL, GH
Basophils - TSH, LH, FSH, ACTH, lipotropin, endorphin, MSH
Thyroid gland - functional morphology
Actively secreting follicles - smaller follicles lined by tall cuboidal/columnar cells
Less actively secreting follicles - larger follicles lined by flattened epithelial cells containing large amounts of stored colloid
C cells - pale cytoplasm, only found in middle third of lateral thyroid lobes
Parathyroid gland - morphology
Third and fourth branchial arches
Chief or principal cells - small with round central nuclei and pale eosinophilic or clear cytoplasm - PTH
Oxyphil cells - larger with copious eosinophilic cytoplasm, increase in number with aging
Pineal gland - morphology
Evagination of the posterior part of the roof of the third ventricle
Pinealocytes - highly modified neurones, prominent nucleoli, granular cytoplasm, many highly branched processes - contain melatonin or serotonin
Neuroglial cells - similar to astrocytes
Pineal sand - basophilic extracellular bodies composed of calcium and magnesium phosphate
Thyroid hormone biosynthesis
Concentration of iodine against a steep gradient - inhibited by hypoxia, CN, 2,4-DNP
Uptake is inhibited by monovalent ions of the same size - thiocyanate and perchlorate
TPO responsible for all steps
Thioureas inhibit iodination
NADP dehalogenase removes iodine from left over MIT and DIT
TSH controls all events - mediated by cAMP dependent kinase
Arcuate nucleus and median eminence synthesize TRH
Somatostatin and DA inhibit TSH
Nodular goiter
Nodules have incomplete fibrous capsules
Non-uniform histology - contrast to adenomas
May undergo retrogressive changes - hemorrhage, fibrosis, calcification
Papillary carcinoma of thyroid
MCC of thyroid cancer
Nodule that is firm, solitary, and cold
Psammoma bodies
Ground glass nuclei
Metastasize via lymphatics
May be multifocal
Excellent prognosis
RET involvement
May secrete thyroglobulin
Follicular carcinoma of thyroid
Spread via bloodstream (BBLL)
Small follicles, large nuclei, poor colloid formation, take up iodine, but do not make hormone
Prognosis less that papillary
RAS oncogene
Hurthle cell tumors
Medullary carcinoma of thyroid
Parafollicular C cell
Associated with amyloid stroma
Commonly metastasize to nodes
Calcitonin, ACTH, prostaglandins, serotonin, melanin
Stain for calcitonin or CGRP
Associated with MEN II
CEA production
Anaplastic carcinoma
Rare, very aggressive, older patients
Rapidly enlarging neck mass -compression, fatal within months
Cellular tumor with epithelial, spindle, or giant cells alone or in combination
Thyroid lymphoma
Most are B cells
Hashimoto association
Symptoms of pituitary adenoma
Visual field defects
Pituitary lesion workup
TSH, T4, T3
Cortisol level 8am, 4 pm
24 hour urinary free cortisol
CT through sella turcica
Visual field studies
Differential diagnosis of sella turcica lesion
Empty sella
Rathke's cleft cyst
Granular cell myoblastoma
Lymphocytic hypophysitis
Pituitary abscess
Differential diagnosis of parasellar/suprasellar lesion
Suprasellar glioma
Arachnoid cyst
Histiocytosis X
Management of symptomatic pituitary adenoma
GH, ACTH, TSH -> surgery
PRL, null -> bromocryptine, octrotide -> surgery if no improvement
Parathyroid - age progression
Childhood - almost all chief cells
Adolescence - appearance of oxyphil cells, water-clear cells, and fat
Middle age - appears to contain 50% fat
Old age - fat decreases and oxyphil cells organized in clusters
DiGeorge syndrome
Thymic and parathyroid aplasia
Failure of development of the 3rd and 4th pharyngeal pouches
Present with tetany due to hypocalcemia
Recurrent viral and fungal infections due to defective T cell immunity
Congenital defects of heart and great vessels
22q11 deletion
Parathyroid tumor mutations
PRAD1 - overproduction of cyclin D1 forcing proliferation
MEN 1 - loss of suppressor gene
Familial hypoparathyroidism
Associated with chronic mucocutaneous candidiasis and primary adrenal insufficiency
Presents in childhood with onset of candidiasis followed several years later by hypoparathyroidism then adrenal insufficiency during adolescence
Physical examination findings of hypocalcemia
Chvostek sign - tapping along the course of the facial nerve induces contraction of the muscles
Trouseau sign - carpal spasm induced by occluding the forearm blood supply using a BP cuff
Biological effects of glucocorticoids
Stimulate gluconeogenesis
Inhibit glucose uptake and metabolism in the periphery
Increase glycogen deposition in liver
Increase lipolysis and plasma free FAs
Tend to stimulate protein and RNA synthesis in liver but breakdown and inhibit protein synthesis in peripheral tissues
Maintain vascular reactivity to vasoactive agents
Induce cardiac proteins - maintain contractility
Maintain ability to secrete a water load
Modulate electrolytes - regulate GFR, ADH synthesis, and ANP synthesis and action
Affect brain function
Inhibit fibroblast function
Stimulate type II pneumocytes
Partially block Ca2+ absorption in the gut and calcium reabsorption in the kidney
Increases bone resorption
Decrease linear growth
Anti-inflammatory and immune suppression
Mechanisms of mineralocorticoids
Regulation of ENaC - opening of preexisting channel by SGK on the apical membrane
Induction of Na/K ATPase on basolateral side
Induction of mitochondrial proteins with resultant increases in energy
Regulation of aldosterone
Angiotensin II (increased with low pressure or low Na+)
Plasma potassium
ACTH (transient effect)
ANP inhibits renin -> inhibits aldosterone release
Catecholamine synthesis
Sympathetic stimulation and ACTH regulate conversion of tyrosine to dopa (rate limiting step) and conversion of dopamine to NE (requires Cu and vitamin C)
Cortisol helps regulate conversion of NE to E (uses SAM)
Catecolamines inhibit tyrosine hydroxylase by feedback inhibition
Effects of catecholamines
Beta 1 - cardiac muscle contraction - increase CO
Alpha 1, alpha 2 - vasoconstriction - increase peripheral resistance
Beta-2 - vasodilation - heart, SM, bronchial smooth muscle
Changes patterns of blood flow
Increases sweat
Mobilizes carbohydrates and fat stores
Inhibits insulin
Therapeutic uses of corticosteroids
Immunologically mediated disease - RA, SLE, dermatomyositis, scleroderma, bronchial asthma, allergic skin reaction
Leukemias of lymphoid series
Replacement therapy - Addison's, CAH
Aggressive immunosuppression
Toxic effects of corticosteroid use
Fluid/electrolytes - increased BP, decreased K+, alkalosis, edema
Protein catabolsm - muscle myopathy, bone osteoporosis
Immunosupression and infection, weight gain, obesity, DM, hyperlipidemia, gastric hyperacidity, CNS effects, cataracts, glaucoma, striae, bruising, suppression of HPA axis (reason for tapering off dosages)
Treatment in Cushing's syndrome
Ketoconazole - CYP450 inhibition
Aminoglutethimide - prevents conversion of cholersterol to pregnenolone
Approach to the inhibition of inflammation/immune responses
Reduce NF-kB synthesis - aspirin
Increase NF-kB degradation/inactivation
Increase I-kB - glucocorticoids
Primary pigmented nodular hyperplasia of the adrenal
Rare - familial AD
Stimulation of adrenal by IgG
May be associated with myxomas
Present in adolescence as moderate or severe hypercortisolism
Liddle's syndrome
Defect on either beta or gamma subunit of ENaC resulting in constituitive activation - responds to amiloride
Type I polyglandular syndrome
Adrenal failure in combination with hypoparathyroidism and chronic mucocutaneous candidiasis
Type II polyglandular syndrome
Adrenal failure in combination with Hashimoto's thyroiditis and/or DM
Waterhouse-Fridericksen syndrome
Adrenal hemorrhage related to meningococcal septicemia or pseudomonas septicemia
Accumulation of very long chain FAs in the adrenal cortex (also brain, testes, liver)
Due to defective beta-oxidation in peroxisomes
ACTH stimulation test
Cosyntropin is administered im or iv
Samples taken just prior and 30, 60 minutes after dose
Response should be >20 ug/dl
Factors stimulating insulin release DIRECTLY
Amino acids - leucine, arginine
FA and ketone bodies - weak
CCK and GIP - GIP may be responsible for higher level of insulin release with oral glucose load
Effects of insulin on muscle
Recruits GLUT4, promotes glycogen synthesis by enhancing transport of hexokinase and activating glycogen synthase, promotes glycolysis through hexokinase, PFK, and PDH, promotes protein synthesis and inhibites protein breakdown
GLUT receptor location
GLUT-1 - brain, RBC, endothelium, beta cells
GLUT-2 - liver, kidney, ileum, beta cells
GLUT-3 - neurones, placenta
GLUT-4 - skeletal muscle, heart, adipocytes
GLUT-5 (fructose) - widely
Inflammatory mediators interfere with insulin signalling
Obesity is an independent state of inflammation
Fasting glucose levels
<100 "normal"
100-125 - impaired fasting glucose
>125 - DM
Glucose >180 mg
Fasting glucose >125 mg -> DM
Pathogenesis of chronic increased glucose occurs at levels below glycosuria level
Diabetic ketoacidosis
Seen much more in type I
Thirst, polyuria, tiredness, vomiting, difficulty breathing, smell of acetone, LOC, death
Tx - saline + insulin
Severe acidosis <7.10 -> titrate HCO3- to pH 7.10-7.12
Vascular complications of DM
Microvascular - retinopathy, macular edema, neuropathy (sensory, motor, autonomic), nephropathy
Macrovascular - CAD, PVD, CVD - aspirin Tx unless CI
Diabetic nephropathy
Type I > Type II
PAS+ material deposition in BM
Diffuse glomerulosclerosis
Nodular glomerulosclerosis - KW nodules
Early marker is microalbuminuria
BM thickening -> mesangial expansion -> glomerular fibrosis and tubulointerstitial scarring
Risk of AMI in DM
Diabetic patients w/o prior AMI have the same mortality risk as non-diabetic patients with prior AMI
Management of chronic DM
Strict control of:
Hyperglycemia - HbA1C <7
HTN (both SBP and DBP) <130/80
Glucose tolerance test
>200 - DM
140-200 - impaired glucose tolerance
<140 - normal
GLP-1 antagonist
Induces insulin production
Does not cause hypoglycemia
Suppression of appetite
Hypoglycemic threshold of counter-regulatory hormones
E/glucagon - 65-70 mg
GH - 65 mg
Cortisol - 55-60 mg
NE - 50 mg
Factors playing a role in obesity
Suppress eating - alpha-MSH, leptin, 5-HT, PYY, GLP-1, CNTF

Encourage eating - NPY/AgRP, ghrelin, critical influences
OB/OB mouse
Lepin deficient
DB/DB mouse
Leptin receptor deficiency
Human equivalent model of obesity
Calories in various food sources
1 lb fat = 3500 Calories
1 g fat = 9 Calories
1 g alcohol = 7 Calories
1 g carbohydrate = 4 Calories
1 g protein = 4 Calories
Influence of adiponectin
Insulin increases the release of adiponectin
Obesity has increased insulin, but with resistance
Increased adiponectin leads to anti-inflammatory effects
Chronically decreased adiponectin leads to a pro-inflammatory state
Influence of diet on inflammation
Macronutrient intake - (+)NF-kB, (-)IkB, (+)ROS, (+)lipid peroxidation
Fasting - (-)ROS, (-)oxidative stress
Obesity - (+)oxidative stress, (+)NFkB, (+)pro-inflammatory cytokines
Health consequences of obesity
Sleep apnea
Ischemic heart disease
Acanthosis nigracans
Marker of insulin resistance in DM
Also seen in Cushing's and pituitary tumor
Blocks re-uptake of 5-HT, DA, NE
Used for weight loss with low calorie diet
SE - constipation, insomnia, HA, dry mouth
Intestinal lipase inhibitor
Indications - BMI>30 or BMI>27 with other risks
SE - reduction of fat soluble vitamins, flatulence, urgent bowel movements, fatty or oily stools, increased number of bowel movements, abdominal pain or discomfort, and incontinence
CI - malabsorption syndrome, cholestasis
Polyol pathways in DM
Glucose can be converted to sorbitol by aldose reductase
Increased sorbitol can lead to increased cellular osmolarity and swelling and/or decreased ATPase activity
Aldosterone inhibitors
Aldosterone stimulators
Muscle weakness
Muscle paralysis
Renal concentrating defect
Widened QT interval with U waves
Myocardial fibrosis
Impaired insulin secretion
Diminished glucose tolerance
Blunted circulatory responses with postural hypotension
Rule of 10's (malignant, bilateral, extra-adrenal, calcified, kids, familial)
5 P's(pressure, pain, perspiration, palpitations, pallor)
Diagnosis - plasma MN and NMN
Tx - pre-op - alpha blocker, beta blocker if tachycardic
operative - IV alpha blocker, IV alpha agonists, IV beta blockers, IV lidocaine (depends on response)
Post-op - regular urinary screening, RET testing of family if MEN
Atypical DM
"DM Type 1.5"
Obese African American
Acanthosis nigricans
Can be weaned off insulin
Autoimmune markers mildly (+)
Low C peptide poor prognostic indicator
Insulin analogs
Decreased self-association - faster absorption - shorter action
Increased self-association - slower absorption - prolonged action
Improve formation stability
Improve patient convenience
Can have faster onset and shorter duration than regular insulin
Hemoglobin A1C
Represents 80% of total glycosylated Hb
% is proportional to the average glycemic level
If measured every 3 months gives the most reliable measure of metabolic control
Normal - 4-6%
Diabetes glucose goals
FBG - 70-120 mg
Pre-prandial - 70-150 mg
2 hour post meal - 70-180 mg
Middle of the night - >70 mg
Diabetes HbA1C goals
<12 - 8%
12-18 - <7.5%
>18 - <7%
Hypoglycemia - patient control
<70 mg/dl
Eat or drink something that contains 15g of simple sugar
Diabetes prevention program trial
Placebo, metformin, lifestyle (7% weight, 150 minutes PE/week)
Metformin - 31% reduction
Lifestyle - 58% reduction
Islet cell transplantation
Human islet cells injected into vein or placed in abdominal cavity (liver)
IS is required
1-3 pancreases are needed to provide enough islet cells
Acute management of thyroid storm
Iodide in high dose
Beta blocker (unless CI - use CCB)
GC in stress dose
Acetaminophen (not aspirin)
IV fluid, O2, thiamine
Myxedema coma
R/O intoxication
ICU admission
IV fluids isotonic +/- K+
High dose T4 - 400 ug
IV GC stress dose
Maintenance T4 + GC
Addisonian crisis
Dx - stressed cortisol level, cortrosyn stimulation (with DEX given to initiate therapy)
Tx - DEX until after testing and then hydrocortisone for maintenance, IV fluids with glucose in isotonic NaCl
Pituitary apoplexy (infarction)
HA followed by asthenia (weakness), nausea and vomiting and later hypotension
Settings - post-partum (Sheehan's), head trauma, pituitary tumor, anti-coagulation/coagulopathy
Tx - life support axes (thyroid, adrenal, ADH)
Acute hypocalcemia
Muscle spasm, tetany, seizures, arrhythmias, laryngospasm, respiratory arrest
Dx - numbness and dysesthesias, Chvostek and Trousseau's signs, low BP, long QT interval
Tx - IV Ca gluconate over 3-5 minutes -> maintenance infusion -> identify cause
Tx - 0.9% NaCl at a high rate
Do not start loop diuretics until patient is volume overloaded
IV palmidronate in malignant hypercalcemia (days)
Prednisone - multiple myeloma, vitamin D mediated, adrenal insufficiency
Plicamycin and gallium nitrate
CRH testing
ACTH response are exaggerated in Addison's disease
ACTH responses are absent in patients with hypopituitarism
Delayed responses usually occur in patients with hypothalamic disorders
Steroid 5-alpha reductase deficiency
Unable to convert testosterone to DHT
Consequences of renal failure
Calcitriol deficiency
Low erythropoietin
Plasma renin activity
Primary aldosteronism - low
Renovascular HTN - high
Parts of the pancreas and relationship to structures
Head -> IVC, renal veins, common bile duct
Neck - portal vein
Body - aorta, IVC, left renal vein
Tail - touches the spleen
Embryonic origin of the endocrine glands
Thyroid - epithelium
PTH/thymus - epithelium
Pancreas - endoderm
Adrenal - outer-mesoderm/inner-ectoderm
Pituitary - two separate ectoderms
Blood supply to the pancreas
From gastroduodenal and SMA
From splenic artery
From splenic and left gastroepiploic artery
Vein - splenic vein
Adrenal blood supply
SSA - inferior phrenic
MSA - aorta
ISA - renal
Central suprarenal vein
Lumbar nodes
Hypophysis embryology
AP - Rathke's pouch
-Anterior cells - adenohypophysis
-Posterior cells - pars intermedia
PP - infundibulum
Glucagon pathway
Adenylate cyclase -> cAMP -> PKA -> phosphrylase kinase-P -> phosphorylase a-P -> breaks down glycogen
Nuclear receptor types
Classic - homodimers - GR, MR, AR, PR
Heterodimers w/RXR - TR, VDR, RAR
Two half sites
Each binds one molecule of the nuclear receptor
Several receptors recognize identical half sites - ER, VDR, TR, RAR
Alpha subunit identity
Stimulates IGF-1 -> cartilage growth
Inhibits insulin action on glucose utilization in muscle
Syngerizes with insulin to increase AA uptake by cells
Increases lipolysis by activating HSL
Inhibited by somatostatin from the hypothalamus
IGF-1 feeds back on the hypothalamus to inhibit GHRH and stimulate somatostatin
Secretion increased by hypoglycemia, arginine, REM sleep, DA, NE, 5-HT
Similarity in sequence to PRL and hCS
Breech the BBB
Turn on ADH secretion in response to increased osmolality
Actions of ADH
Acts through two receptors V1 and V2
V2 - water balance in the kidney
Increased cAMP -> increased aquaporin 2 water channels
Stimulates urinary concentrating mechanism by stimulating urea transporter UT1
Breast and uterus are targets
Maternal oxytocin does not initiate labor, but fetal oxytocin may
The uterus remains insensitive to oxytocin until about 20 weeks of gestation but after that there is a huge increase (80-fold) in the number of OT receptors with a further increase (up to 200-fold) during early labor
Once labor is initiated, maternal OT is released in bursts and the frequency of the bursts increases as labor progress
OT binds to Gaq-coupled receptors in the plasma membrane of uterine smooth muscle cells (and breast myoepithelial cells), triggering the phospholipase C cascade. Uterine contraction occurs and there is increased intrauterine pressure
Effects of suckling
First, it stimulates sensory nerves, which carry the signal from the breast to the spinal cord where they synapse with neurons that carry the signal to the brain.
Second, in the arcuate nucleus of the hypothalamus, the afferent input from the nipple inhibits neurons that release dopamine (DA). Thus, inhibition of DA release leads to an increase in PRL release.
Third, in the SON and PVN, the afferent input from the nipple triggers the production and release of OT in the posterior pituitary.
Fourth, in the preoptic area and arcuate nucleus, the afferent input from the nipple inhibits GnRH release and lowers LH and FSH release, and thereby inhibits the ovarian cycle.
Prolactin vs. oxytocin
Prolactin is a lactogenic hormone promoting initiation of milk production by alveolar cells. Oxytocin is a galactokinetic hormone promoting contraction of myoepithelial cells, and thus milk ejection