Endocrine Flashcards
A defect in the endocrine gland is a ___ defect; a defect in another related organ is a ___ defect.
Primary; secondary or tertiary
Hormone binding proteins are mostly for what type of proteins? There are 3 additional hormones that have binding proteins that do not fit this category. What are they?
Steroid hormones (lipophilic) IGF-1, GH, T4/T3
What is the difference between a free hormone and a bioavailable hormone?
A free hormone is unbound; a bioavailable hormone is bound to albumin only.
Kd = ?
Ligand (hormone) concentration that occupies 50% of binding sites (receptors)
Ki = ?
Ability to displace ligand (hormone) at 50% of maximum activity
Small Kd = ? (affinity)
Higher affinity
Smaller Ki = ? (specificity)
Higher specificity
True or false - the ligand concentration for maximal physiological response correlates with the Kd.
False - not necessarily
Hormones are transcribed as ___, which contain a signal peptide sequence. The signal peptide is cleaved to form a ___, which is the hormone plus any copeptides. Subsequent processing and packaging into ___ cleaves the hormone from its associated copeptides.
Preprohormones; Prohormone; Vesicles
What are the 4 examples of positive feedback in the human body?
- Parturition
- Lactation
- Ovulation
- Blood clotting
High basal TSH but normal pituitary response to TRH indicates a ___ defect.
Primary
Undetectable basal TSH and a lack of pituitary response to TRH indicates a ___ defect.
Secondary
Low basal levels of TRH and a delayed returned to baseline following TRH stimulation indicates a ___ defect.
Tertiary
The hypothalamus forms the floor of the ___.
Third ventricle
What hypothalamic nucleus regulates sleep?
SCN
What hypothalamic nucleus regulates feeding behavior/satiety?
ARC
What hypothalamic nucleus regulates thirst?
PVN
What hypothalamic nucleus regulates reproduction?
POA
What hypothalamic nucleus regulates circadian rhythms?
SCN
What hypothalamic nuclei regulate mood/motion/stress?
PVN/ARC
What hypothalamic nucleus regulates body temperature?
POA
What hypothalamic nucleus regulates blood pressure?
PVN
What is regulated by the PVN?
Thirst, mood/emotion/stress, blood pressure
What is regulated by the POA?
Reproduction, body temperature
What is regulated by the ARC?
Feeding behavior/satiety, mood/emotion/stress
What is regulated by SCN?
Sleep, Circadian rhythms
From which nuclei are GnRH/GnIH released?
POA
From which nuclei is CRH released?
PVN
From which nuclei is TRH released?
PVN
From which nuclei is GHRH released?
ARC
From which nuclei is Somatostatin released?
PeVN
From which nuclei is Dopamine released?
ARC
What is Kallman Syndrome?
Rare genetic disease in which the GnRH neurons fail to enter the CNS; results in reproductive failure and anosmia
Activation of IP3 by GnRH leads to hormone ___ (release or synthesis). Activation of DAG and PKC by GnRH leads to hormone ___ (release or synthesis).
Release; synthesis
High GnRH pulse frequency favors transcription of ___ (LH or FSH); low GnRH pulse frequency favors transcription of ___ (LH or FSH)
LH; FSH
What three hormones share a common alpha subunit?
TSH, FSH, LH
What is the tuberoinfundibular system?
Comprises all neurons that send axonal projections to the median eminence; hormones target the anterior pituitary through the capillary system
What is the neurohypophysial tract?
Comprises all neurons whose axons terminate in the posterior pituitary.
What are the three parts of the anterior pituitary?
Pars distalis (90%) Pars tuberalis Pars intermedia
What are the two parts of the posterior pituitary?
Pars nervosa
Infundibulum (stalk)
Describe the tissue differences between the anterior and posterior pituitary.
Anterior: glandular
Posterior: neural
From what are the anterior the posterior pituitary derived, respectively?
Anterior: embryonic foregut
Posterior: neuroectoderm
Describe the components of the neurohypophysis.
Axons from the magnocellular neurons of hypothalamus terminate in the posterior pituitary. Hormones are released from here into systemic circulation.
What are dilations of unmyelinated axons near the terminals in the posterior pituitary from which hormones are released?
Herring bodies
What are glial-like cells of the posterior pituitary?
Pituicytes
What is neurophysin?
The binding protein to which AVP or OXY are bound at release from the posterior pituitary
What are the two types of acidophils in the anterior pituitary?
Somatotropes
Lactotropes
What are the three types of basophils in the anterior pituitary?
Corticotropes
Gonadotropes
Thyrotropes
What is the most abundant category of cells in the anterior pituitary?
Acidophils
What is released from somatotropes?
GH
What is released from lactotropes?
Prolactin
What is released from corticotropes?
ACTH
What is released from gonadotropes?
LH/FSH
What is released from thyrotropes?
TSH
Describe how hormones are released from the anterior pituitary.
Axons from the parvicellular neurons of hypothalamus terminate at the median eminence. Hormones are released from here into long portal veins which travel to the anterior pituitary, which releases hormones into systemic circulation.
Most pituitary hormones are released in what fashion?
Circadian
Neurophysin I is bound to ___ as a prohormone; neurophysin II is bound to ___ as a prohormone.
OXY
AVP
What stimulates AVP release?
Increased plasma osmolality
Decreased blood volume
What is diabetes insipidus?
Excessive urine production caused by a defect in AVP
What are the two main causes of diabetes insipidus?
- Decreased AVP release (secondary or tertiary defect due to trauma, cancer, or infection)
- Decreased renal responsiveness to AVP (genetic or acquired via lithium treatment, hypokalemia)
What is SIADH?
Syndrome of Inappropriate Vasopressin Secretion - hyponatremia in the absence of edema
GH is structurally similar to ___.
Prolactin
What is gigantism?
GH excess that occurs before the closing of the epiphyseal plate; increases long bone growth resulting in extreme hight
What is acromegaly?
Gradual enlargement of hands and feet (arthritis), changes in facial features (protruding lower jaw, enlarged lips, tongue, nose), increased organ size
What are the two types of dwarfism?
Laron syndrome and African pgymy
What is Laron syndrome?
Genetic defect in GH receptor, no production of IGF-I (plasma GH levels are normal to high)
What is African pygmy?
Partial defect in GH receptor, some IGF-1 response, plasma GH levels normal
Why can high levels of GH cause galactorrhea?
GH is similar to Prolactin and can bind to its receptor
What is Sheehan’s Syndrome?
Partial pituitary destruction resulting from excessive blood loss/shock during childbirth; affects other pituitary cell types leading to loss of axillary and pubic hair
What two hormones act synergistically to increase the amplitude of ACTH release from the anterior pituitary?
AVP and CRH
Under the control of CRH, what products are formed from the preprohormone for ACTH?
ACTH, beta-lipotropin
Under the control of norpeinpehrine, what products are formed from the preprohormone for ACTH?
Beta-endorphin, melanocortin stimulating hormone, enkephalin
What happens when there are supraphysiolgoical ACTH levels?
ACTH binds to low-affinity MC1R receptors in the melanocytes in the skin, melanin synthesis increases and skin darkens. Note this is different than what happens vi UV light (affects keratinocytes, increases POMC expression, produces alpha-MSH which binds to the MC1R receptor)
The adrenal cortex is derived from the ___; the adrenal medulla is derived from the ___.
Mesoderm; neural crest
The ___ artery gives rise to arterioles that peruse the cortex to the adrenal medulla.
Capsular
What is produced in the 4 distinct areas of the adrenal gland?
- Cortex:
- Glomerulosa: mineralocorticoids
- Fasciculata: glucocorticoids
- Reticularis: androgens - Medulla: catecholamines
Where are glucocorticoids made?
Zona fasciculata
To what is cortisol bound in circulation?
CBG (90%)
Albumin (7%)
Free (3-4%)
CBG has a thirty-fold higher affinity for cortisol than ___.
Aldosterone
What two things decrease CBG, leading to an increase in free cortisol?
Estrogen and shock/severe infection
How is cortisone activated to cortisol?
11-beta-HSD1
What are the metabolic effects of cortisol action?
Mobilize energy stores, increase plasma glucose (counter-regulatory hormone to insulin) via increased gluconeogenesis, decreased glucose uptake, inhibits calcium absorption
How does cortisol increase gluconeogenesis?
Increases key hormones: tyrosine aminotransferase, PEP carboxykinase, and glucose 6-phosphatase
Cortisol decreases ___ insertion in the membrane of muscle cells.
GLUT 4
What are the effects of cortisol on muscle?
Decreased protein synthesis and increased protein degradation, leading to atrophy
How does cortisol lead to muscle breakdown?
Cortisol increases transcription of the E3 ubiquitin ligase MuRF-1 while simultaneously inhibiting amino acid uptake and AKT-phosphorylation.
NFkappaB is needed to activate MuRF-1.
Normally, phosphorylated AKT increases protein synthesis.
What are the effects of cortisol on adipose tissue?
Increased lipolysis; redistributes fat from the limbs to the abdomen
How does cortisol increase lipolysis in adipose tissue?
Increases transcription of:
- Mg11 gene (codes for MAG lipase)
- Lipe gene (codes for hormone sensitive lipase)
- Angpt14 gene (increases cAMP, activates hormone sensitive lipase)
What are the effects of cortisol on the immune system?
Decreases inflammation
How does cortisol decrease inflammation?
Normally, NFkappaB is unbound from IkappaB (stops inhibition) by cytokines. NFkappaB moves to the nucleus, where it increases the expression of genes for cytokines, enzymes, and adhesion molecules. Cortisol interrupts this process by binding to activated NFkappaB directly to prevent its nuclear binding and by increasing transcription of IkappaB
What are the 4 ways in which cortisol inhibits immune function?
- Stimulates anti-inflammatory cytokines
- Inhibits prostaglandins
- Suppresses antibody production by inhibiting T cell function
- Increases neutrophils, platelets, and RBCs (inhibits neutrophil function)
What are the effects of cortisol on bone?
- Inhibits intestinal calcium absorption
- Inhibits bone formation
- Increases bone resorption
(increases plasma Ca2+)
How does cortisol affect the bone?
- Inhibits intestinal calcium absorption via decreased active transport (?)
- Inhibits bone formation by decreasing IGF-1 receptors
- Increases bone resorption by activating osteoclasts
How does cortisol affect the cardiovascular system?
- Stimulates RBC production
- Maintains responsiveness to catecholamine pressor effects (constrict peripheral vessels via alpha-adrenergic receptors. dilate coronary arteries via beta-adrenergic)
- Maintains vascular integrity and reactivity
How does cortisol affect the CNS?
Emotional responses, increased perception, negative feedback on CRH and ACTH
What disease is caused specifically by excessive cortisol secretion due to pituitary adenoma? What disease is caused by excessive cortisol for other reasons?
Cushing disease; Cushing syndrome
What are the symptoms of Cushing’s?
- Change in body fat distribution (moon face, buffalo hump, abdominal obesity, thin skin, bruising)
- Osteoporosis due to inhibition of intestinal calcium absorption
- Hypertension (excess glucocorticoids activate MR)
- Glucose intolerance (antagonism of insulin action)
- Purple striae (fragile thin skin stretches over increased abdominal fat, vessels hemorrhage into striae)
What happens to the HPA axis due to chronic glucocorticoid therapy or primary adrenal excessive cortisol production?
Exert negative feedback on CRH and ACTH; prolonged shutdown of HPA axis leads to atrophy of the zona fasciculata and inability to synthesize endogenous glucocortioicds
What is the glucocorticoid:mineralocorticoid effect ratio of cortisol?
1:1
What is the glucocorticoid:mineralocorticoid effect ratio of prednisone?
3-4:0.5
What is the glucocorticoid:mineralocorticoid effect ratio of methylprednisone?
10:0.5
What is the glucocorticoid:mineralocorticoid effect ratio of dexamethasone?
20:0
What is the glucocorticoid:mineralocorticoid effect ratio of fludrocortisone?
12:125
What is adrenal insufficiency?
Failure of adrenal gland to secrete glucocorticoids, mineralocorticoids, or both
What is a primary adrenal insufficiency?
Failure at the adrenal gland
What is Addison’s disease?
Type of primary AI involving autoimmune destruction of adrenals; cause of 70% of primary AI cases
What is a secondary adrenal insufficiency?
Failure to secrete CRH or ACTH
What is the most common cause of secondary AI?
Sudden cessation of glucocorticoid therapy
Contrast Aldosterone and AVP/ADH.
Aldosterone is a primary regulator of extracellular volume. It stimulates sodium primarily, as well as water reabsorption secondarily in the kidney.
AVP/ADH is a primary regulator of free water balance. It stimulates water retention, decreases plasma osmolality (secondarily affects sodium)
Despite the fact that it binds glucocorticoids with higher affinity than mineralocorticoids, MR is the primary mineralocorticoid receptor. Why?
95% of glucocorticoids are bound to CBG and aldosterone does not have a specific binding protein.
How is cortisol inactivated to cortisone?
11-beta-HSD type 2
What are the three causes of congenital adrenal hyperplasia?
- 21 hydroxylase deficiency
- 11 hydroxylase deficiency (CYP11B1 gene)
- 17 hydroxylase deficiency
What is the major cell type in the adrenal medulla?
Chromaffin cells (pheochromocytes)
What are the arousal effects of EPI?
Pupil dilation, sweating, GI and bronchial muscle relaxation
What are the metabolic effects of EPI?
Glucose release, increased metabolic rate
What are the cardiovascular effects of EPI?
Vasoconstriction, increased heart rate
What are the metabolic effects of EPI on muscle, liver, and fat?
Muscle: block glucose uptake, release glycogen
Liver: synthesize;release glucose
Fat: release fatty acids
NE stimulates ___ to initiate a response to long-term stress.
CRH neurons (HPA axis)
What are pheochromocytomas?
Tumors originating from chromaffin cells
What are symptoms of pheochromocytomas?
Hypertension that does not respond to medication, headaches, tachycardia
How are pheochromocytomas diagnosed?
Measure urinary metanephrines
How are pheochromocytomas treated?
Surgery and alpha/beta blockers prior to surger
Why are pheochromocytomas called the 10% tumor?
10% are:
- Malignant
- Bilateral
- In children
- Familial
- Recur
- Associated with MEN syndromes
- Present w/stroke
- Extra-adrenal
What are the 4 major extra-adrenal sites of pheochromocytomas?
- Sympathetic nerve chain along spinal cord
- Overlying distal aorta
- Within ureter
- Within urinary bladder
What innervates the thyroid gland?
Middle and inferior cervical ganglion of the sympathetic nervous system
What is the functional unit of the thyroid gland?
Follicle
From what is the thyroid gland derived?
Branchial pouch of the endoderm
Parafollicular (C) cells produce ___.
Calcitonin
The lumen of follicles are filled with ___, which is the extracellular storage site of what three things?
Colloid
T3, T4, thyroglobulin
What are the two precursors of thyroid hormones?
Thyroglobulin (TG) and iodide
Less than ___ micrograms/day of iodide results in TH deficiency.
20
Describe the autoregulation of iodide uptake.
Wolf-Chaikoff effect: increased iodide intake decreases gland transport and hormone synthesis.
What happens when a very high iodide dose is given?
Rapidly shuts down TH production
What is the most preventable cause of mental retardation?
TH deficiency
Describe the 7 steps in TH synthesis.
- Iodide trapping: TSH stimulates iodide trapping by increasing activity of the NIS co-transporter in the basal membrane of the follicular epithelial cell.
- Transport: iodide is transported to the lumen and oxidized by thyroid peroxidase to form iodine; thyroglobulin is transported to the lumen.
- Iodination of tyrosyl residues on thyroglobulin
- Conjugation of iodinated tyrosines to form T4 and T3-linked TG
- Endocytosis of conjugated complex into follicular epithelial cell
- Proteolysis releases TG, MIT, DIT, T4, and T3
- Secretion of T4 and T3 into circulation
___ inhibits NIS co-transporter.
Lithium
What events occur at the apical surface of the thyroid follicle?
- TH synthesis
2. Iodination of TG
What events occur at the basolateral surface of the thyroid follicle?
- Iodine uptake (trap)
2. TH release
Which TH binds to the receptor with low affinity?
T4
Describe the formation of T3.
Tyrosine is converted to MIT by TPO. 1 MIT and 1 DIT form T3.
Describe the formation of T4.
Tyrosine is converted to MIT by TPO. MIT is converted to DIT. 2 DIT form T4.
How are T3 and rT3 distinguished from one another?
T3: 2 iodinated residues on inner ring
rT3: 2 iodinated residues on outer ring
What drug inhibits thyroid peroxidase?
Carbimazole
Normal uptake of iodide is ___% after 24 hours. Describe the definitions of hyperthyroidism and hypothyroidism.
25
Hyper: >60%
Hypo: <5%
___ is seen in hyperstimulated thyroid glands (Graves disease).
Accelerated turnover
What is an organification defect?
Inability to incorporate iodide into tyrosine
How can an organification defect be tested?
Block NIS with inhibitor (perchlorate)
Which deiodinases can convert T4 to active T3?
Type I, Type II
Which deiodinases can convert T4 to rT3?
Type I and Type III
What is the primary source of T3 in circulation?
Type I deiodinase
What is the thyroid hormone sensor in the pituitary?
Type II deiodinase
Describe the distribution of TH binding proteins.
TBG: 70% bound
TTR: 10% bound
Albumin: 15-25% bound
What two things increase TBG?
Estrogen and hepatitis
What two things decrease TBG?
Nephrotic syndrome, steroids
When TH binds, thyroid hormone receptors form heterodimers with ___.
Retinoic acid receptor (RXR)
TH receptors have a high affinity for ___.
T3
Describe what an increase in TH does to BMR, carbohydrate/protein/lipid metabolism, and thermogenesis.
- Increased BMR
- Increased gluconeogenesis, glycogenolysis (normal serum glucose)
- Increased protein synthesis, proteolysis
(muscle wasting) - Increased lipogenesis, lipolysis, decreased serum cholesterol
- Heat intolerance
What are the physiological effects of T3 on the brain?
- Neuronal cell migration/differentiation
- Myelination
- Synaptic transmission
What is cretinism?
Iodine deficiency during development
What are the symptoms of cretinism?
Short stature/impaired bone formation, mental retardation, delayed motor development
What are the physiological effects of T3 on the heart?
Increased CO, increased resting heart rate and SV, increased beta-adrenergic receptors
What is the main form of hyperthyroidism?
Grave’s Disease
What is Grave’s Disease?
Autoimmune disorder in which antibodies (long-acting thyroid stimulators) stimulate the TSH receptor, leading to elevated TH
What are the symptoms of Grave’s Disease?
Diffuse symmetrical goiters, tachycardia, opthalmopathy, irritability, hyperactivity, heat intolerance, weight loss, nervousness, muscle wasting
What are the two types of hypothyroidism?
Hashimoto’s thyroiditis, iodine deficiency
What is Hashimoto’s thyroiditis?
Autoimmune destruction of thyroid follicles due to antibodies against TPO and TG
What are the symptoms of Hashimoto’s?
Diffuse goiter, lethargy, fatigue, hair loss, cold intolerance, brittle nails, decreased appetite, weight gain
___ levels are good indicators of free calcium availability.
Albumin
What are the two primary regulators of calcium?
PTH and Vitamin D/Calcitrol
___ cells of the parathyroid gland synthesize PTH.
Chief
Describe the synthesis of PTH.
- Signal peptide of preprohormone directs processing to the ER.
- Pro PTH is made of the N-terminal fragment (1-34) and the C-terminal fragment (35-84).
Describe the differences between the 1-84, 1-34, and 35-84 fragments of PTH.
1-84: clinically important measurement
1-34: binds to PTH receptor
35-84: longest half-life, inactive
What is PTHrP?
PTH related peptide; mimics action of PTH in bone and kidney; normally found at very low concentrations and thus does not regulate plasma Ca2+
What is the primary PTH receptor?
PTH 1R
What binds to the PTH 1R? The 2R?
PTH 1R: 1-34, 1-84, PTHrP
PTH 2R: 1-34
What are the net effects of PTH?
Increase plasma calcium, decrease plasma phosphorus
What do osteoblasts do?
Bone formation and mineralization
What do osteoclasts do?
Bone resorption
Which bone cells have PTH receptors?
Osteoblasts
From what are osteoblasts derived?
Mesenchymal stem cells
From what are osteoclasts derived?
HSCs
Describe the effects of PTH.
- PTH binds to osteoblasts and stimulates M-CSF production.
- M-CSF stimulates differentiation of osteoclast precursors.
- PTH also stimulates RANK ligand, which leads to maturation of osteoclasts.
- Osteoclasts absorb bone by secreting H+ and acid proteases which dissolve bone.
True or false - PTH stimulates osteoclasts directly.
False - PTH stimulates osteoclasts indirectly
What antagonizes RANK ligand?
Osteoprotegerin (OPG)
What stimulates OPG? What inhibits it?
Estrogens stimulate; glucocorticoids inhibit
Describe the effects of PTH on the kidney.
- Stimulates CYP1-alpha, which encodes 1-alpha-hydroxylase, which converts the inactive form of Vitamin D to the active form.
- Stimulates calcium channel insertion in the apical membrane of the DT, increasing calcium reabsorption
- Reduces phosphate reabsorption in the kidney
How do CaSR (calcium-sensing receptors) regulate PTH?
Binds ionized calcium, inhibits PTH synthesis at the promotor level, stimulates degradation of preformed PTH
How does Vitamin D regulate PTH?
Binds its receptor, inhibits PTH synthesis at promoter level, stimulates CaSR gene transcription
What is the general term for vitamin D and other natural structural analogs?
Calciferol
What is the term for vitamin D3 from animal tissues?
Cholecalciferol
What is the term for vitamin D2 from vegetables?
Ergocalciferol
What is another name for 25-hydroxy-vitamin D, the immediate precursor to active vitamin D?
Calcidiol (calcifidiol)
What is another name for 1-25, dhydroxy-vitamin D, the active form of vitamin D?
Calcitriol (calcifitriol)
Broadly, what drives conversion of inactive vitamin D to active vitamin D?
Vitamin D deficiency
Hypocalcemia
Hypophosphatemia
Broadly, what drives conversion of active vitamin D to inactive vitamin D?
Vitamin D sufficiency
Normo/hypercalcemia
Normo/hyperphosphatemia
What does Vitamin D do in the bone?
Mobilize Ca2+, stimulate osteoclast proliferation/differentiation, increase plasma Ca2+ (which promotes bone mineralization)
What does Vitamin D do in the intestine?
Increase transcellular calcium absorption in the duodenum, stimulates phosphorus reabsorption
How does Vitamin D increase calcium absorption in the duodenum?
Increases TRPV5/6, calbindin, calcium-ATPase pump
How does Vitamin D increase intestinal phosphate absorption?
Increase expression of Na+-Pi cotransporter
What is the normal serum Ca2+ range?
2.2-2.6 mM (8.8-10.3 mg/100 mL)
What is the normal serum phosphate range?
0.8-1.45 mM (2.4-4.1 mg/100 mL)
What is osteoporosis?
Reduced bone density (mainly in trabecular bone)
What causes osteoporosis?
Genetics
Menopause (low estrogen)
Glucocorticoid therapy/chronic stress
Low dietary Ca2+
How is osteoporosis treated?
Estrogens
Calcitonin
Bisphosphonates (inhibit bone resorption)
Vitamin D
What causes primary hyperparathyroidism and what are symptoms?
Hyperplasia, carcinoma of parathyroid gland
Symptoms: hypercalcemia, kidney stones
What causes secondary hyperparathyroidism and what are the symptoms?
Chronic renal failure, reduced Vitamin D leads to excess PTH synthesis
What are the symptoms of hypoparathyroidism and who can it be tested?
Hypocalcemic tetany
Chvostek sign: twitching of facial muscles in response to tapping of facial nerve
What causes rickets in children and osteomalacia in adults and what are the symptoms?
Unmineralized bone due to Vitamin D deficiency
Bowing of long bones (children)
Decreased bone strength
What causes pseudohypoparathyroidism?
Congenital defect in G protein that associates with PTH R1; leads to generalized resistance to PTH, TSH, LH, FSH
What are the clinical signs of pseudohypoparathyroidism?
Low Calcium
High Phosphorus
High PTH
Short stature
How can calcitonin be used in the clinic?
Inhibits osteoclast resorption and slows bone turnover, leading to reduction of plasma calcium; used to treat Paget disease (high bone turnover)
What is the escape phenomenon of calcitonin?
Rapid downregulation of calcitonin receptors; causes the antiosteoclastic actions of calcitonin to diminish within a few hours
What bond is cleaved by renin to convert angiotensinogen to angiotensin 1?
Leu-Val
ANP and BNP are potent ___ and they increase ___.
Vasodilators; natriuresis
What does PCB (polychlorinated biphenyl) do?
Competes with TH for binding to its transport protein in the blood; circulating TH is degraded faster, compensatory increase TH production
What does DES do?
Associated with increased cervical/vaginal cancer in DES daughters
What does BPA (bisphenol A) do?
Estrogenic, antagonizes TH receptor
The endocrine pancreas consists of 3 major cell types clustered in groups known as ___.
Islets of Langerhans
What do the beta cells of the pancreas secrete?
Insulin
What do the alpha cells of the pancreas secrete?
Glucagon
What do the delta cells of the pancreas secrete?
Somatostatin (SS14)
What do the PP cells of the pancreas secrete?
Pancreatic polypeptide (inhibit acinar cells)
What do the epsilon cells of the pancreas secrete?
Ghrelin
Describe the blood flow of the pancreas.
Blood flows from the center of the islet outward.
Describe the arrangement of alpha and beta cells in the pancreas.
Beta cells cluster in the core; alpha cells surround the beta cells as a sandwhich
What is the primary role of insulin?
Energy storage (anabolism)
What is the primary role of glucagon?
Energy mobilization (catabolism)
Describe the synthesis of insulin.
Proinsulin has an amino terminal beta chain and a carboxy terminal alpha chain linked by a C-chain. The C-chain is critical for proper folding and formation of disulfide bonds between the alpha and beta chains. Cleavage of the C-chain exposes the part of insulin that interacts with its receptor. Insulin and C-peptide are packaged together in vesicles.
Describe the process of insulin release from a pancreatic beta cell.
- Glucose enters the beta cell via GLUT-2
- Glucose is phosphorylated by glucokinase to G6P
- Glucose is metabolized and ATP is produced
- Increased ATP closes K+ channels, which depolarizes the cell.
- Depolarization opens calcium channels
- Calcium influx causes exocytosis of insulin-containing vesicles
Describe GLUT-2’s affinity for glucose.
Low
How do sulfonylurea drugs work?
They close the K+ channel of beta cells (the channel has an SUR subunit) and bypass glucose binding step.
What else can increase ATP in beta cells through oxidation?
FFAs and amino acids
What do incretins (GLP-1) do to insulin release?
Potentiate insulin release
What do catecholamines do to insulin release?
Inhibit insulin release
Describe insulin binding to its receptors.
Insulin binds receptor tyrosine kinase at alpha subunit, which causes autophosphorylation of the beta subunit
True or false - glucose cannot enter a muscle cell without insulin.
True
How does glucose enter a muscle cell?
Insulin binds to its receptor. Autophosphorylation recruits insulin receptor substrates (IRSs), which activate intracellular signaling cascades. GLUT4 is inserted into the membrane.
Which GLUT transporter is insulin-dependent?
GLUT-4
What are the physiological effects of insulin in the liver?
Promote glycogen and TG production, reduce glucose production/output, increase glucose uptake
What are the physiological effects of insulin in the muscle?
Promote glycogen and TG production, protein synthesis, increase glucose uptake
What are the physiological effects of insulin in adipose tissue?
Promote TG production, release of FFAs from chylomicrons, inhibit lipolysis, increase glucose uptake
Describe the biosynthetic processing of glucagon.
Proglucagon: GRPP, glucagon, GLP-1, GLP-2
In pancreatic alpha cell: GRPP cleaved, glucagon secreted as active peptide, GLP-1 and GLP-2 remain bound and inactive
In intestinal L cell: GRPP and glucagon remain bound and inactive, GLPO-1 and GLP-2 are cleaved and activated
___ stimulate GLP release in intestines.
Carbohydrates
How are the relative rates of gluconeogenesis and glycolysis regulated?
By the actions of glucagon and insulin on a single bifunctional enzyme:
Insulin dephosphorylates the enzyme, conferring kinase activity; phosphorylation of downstream enzymes promotes glycolysis
Glucagon phosphorylates the enzyme, conferring phosphatase activity; dephosphorylation of downstream enzymes promotes gluconeogenesis
What is the primary role of glucagon?
Energy mobilization
What are the targets of glucagon?
Liver and adipose tissue (no receptors in skeletal muscle)
What stimulates somatostatin release? What inhibits it? What does it inhibit?
Stimulated by high fat, high carb meals
Inhibited by insulin
Inhibits insulin release
___ is released with insulin from vesicles in beta cells; it acts synergistically with insulin.
Amylin
What is the function of ghrelin?
Stimulates food intake at level of hypothalamus
Stimulates GH release
What is the relationship between circulating ghrelin and obesity?
Decreased ghrelin leads to increased obesity
What does ghrelin inhibit?
Insulin release
How do GH and cortisol counter-regulate insulin?
Permissive effects on gluconeogenesis and lipolysis; defends against prolonged hypoglycemia
Wasting leads to what three effects?
- Release of pro-inflammatory cytokines
- Activation of HPA axis
- Dysregulation of GH and IGF-I
What are the 4 characteristics of metabolic syndrome?
- Visceral obesity (waist >40” in men, >35” in women)
- Insulin resistance (fasting glucose > 100 mg/dL)
- Dyslipidemia (TG >150 mg/dL, HDL <40 mg/dL
- Hypertension (BP >135/80)
What hormone is produced by white adipose tissue?
Leptin
Describe the relationship between total fat and plasma leptin.
Higher body fat correlates with increased plasma levels.
What are two important transcription factors produced in adipose tissue?
SREBP-1C (promotes TG synthesis)
PPAR-gamma (regulates TG storage and adipocyte differentiation)
How are PPAR-gamma agonists used in clinic (Thiazolidinediones - TZD)?
Treat insulin resistance and T2DM –> induces differentiation of adipocytes to make more fat cells and increase fat storage
What are 2 stimulators of appetite?
Neuropeptide Y and AGRP
What are 2 inhibitors of appetite?
alpha-MSH, CART
How does Leptin inhibit appetite?
Inhibits release of Neuropeptide Y and AGRP, activates release of alpha-MSH and CART
What occurs in insulin resistance?
Insulin does not efficiently transport glucose into cells, leading to high levels of glucose and insulin; high insulin leads to downregulation of insulin receptors; pancreas reduces insulin output
What causes conversion of T2DM to T1DM?
Beta cell depletion
What characterizes T2DM?
Impaired beta cell function and insulin resistance
How is T2DM diagnosed?
- Elevated HbA1C >48 mMol/1
- Fasting blood glucose >125 mg/dL
- Oral glucose tolerance test >200 mg/dL
What are the 3 symptoms of T2DM?
- Polyphagia (excessive hunger)
- Polyuria (excess glucose in blood leads to increased plasma osmolality and excessive water and sodium loss)
- Polydipsia (excessive thirst due to severe dehydration)
How is T2DM treated?
- Sulfonylureas: close ATP-dependent K+ channels in beta cells causing insulin release
- Metformin: inhibits hepatic gluconeogenesis, increases insulin receptor activity making cells more sensitive to insulin
- Alpha-glucosidase inhibitors: delays intestinal absorption of carbohydrates
What is T1DM characterized by?
Development of ketoacidosis in the absence of insulin therapy and destruction of pancreatic beta cells (insulin dependent)
How is T1DM treated?
Insulin injections, close monitoring of blood glucose levels, diet
Describe the formation of diabetic ketoacidosis.
Decreased insulin and increased couterregulatory hormones leads to increased FFA release; metabolism of ketone bodies for energy results in increased blood acidity
Mental acuity is a function of ___.
Osmolality (gets worse as osmolality increases)
What are the genetic risk factors for T2DM?
Genes that affect beta cells, insulin signaling, glucose transport, obesity; most high associated with genetic polymorphism in TCF72 (Wnt signaling, coactivator of beta-catenin)
What are environmental risk factors of T2DM?
Impaired beta cell proliferation during childhood (malnutrition, maternal factors), increased propensity for insulin resistance (high caloric diet, lack of activity, acquired organ dysfunction for glucose homeostasis)
What is a key early characteristic of T2DM?
First phase insulin secretion is impaired
Islet neogenesis occurs during embryonic development and beta cell replication continues during childhood/adolescence. ___ is important for both islet neogenesis and beta cell proliferation. ___ targets regulate beta cell proliferation. ___ is key for endocrine cell development.
PDX-1; TCF72; Neurogenin 3