Endocrine System Flashcards
Arnold Adolph Bertold
1849 conducted the first formal study of endocrinology
Professor at Gottingen University
The effect of castration on the development of male phenotype:
Observation 1: Removal of testes leads to the development of female like phenotype (capon)
Observation 2: Transplanted testes supported the development of male phenotype. This effect could not be mediated by nerves, which were cut.
Conclusion: Therefore, Berhold postulated existence of a substance that travels through the bloodstream to target organs (hormones/ testosterone)
Caponization: development of female phenotype, makes meat taste better
Hormone definition: What it is?
A signaling molecule released by a cell and conveyed by the blood stream, by neural axons, or by local diffusion to cells in target tissues.
Hormone definition: What is its chemical nature?
Protein, peptide, catecholamine, steroid or iodinated tyrosine derivative
Hormone definition: What does it do to target tissue?
Regulates existing metabolic pathways (through second messengers) or regulates synthesis of enzymes and other proteins at the DNA level. In this way, it regulates the rates of specific reactions without itself contributing energy or initiating the process
metabolism
sum of all chemical reactions in cell
Main endocrine glands
Pituitary gland, hypothalamus, pineal gland, Thyroid gland, parathyroid glands, adrenal gland, kidney, gut, ovary, testis, placenta, pancreas, liver, heart,
Hypothalamus interactions with pituitary gland.
Pineal gland located in diencephalon
Heart has cells that secrete hormones
GI system secretes more than 40 types of hormones
endocrine secretion
hormone releasing cells secrete hormones into the internal environment (interstitial fluid)
exocrine cells secrete products outside into ducts
endocrine cells
cells that release hormones are therefore called endocrine cells
endocrine glands
endocrine cells can be either scatter through tissues, or they are parts of specialized _______
endocrine system
the collection of endocrine glands a other endocrine cells forms the endocrine system
endocrinology
sub-discipline of physiology that studies the endocrine system
Functions of the endocrine system
To regulate metabolism, fluid status, growth, sexual development, reproduction
The endocrine and nervous systems work together to maintain homeostasis
autocrine
hormone acts on the cell which released it
Paracrine
hormone acts on adjacent cells without entering the blood stream
Endocrine
before reaching target cells, hormone first enters the blood stream
neurocrine
hormone secreted by neurons, inconsistent use of the term
neuroendocrine
the interaction between neurons and endocrine cells
distance to closest capillary
50 to 100 microns away, thinner than human hair
4 categories of hormones
- peptide, protein , and glycoprotein hormones
- Catecholamine hormones
- Thyroid hormones
- Steroid hormones
- Lipokines? new category
Peptide and protein hormones
eg: peptides; vasopresin, oxytocin, glucagon
proteins; insulin, growth hormone, prolactin
Synthesis: DNA, mRNA, preprohormone, prohormone, hormone
Storage: stored in secretory granules originating from Golgi apparatus
Secretion: secreted by exocytosis
catecholamine hormones
eg. epinepherine, norepinephrine, dopamine
Synthesized form the amino acid tyrosine
Stored in secretory granules in the cells that synthesize them
Released by exocytosis
Also work as neurotransmitters
Thyroid hormones
eg. thyroxine (T4), triiodothyronine (T3)
Synthesized from tyrosine and iodide
Stored extracellularly in follicles of thyroid gland as a component of a large protein molecule
Secretion requires retrieval from follicle and enzymatic release from the storage protein
Are lipophilic, transported in plasma where they are bond to carrier proteins.
Although they are lipophilic, they are charged and require transporters to cross membrane
Steroid hormones
eg. cortisol, aldosterone, androgens, vitamin D
Synthesized from cholesterol
Not stored in the gland of origin or elsewhere, the increase of secretion achieved by mobilizing the synthesis from cholesterol
Are lipophilic, transported in plasma where they are bond to carrier proteins
Cortisol has mineralocorticoid activity.
Aldosterone has glucocorticoid activity.
negative feedback
hormone secretion controlled by negative feedback. Dominant mechanism of regulating hormone secretion and release.
Processes controlled by negative feedback are common, stable, critical for the maintenance of homeostasis.
The result of the process “feeds back” into the process to stop it. Can inhibit further hormone secretion from endocrine cells.
Could be a long or short loop.
Positive feedback
rare and controls surges of hormones
The out come of the process “feeds back” to the process to produce more of the same outcome. Target cells produce a product which further stimulates endocrine cell to secrete more hormone.
Processes controlled by the positive feedback are rare unstable, used when a surge of hormone is required, such as the luteinizing hormone surge before ovulation
Hormone turnover
After secretion into the extracellular fluid, hormones circulate either free or bound to other plasma constituents.
Eventually, hormones are taken up by cells and are metabolically degraded, or removed by urinary or biliary secretion.
hormone half-life time`
t1/2, the time during which the hormone loses 50% of its biological activity, varies between hormones. Peptides/ proteins from minutes to tens of minutes (eg ~15 days for Vitamin D)
Cellular events triggered by hormones
- Hormone binds to a specific receptor in the target cell. (The target cells are sub-populations of cells that are programmed to express receptors for the given hormone)
- This initiates intracellular events leading to the final physiologic effect.
- Specifically, the receptor activation triggers changes in enzyme activity or concentration, leading to the regulation of multiple metabolic pathways and eventually to changes detectable at the level of cell and whole organism
The hormone concentration together with the number and sensitivity of involved receptors determine the magnitude of the hormone effect
Change enzyme activity or concentration
Hormone actions on target cells
- Water soluble (and lipophobic) hormones bind to receptors located in the target cell membrane. This either directly or vie second messengers, regulates activity of existing enzymes. Fast. Uses signal cascade
- Water insoluble (and lipophilic) hormones bind to nuclear receptors, to regulate the gene transcription and/ the synthesis of new enzymes or structural proteins. Slow
Number of receptors on a single cell
2,000 to more than 100,000
Action of catecholamine and polypeptide hormone action
many activate either cAMP or IP3/DG as second messengers
Second messengers activate protein kinases and these phosphorylate (activate) other proteins, leading to the eventual physiologic effect.
Hormones are considered the first messenger.
cAMp messenger system
cAMP activates protein kinase A (PKA), which in turn activates other enzymes by phosphorylating them
Besides phosphorylating existing enzymes, PKA can alter gene expression via CREB- CRE pathway in the nucleus
Some hormones can both inhibit and stimulate the adenylate cyclase. For instance, epinephrine stimulates cAMP in cells that express beta 2 receptor, but it inhibits cAMP in cells that express alpha 2 receptor
In some cases, tow hormones can regulate the same cascade. Glucagon can stimulate cAMP and insulin stimulates its breakdown
One hormone can stimulate adenylate cyclase in some cells and inhibit adenylate cyclase in other cells
Ca diacylglycerol messenger system
regulate protein activation and/or phosphorylation
G protein couples to phospholipase C, Diacylglycerol can regulate phospholipase C, calcium is third messenger, cofactor in activation of enzymes or bind to calmodulin to form complex and activate CaCaM protein kinase
Ca is low concentration in ICF, IPC triggers release of calcium from ER
Ca is derived from both external and internal sources at the cellular level
amplification
the plasma concentration of hormones is very low (pmol or nmol/L) and only a few molecules reach each target cell. Intracellular signal amplification allows small number of signaling molecules to elicit physiologic response.
a single ligand (hormone) activates multiple G proteins and each of these activates an enzyme that produces multiple molecules of the second messengers, activate other enzymes, and these other enzymes catalyze reactions on multiple molecules of the substrate
Mechanisms of steroid and thyroid hormone action
In addition to nuclear receptors, steroids can have receptors also in cell membrane
Steroid and thyroid hormones regulate about 1% of all genes in target cells.
Products: enzymes, structural proteins, receptor proteins, transcriptional proteins
Thyroid hormones still need transporter to get inside the cell
synergism of hormonal action
in some instances, different types of hormones work together (eg. steroids increase the synthesis of enzymes which are regulated by catecholamines/polypeptides)
gluconeogenesis
cortisol increases synthesis of hepatic gluconeogenic enzymes
These enzymes are stimulated by epinephrine and/or glucagon
Hypothalamic-pituitary system
hypothalamus controls,
pituitary releases hormones that control
Target endocrine and non-endocrine tissues
Helps to control processes that are independent of other endocrine glands
Thalamus, epithalamus and hypothalamus
lateral walls of Third ventricle in the middle
Median eminence is rotated 90 degrees/distorted.
Pars tuberalis wraps around pituitary stalk
anterior lobe
pars distalis, adenohypophysis, originates from ectoderm of oral cavity called Rathke’s pouch
darker staining on histology
Cells are controlled by hypothalamic releasing hormones (RH) and inhibiting hormones (IH). These are brought from hypothalamus by portal vessels
In response to RH and IH, anterior lobe releases tropic hormones which regulate hormone secretion in other glands (FSH, LH, TSH, ACTH) and other hormones that control metabolism in non-endocrine tissues (GH, PRL, MSH)
posterior lobe
neurohypophysis, neural tube,
originates from neural tissue
Surrounded by darkly staining pars intermedia
Hypothalamic-pituitary system controls endocrine glands and non-endocrine tissues
mediator between nervous and endocrine control systems
Secretes two categories of hormones:
1. Hormones that are transported via axons to and released in the posterior pituitary
2. the release and inhibiting hormones that are released in the hypothalamus, reach the anterior pituitary via portal vessels and regulate activity of anterior pituitary endocrine cells
Capillary beds in median eminence travel through pituitary stock and has 2 beds in series connected by portal vein. Connects the beds between hypothalamus and anterior pituitary
Posterior pituitary does not have endocrine cell bodies but the anterior pituitary does so the anterior pituitary has the glands to synthesize and secrete hormones
Neurons are endocrine cells secreting hormones in posterior pituitary
Another set of neurons terminate in median eminence and release, hormones in capillaries in median eminence to travel to anterior pituitary. These include release hormones that stimulate secretion in anterior pituitary or inhibitory hormones to inhibit secretion in anterior pituitary
hypothalamic hormones released in pituitary
(2), oxytocin and antidiuretic hormone (ADH)
true pituitary hormones
(7)
Control other glands: Follicle-stimulating hormone (FSH), Luteinizing hormone (LH), thyrotropin (TSH)
Adrenocorticotropin (ACTH)
(FSH and LH are Gonadotropins)
Control non endocrine tissues: Prolactin (PRL), Somatotropin (GH), Melanotropin (MSH)
vasopressin
antidiuretic hormone (ADH), water metabolism, increases water reabsorption,
nanopeptide, secreted by posterior pituitary
inhibits diuresis and controls blood volume and pressure
oxytocin primary function
Lactation, milk secretion and uterine contractions
prolactin
PRL, lactation, milk secretion and uterine contractions
“mother love hormone”, causes stimulation of maternal behavior and pair bonding
melanotropin
skin pigmentation, melanocyte stimulating hormone, MSH, stimulates melanogenesis,
Polypeptide, precursor is proopiomelanocortin turning into ACTH then into MSH
Secreted by anterior pituitary (or pars intermedia) and also by skin keratinocytes (involved in tanning in humans)
Functions in mammals: acquisition of brown summer hair in animals such as short-tailed weasel, suppresses appetite, increases sesual arousal, Humans: skin darkening in response to sun light (mostly via paracrine action of MSH from keratinocytes), Memory enhancement, fetal steroidogenesis, skin darkening (melanosome dispersion), Brown summer hair coat, pheromone secretion
Amphibians have melanosomes as mechanism of camouflage
Melanotan II is a synthetic analogue of the MSH. Developed for tanning, but found to support erectile function as well.
Note: besides the MSH, another pituitary hormone, the ACTH, can also stimulate melanin production. Because of this, pituitary-dependent Cushing’s disease and Addison’s disease patients, who have high levels of ACTH, exhibit hyperpigmentation
somatotropin
growth hormone, body growth
direct effect on mobilization of fuels during starvation
indirect effect on growth- IGF-1
hyper and hyposomatotropism
Follicle stimulating hormone
FSH, reproduction and gonads
luteinizing hormone
LH, reproduction and gonads
thyrotropin
TSH, thyroid stimulating hormone
adrenocorticotropic hormones
activity of thyroid and adrenal glands
besides the MSH, another pituitary hormone, the ACTH, can also stimulate melanin production. Because of this, pituitary-dependent Cushing’s disease and Addison’s disease patients, who have high levels of ACTH, exhibit hyperpigmentation
somatotropin secretion
Protein (191 amino acids) produced by somatotrophs of the anterior pituitary and also in smaller amounts by mammary glands in cats dogs and humans
Regulated by hypothalamic GHRH (somatokrinin) and GHIH (somatostatin)
secreted in pulsatile fashion during day, secretion declines with age
function of somatotropin
promotes growth and provides a ready source of energy during starvation
Traditional view: promotes growth mostly indirectly by stimulating liver to release IGF-1. It also directly stimulates carbohydrate metabolism to produce glucose. Stimulates gluconeogenesis in the liver.
baso hormone secretion
hormones have base level of secretion with peaks of secretion beyond this
tapering off of secretion of growth hormone with aging
anabolic action of somatotropin
indirect growth promoting action,
stimulates liver to secrete IGF-1. (Liver is endocrine gland)
anabolic action prevails in well-fed animals
Promotes growth via IGF-1 in liver, muscle, and bone
IGF-1
insulin like growth factor, related to insulin
stimulates lipogenesis, protein synthesis, cell multiplication, cell enlargement and also the deposition of extracellular matrix
Promotes accumulation of chondrocytes in long bone growth plates
Synthesized in almost all tissues
catabolic action of somatotropin
direct, fuel-mobilizing action, typically prevails in poorly fed animals, lipolysis
IGF-1 variation in breeds
levels correlate to size of breed. Large breeds have more IGF-1
Factors regulation growth hormone release
Many are species dependent. For example, stress increases GH in primates and decreases GH in rodents and has not impact on ungulates
Glucocorticoids have negative impact, concentration dependent
promotion by Ghrelin in stomach
Cells of mammary gland and somatotrophs of anterior pituitary produce GH so progestin (synthetic progesterone) can cause increased production of GH
Factors regulating IGF-1 release
Pituitary produces GH
Pancreas produces insulin
Intestine has good nutrition
All of these positivity feedback on IGF-1 production
Cortisol, estrogen, and malnutrition inhibit IGF-1 production
Hyposomatotropism
low level of GH
hypersomatotropism
high level of GH
Pituitary dwarfism
inherited or acquired as a consequence of prolonged administration of glucocorticoids, hyposomatotropism, failure to secrete enough of the GH in young animals
Giantism
Hypersomatotropism before epiphyseal plate closure, becomes acromegalic gigantism
acromegaly
hypersomatotropism after epiphyseal closure
Feline acromegaly is relatively rare, >8 year old male cats
Acromegaly dogs are more frequent, often associated with progestin-induced mammary hyperplasia
Diabetes melitus is possible sign as GH interferes with insulin intracellular signaling, frequently undiagnosed cause of diabetes melitus
recombinant GH
GH can be synthesized using recombinant methods
Human recombinant GH is used for the treatment of dwarfism (hormone replacement therapy). However, because of its anabolic function, it is also abused in sports.
Bovine synthetic GH (bovine somatotropin, bST) is one of top-selling cattle pharmaceutical products in US. This is because bST prevent mammary gland cell death, can be used to increase milk production. Given by injection, can’t be in feed because the protein would be broken down in digestion
Controversy: consumer groups fight bST use in milk production because of fear that bST or IGF-1 in cow milk could possibly affect human health. GH from cadavers caused spread of disease.
Unsubstantiated because: bST is not active in humans. When ingested, bST and IGF-1 are digested (not absorbed), Thus, bST treatment is considered safe by FDA. But it has been banned in Europe and Canada.
Federal law prohibits any hormone use in the poultry and pork industry
Regulation of gonadotropin
GnRH: Gonadotropin release hormone
GnRH stimulates release of Lh and FSH.
Causes germ cell development and production of estrogen, testosterone and progesterone
Gonadotropins
LH (luteinizing hormone) and FSH (follicle stimulating hormone)
Proteins (half life of a few minutes), secretion controlled by GnRH
Patterns of release: basal, pulses, surges
Positive feedback controls surges
FSH function
stimulates growth and maturation of immature ovarian follicles
Also stimulates follicular granulosa cells to produce estrogen (steroid)
LH function
triggers ovulation and development of the corpus luteum
Also stimulates follicular theca cells to produce androgens. corpus luteum (CL) produces progesterone (steroid)
Oogenesis and follicular development during estrous cycle
Females are born with ovaries that contain a finite number of primordial follicles (cow ~100,000, human ~1 million). In sexually mature females, ovaries undergo cyclic changes, Each cycle culminates with ovulation that presents the egg for fertilization
During each estrus cycle, several waves of follicles start to grow and mature. Maturing follicles secrete estrogen.
In fully primary oocyte finishes the division and becomes a secondary oocyte
primary oocyte
contained in each primordial follicle
diploid cell arrested at the stage of the first meiotic
secondary oocyte
first haploid cell division, starts the meiotic division and close to the time it is finished, it is released from follicle during ovulation
estrous cycle definition
recurring set of physiological and behavioral changes that occur in sexually mature mammalian females in a time period from one estrus to another. Controlled by pituitary and ovarian hormones.
Proestrus
build up to estrus, luteolysis is completed, follicular growth and maturation, low progesterone, high estrogen (produced by follicles), stimulates endometrial proliferation as uterus lining has regressed during anestrus,
FSH and LH stimulate follicular growth and production of estrogen. Estrogen suppresses LH and FSH secretion (negative feedback mechanism), this is mediated by GnRH
High levels of estrogen stimulates a LH surge (switch to positive feedback mechanism). The surge of LH triggers ovulation
Estrus
female becomes sexually receptive, ovulation induced
Metestrus
corpus luteum is forming, secretes Progesterone which suppresses FSH and LH secretion, stimulates endometrial secretion in preparation for implantation and also supports pregnancy
Diestrus
corpus luteum fully formed, secretes large amounts of progesterone
If not pregnant, the animal will enter proestrus after this stage, the corpus luteum regresses as a consequence of locally released uterine prostaglandin F2 alpha. The resulting decrease of progesterone levels removes LH and FSH inhibition and the cycle can start again.
If pregnant, the corpus luteum is rescued from regression by placental hormone chorionic gonadotropin in most mammals and interferon tau in cattle.
Anestrus
Activity of ovary is suppressed, could be due to pregnancy or entering season where unreceptive to breeding in seasonal breeders,
In seasonal breeders at beginning of breeding season or after parturition, animal enters proestrus. This transition is controlled by Melatonin (released by pineal gland).
Which hormone is responsible for primary follicle development?
Trick question! the development of the primary follicle is an intrinsic process in the ovary
Theca cells
means “box”, follicle is boxed in by theca cells, Ovarian cells that secrete androgens, express LH receptors, synthesize mostly androgens during follicular phase, Switch to low-level estrogen synthesis during luteal phase
Granulosa cells
ovarian cells that convert androgens into estrogen,
express FSH receptors, Synthesize estrogen during follicular phase, Produce progesterone during luteal phase, Together with progesterone, granulosa cells secrete hormone inhibin that inhibits FSH,
interaction between hypothalamus, pituitary, and ovary during estrous cycle
- GnRH travels through hypothalamo hypophyseal portal system to Gonadotropes to secrete FSH and LH
- Follicles grow in response to FSH and produce estrogen
- Negative feedback predominates from estrogen
- LH causes ovulation
- After LH surge triggers ovulation, corpus luteum produces progesterone. (stimulates endometrial secretion)
- Progesterone negative feedback inhibits further gonadotropin secretion
Gonadotropins in males
released in steady fashion to stimulate secretion of testosterone and estrogen and to support spermatogenesis.
sertoli cells
nurse cells of seminiferous tubules, receptors for FSH, analogous to granulosa cells of ovary
Leydig cells
produce testosterone, receptors for LH, analogous to theca cells in ovary
GnRH
Gonadotropin release hormone, reach gonadotrophs in anterior pituitary through portal veins
structure of ovary
vascularized medulla surrounded by cortex with follicles
spermatogenesis
with the onset of puberty, pituitary starts to produce more gonadotropins (FSH and LH). These hormones stimulate spermatogenesis. Occurs in the walls of seminiferous tubules, where germinal cells turn into primary spermatocytes which undergo meiosis, yielding 4 haploid spermatozoa. Nursed by Sertoli cells. Spermatogenesis requires high concentrations of testosterone that is secreted by Leydig cells that surround seminiferous tubules.
Immature spermatozoa are transported to epididymis where they accumulate and mature
In sexually active males, spermatogenesis is continuous and billions of sperm are produced daily.
Most of daily produced sperm is lost in urine.
Hormonal regulation of testes and testosterone function
Leydig cells of testes produce testosterone
Secretion of testosterone is regulated by the hypothalamic GnRH and pituitary LH
Pituitary FSH stimulates activity of testicular nurse cells- Sertoli cells
Testosterone
steroid hormone that stimulates spermatogenesis, activity of sexual accessory glands, development of secondary sexual characteristics, development and maintenance of libido
Chorionic gonadotropin
analogous to LH, produced by human trophoblastic cells of blastocyst, rescues corpus luteum from regression. This keeps producing progesterone, which is necessary for suppression of pituitary gonadotropins and for preventing regression of endometrium. Used for pregnancy test in humans.
Interferon tau
Produced by bovine and ovine trophoblast. Performs similar function as human chorionic gonadotropin
Placental lactogen
analog to GH and prolactin, supports maternal metabolism and initiates milk synthesis, antagonizes maternal insulin.
Relaxin
relaxes pelvic ligaments, increases oxytocin synthesis, preparation for parturition
functions of oxytocin
milk ejection, myometrial contractions during labor (together with prostaglandins), CNS effects, stimulates secretion of uterine prostaglandin 2 alpha toward the end of pregnancy, stimulates contraction of smooth muscles of reproductive organs during copulation, central release induces maternal behavior and pair bonding
Can stimulate ADH receptors, severe water retention when it is used to induce labor
alveolus
basic unit of mammary gland, hollow spherical group of milk secreting cells
milk ducts
where the alveoli empty into
lobi
groups of alveoli
lobes
groups of lobi
major ducts
where the milk ducts of the lobi empty into, connect to gland cistern, which then connects to a treat and empties into the teat cistern
structure of bovine udder
four quarters and four teats. Each teat is supplied by the milk from the corresponding quarter. The teat meatus (streak canal) is closed by a sphincter
Is the mammary gland an endocrine or exocrine gland?
Exocrine
Prolactin
secreted by lactotrophs in anterior pituitary, polypeptide, stimulates lactogenesis in secretory alveolar cells
oxytocin
synthesized in hypothalamus, secreted by hypothalamic neurons, released and stored in posterior pituitary, nanopeptide (very similar to ADH, made of nine amino acids, reactivity to each other), triggers milk ejection by stimulating contraction of myoepithelial cells (smooth muscle),
secreted by corpus luteum in swine and ruminants
supra optic and paraventricular nuclei of the hypothalamus cause secretion of oxytocin
secretion also impacted by somatosensory information from teat during suckling
lactogenesis
milk synthesis and secretion, stimulated by prolactin
milk ejection
stimulated by oxytocin
regulation of prolactin release
only pituitary hormone for which there is evidence of at least two stimulatory and 2 inhibitory release hormones. Inhibitory control predominates
Teat contains somatosensory neurons, induce automatic release of prolactin during suckling PRL released in CNS, can’t cross blood brain barrier
galactorrhea
secretion of milky fluid from the breasts of males (or females that aren’t nursing). Hypothyroidism causes increase of TRH which increases prolactin
prolactin in amphibians and birds
Amphibians: larval growth, osmoregulation (analogous to amniotic fluid regulation in mammals?)
Birds: photostimulation induced premigratory fattening
Primary action of ADH
control of blood volume, pressure and osmolarity
Renal water reabsorption determines blood volume and pressure, 5-24% of water reabsorbed in collecting ducts
ADH increases water reabsorption by stimulating incorporation of aquaporins in the apical membrane
secondary actions of ADH
- Pressor action (constriction of systemic, coronary and pulmonary vessels, dilation of cerebral and renal vessels)
- In large amounts stimulates ACTH
Primary triggers of ADH secretion
information from hypothalamic chemoreceptors (sensitive to 1% change) and atrial volume receptors (low pressure volume baroreceptors are less sensitive, detect 5-10% change)
1. Plasma osmolarity detected by osmoreceptors
2. Blood pressure signals conveyed directly to the brain
Hypovolemia, hypernatremia, and Angiotensin II stimulate ADH secretion
Diabetes insipidus
insufficient ADH action
patients produce large volumes of dilute (hypotonic), tasteless (insipid) urine and exhibit intense thirst (polyuria and polydipsia)
suspected when water consumption is greater than 100 ml/kg/day and urine production (without glucose) is greater than 50 ml/kg/day
Can be central, nephrogenic, and idiopathic
psychogenic polydipsia is behavioral, dipsogenic diabetes insipidus involves thirst mechanisms
Treated with desmopressin, synthetic analog of ADH (no pressor effects), does not impact blood vessel vasculature
causes of diabetes insipidus
pyometra, hypercalcemia, hyperadrenocorticism, and hypokalemia cause decreased responsiveness to ADH
hepatic insufficiency, and hypoadrenocorticism cause decreased medullary concentration gradient
cortisol
steroid, aka hydrocortisone, insulin opposing function, plasma half-life is 60-90 minutes
stress stimulates cortisol secretion and cortisol mobilizes fuels (stimulates hepatic gluconeogenesis, lipolysis, proteolysis, and insulin resistance) and suppresses inflammation
mediates long term adaptation of stress
Takes hours or days for target tissues to fully respond because effector proteins need to be synthesized, and are dependent on transcription factors from receptors on nucleus
The negative feedback suppresses CRH and ACTH for long periods, problematic when cortisol used for therapeutic suppression of inflammation
hyperadrenocorticism
Cushing’s like syndome
adrenal gland
most important bilateral glands, means on top of kidney has medulla (20% of adrenal gland) that secretes catecholamines (norepinephrine and epinephrine) and a cortex (80% of adrenal gland) that secretes steroid hormones cells in each zone have different enzymes to produce different hormones, cholesterol is the precursor for all of them
zona glomerulosa
(zona arcuata), secretes mineralocorticoids such as Aldosterone, 25% of cortex,
Pregnenolone to progesterone to 11-Deoxycorticosterone to Corticosterone to aldosterone
stimulated by potassium
Zona fasciculata
secretes glucocorticoids such as cortisol and cortisone, 60% of cortex,
17 OH Pregnenolone to 17 OH Progesterone, to 11 Deoxycortisol to cortisol
Zona reticularis
produces androgens (steroid hormones) like androstenedione, testosterone, and estradiol, DHEA, to Androstenedione, to testosterone to estradiol
aldosterone
steroid hormone, secreted in zona glomerulosa of adrenal cortex, stimulates reabsorption of sodium, and potassium and hydrogen ion excretion in the distal tubules of kidney,
secretion is increased during day time
targets cells in wall of distal tubules
ACTH
(corticotropin) the primary regulator of adrenal cortical activity leading to glucocorticoid secretion, also stimulates production of androgens, but does not have large impact on aldosterone secretion
produced by corticotropes
response to ACTH
Response to ACTH starts in 1-2 minutes and peaks in 15 minutes (fast), Stress induces hypothalamus to produce CRH, effects cAMP mediated activation of CEH by PKA is one of several mechanisms by which ACTH stimulates cortisol secretion
In plasma, cortisol is bond to trancortin (alpha globulin), cortisol released with circadian rhythmicity
cortisol’s impact on intermediary metabolism
bound to transcortin (globulin) in plasma. Converted to cortisone in peripheral tissues, which is less active, this is reversible reaction as cortisone is both metabolite and precursor for cortisol
generally opposite effects of insulin and in times of need makes more glucose available in plasma
Cortisol acts permissively to mobilize fuel in times in times of need (potentiates effects of glucagon, epinephrine and GH)
increases appetite,
restores depleted glycogen, inhibits utilization of glucose by muscle, lymphoid tissue, adipose tissue, and connective tissue
intermediary metabolism
metabolism of fuels, proteins are form of stored fuel, ketone bodies can be used as fuel or packaged in VLDL and transported
Other impacts of cortisol
decreases ADH, TSH and GH
decreases collagen synthesis
GI tract: decreases mucosal barrier, potentially causing ulcers, decreases Ca absorption
Fetal cortisol prepares fetus organ systems for birth (stimulates production of the lung surfactant). The surge of fetal cortisol triggers parturition
decreases inflammatory and immune response to limit destruction of normal tissue during injury
decreases calcium deposition
Cushing’s disease
PDH, pituitary dependent hyperadrenocorticism, secondary hypoadrenocorticism,
Excessive ACTH secretion,
Most animals with PDH have pituitary tumor
Occurs in dogs (poodle, dachshund, boxer) rare in cats. Relatively common in older horses (hyperplasia of pars intermedia caused by loss of inhibition of dopamine)
Cushing’s syndrome
primary hyperadrenocorticism (functional adrenocortical tumors)
Iatrogenic Cushing’s-like syndrome
chronic exposure to excess of exogenous glucocorticoids
iatrogenic
caused by veterinarian
Signs of cushing’s-like syndrome
polyuria/polydipsia, leads to dehydration, exophthalmos (bulging eyes), abnormal deposition of fat in neck and abdomen, but muscle wasting in the limbs, bruising due to thinning of skin (bilateral alopecia), exercise intolerance, lethargy and obesity, heat intolerance, skin infections
Equine cushing’s disease
equine PPID, pituitary pars intermedia dysfunction. cells in the pars intermedia lose hypothalamic dopaminergic inhibition. As a consequence, pars intermedia secretes large amounts of POMC derivatives, such as MSH and ACTH.
Hirutism, laminitis, polyuria, polydipsia
Treated with dopamine agonists and serotonin antagonists (suppress abnormal production of ACTH and other POMC derivatives in pituitary)
hirsutism
long hair coat, horse does not shed out in spring and summer
Cushing’s disease in dogs
most often due to pituitary dysfunction, but could also be due to adrenal cortical tumors
Treated with Mitotane, which is a DDT derivative and is used for controlled destruction of adrenal cortex
Alternative treatment of trilostane, blocks synthesis of cortisol
complications of treatment for Cushing’s
can cause hypoadrenocorticism/ Addison’s disease if dosage is too high
adrenal medulla
secretion of epinephrine in response to stress, modified sympathetic ganglion
Chromaffin cells secrete catecholamines epinephrine and norepinephrine when sympathetic nervous system is activated in emergency or during stress, secrete more epinephrine than norepinephrine
functions of Aldosterone
(similar to ADH) excretes H+
- Sustaining extracellular fluid volume by conserving body sodium
- Preventing the overload of potassium by accelerating its excretion
triggers of aldosterone release
not dependent on ACTH
reduced volume of circulating fluid, decreased blood pressure and glomerular filtration rate (detected and stimulated by the renin/ angiotensin system)
increased potassium in plasma or increased angiotensin II
renin
regulates angiotensin II levels,
enzyme responsible for cleaving angiotensinogen into angiotensin I, which is then turned into angiotensin II by ACE
secretion in juxtaglomerular cells stimulated by renal hypotension and decreased Na concentration in distal tubular filtrate, prostaglandins act on juxtaglomerular cells in response to decreased NaCl concentration in distal tubule
ANP
atrial natriuretic peptide, secreted by
atrial cardiomyocytes and inhibits secretion of aldosterone
secreted in response to atrial stretch (hypervolemia, hypertension, hypernatremia)
antagonizing the action of aldosterone, ADH and angiotensin II, contrary activation to these
ACE
angiotensin converting enzyme
ACE inhibitors are used for hypertension treatment
actions of angiotensin II
peripheral vasoconstriction and efferent arteriolar vasoconstriction
promotes aldosterone secretion
Other functions of angiotensins
One of the most potent vasoconstrictors known, stimulate release of catecholamines from adrenal medulla, stimulate thirst, promote ADH secretion
primary stimuli for angiotensin generation
decrease in blood volume, and/or pressure,
decrease in the glomerular filtration rate
cellular mechanisms of aldosterone action
3 hypothesis, all seem to be correct
1. Metabolic hypothesis: stimulation of ATP production
2. Na pump hypothesis: synthesis of more Na K ATP ase pumps
3. Permease hypothesis: more sodium channels
Note: because water is passively reabsorbed with sodium
Consequences of bilateral adrenalectomy
decreased aldosterone, Na loss in urine, K and H+ retention, H2O loss from extracellular and intracellular fluid, Peripheral circulatory failure/renal failure, death
function and primary effect of natriuretic peptide
reduces both Na and fluid levels through actions on blood vessels, hypothalamus and adrenal cortices, and the kidneys
decreased venous return, vasodilation and fluid to interstitium, decreased aldosterone, decreased ADH and ACTH
Primary effect: natriuresis and diuresis
Control of ANP release
triggered by plasma volume expansion
Causing: 1. Natriuresis, 2. Diuresis 3. increase glomerular filtration rate by vasodilation of afferent arterioles and vasoconstriction of efferent arterioles 4. decreased renin and angiotensin II
Addison’s like disease
Adrenocortical insufficiency (hypoadrenocorticism)
Described by Thomas Addison in 1855 in humans
First naturally occurring animal case reported in 1950s
Most common in young to middle-aged dogs, occasionally in horses
Many signs which frequently imitate symptoms of other diseases (complex diagnosis)
deficiency of glucocorticoids and mineralocorticoids
Most common causes of Addison’s like disease
Autoimmune destruction of adrenal cortex
Iatrogenic (adrenal suppressive therapeutic agents - Mitotane (cytotoxic); or prolonged glucocorticoid administration)
too much glucocorticoids have negative feedback on anterior pituitary and it produces less CRH
Signs and symptoms of Addison’s-like disease
hyponatremia, hyperkalemia, decreased sodium/ potassium ratio, increased ACTH, decreased cortisol, decreased aldosterone
acidemia
Famous individuals with Addison’s disease
John F Kennedy and Osama Bin Laden
Treatment of Addison’s disease
prednisone (potent, long-lasting cortisol analog) and if needed, 9 alpha-fluorocortisol (potent synthetic mineralocorticoid)
fight or flight response
outcome of catecholamine action, emotional, behavioral and physiological components
Obligatory parts: increased heart rate, pupil dilation, bronchiolar relaxation, diversion of blood to muscles, energy metabolism
interaction of sympathetic nervous system and adrenal medulla
Hypothalamus is central component of sympathetic nervous system. Controls spinal cord at high levels, send axons to sympathetic ganglia including adrenal gland
Pre and post ganglionic neurons arranged in series. Preganglionic neurons release acetylcholine and postganglionic release norepinephrine and regulates local physiology of target cells
epinephrine released in adrenal medulla by postganglionic neurons, then it is transported in endocrine fashion
preganglionic neurons
located in lateral horns of the spinal cord between segments T1 and L2
use acetylcholine as neurotransmitter
Send their axons to paravertebral ganglia of the sympathetic trunk, some of them synapse there and the postganglionic neurons continue in splanchnic nerves or in somatic nerves to target organs
Axons of preganglionic neurons just pass through the paravertebral ganglia, continue in splanchnic nerves to prevertebral ganglia. There they synapse on postganglionic neurons
prevertebral ganglia
celiac or mesenteric ganglia
postganglionic neurons
most use norepinephrine as neurotransmitter to affect target organs
neurotransmission in the ANS
All ANS preganglionic neurons, similar to the somatic motor neuron, release acetylcholine
All ANS postganglionic neurons are activated by acetylcholine binding to nicotinic receptors
parasympathetic postganglionic neurons
Most release acetylcholine, which stimulates muscarinic receptors in target tissues
sympathetic postganglionic neurons
most release norepinephrine, that stimulates alpha and beta adrenergic receptors in target tissues
alpha and beta adrenergic receptors
differentially expressed in target tissues and the particular physiologic effect on the target tissue depends on the mechanism by which a specific receptor type is coupled to physiological processes in the cell
Note: specific agonists and antagonis for each specific receptor are available
impact of drugs on neurotransmission in ANS
available for manipulating specific components of these signaling pathways.
eg. atropine blocks selectivity muscarinic receptors. Can be used to dilate pupil or to stimulate the heart.
Or albuterol, which activates selectively beta 2 adrenergic receptors.
Can be used to relive bronchospasms during asthma
Norepinephrine (noradrenaline) and epinephrine (adrenaline)
Naming: epinephrine is Greek and adrenaline is Latin. Catecholamines secreted by chromaffin cells of adrenal medulla
Epinephrine is most abundant, with 2 minute half life in plasma
Synthesis mosulated by ACTH and cortisol
Produce, together with sympathetic system to make “fight or flight response
Neurons stop synthesis at level of neuroepinephrine
short term response to stress
mediated by sympathetic nervous system and adrenal medulla
Secretion of catecholamines from adrenal medulla is controlled by the sympathetic neurons system
Chromaffin cells controlled by neurons in spinal cord
Involves co-activation fo the adrenal medulla and the rest of the sympathetic nervous system
emotional stress
anxiety, apprehension
Biochemical stress
hypoglycemia, hypoxemia, too low or too high pH
Physical stress
exercise, injury hypotension, hypothermia
alpha 1 receptors
smooth muscle contraction (blood vessels, sphincters, pupil dilator etc.)
increased sweating
alpha 2 receptors
inhibition of neurotransmitter and hormone release
decrease of insulin secretion
beta 1 receptors
increase cardiac output
beta 2 receptors
smooth muscle relaxation
glycogenolysis, gluconeogenesis, lipolysis, increase hormone secretion
systems in integrated response to stress
i. the somatic nervous system
ii. sympathetic nervous system
iii. hypothalamic-pituitary-adrenal axis
cortisol regulates the slow and long lasting response to stress
results in arousal behavioral activation, aggressiveness, inhibiting of feeding and sexual activity, growth and reproductive function, inflammation, and visceral function
stimulating of energy mobilization and redistribution, cardiovascular responsivity
Pheochromocytoma
catecholamine secreting tumors, 90% are located in adrenal medulla, the other 10% can be in other sympathetic ganglia
relatively high incidence in older dogs
not innervated- excess release of catecholamines could be either continuous or episodic
Treated by the tumor resection, drugs to control hypertension
acetylcholine
neurotransmitter instead of a hormone because it does not diffuse
released by parasympathetic postganglionic neurons, and all preganglionic neurons
thyroid gland hormones
includes T3, T4 and calcitonin
Synthesized from tyrosine and iodide by follicular cells
Thyroid gland stores 90% of I-
produces mostly tetraiodothyronine (T4, thyroxine) and small amount of triiodothyronine (T3)
Stored bound to thyroglobulin in colloid
T3 is most and is made from T4 (prohormone) in target tissues
Reverse T3 is an inactive form
produced by liver
Water insoluble, transported in bloodstream by carrier proteins
main function of thyroid hormones
to increase basal metabolic rate. Resulting in an increase in O2 use and thermogenesis
parathyroid gland
wrapped in thyroid gland
Follicular and parafollicular cells
found in thyroid gland
Follicular cells secrete T3 and T4
Colloid in follicular cells stores T3 and T4
Parafollicular cells secrete calcitonin
goiter
enlarged thyroid gland,
consequence of hyperthyroidism (cats)
can be caused by Graves disease (autoantibodies stimulate TSH receptors of follicular cells) or Iodine deficit
Thyroid hormone synthesis reactions
T3 is more potent form of the hormone and T4 is converted to T3 in target issues
T3 can be inactivated by conversion into reverse T3
DIT: diiodotyrosine
Condensation of two DITs yields thyroxine
Condensation of DIT and MIT (monoiodotyrosine) yields triiodothyronine
Deiodionation of T4 in the outer ring can also yield T3 in extrathyroidal tissue
Deiodination of the inner ring of T4 yields reverse T3
thyroid hormone chemistry
The precursor for TH is the amino acid tyrosine
Tyrosine can be iodinated forming either monoiodotyrosine or diiodotyrosine
Condensation of these two molecules yields either T3 or T4
T3 is the most active and T4 is converted into T3 in target tissues
Thyroid hormone synthesis
- Follicular cells synthesize protein thyroglobulin and also “trap” I- (against concentration gradient, using Na/I symporter)
- TG and I- are released in the follicle lumen, I- is converted into highly reactive I0, and this molecule iodinated tyrosine molecules within the TG. If adjacent iodinated tyrosines condense, forming T3 and T4.
- TG containing T3 and T4 is taken up by phagocytosis and inside of follicular cells it is attacked by proteases, which free T3 and T4
- T3 and T4 can exit cells and enter circulation, where they circulate bound to plasma proteins
Regulation of the TH secretion in thyroid gland
- Deviations from homeostasis, such as the drop of body core temperature, are detected by hypothalamus and this stimulates T4 and T3 release using the following mechanism
- Deviation from homeostasis activates secretion of the TRH (thyrotropin release hormone) by hypothalamic neurons
- TRH stimulates secretion of TSH (thyrotropin) by the anterior pituitary
- TSH enters circulation and stimulates the thyroid gland to release T3 and T4.
- Released thyroid hormones stimulate basal metabolic rate in many cells in the body causing increase of thermogenesis, adaptation to cold, and homeostasis is restored
regulation of thyroid hormone secretion outside of thyroid
Photoperiod, physiologic stress, ambient temperature, nutritional status, hibernation or other environmental factors cause Higher CNS to secrete histamine increasing TRH, or somatostatin and dopamine
Somatostatin and dopamine inhibit thyrotropes while TRH stimulates it
Estrogen stimulates thyrotropes, growth hormone and cortisol inhibit it
Thyrotropes make TSH that causes thyroid to produce rT3 T4 and T3 that negatively feedback on TRH production in hypothalamus and thyrotropes
Dopamine inhibits secretion of ACTH and TCH
Metabolic effects of thyroid hormones
require transporter and form thyroid hormone pool in cytoplasm, can bind to cytoplasmic binding protein
T3 acts on receptor on nucleus to cause transcription factors to change proteins synthesis and increase metabolic rate
Tissues not affected by thyroid hormones
Neves (adults), Adenohypophysis, Lymph nodes, Spleen, Lungs, Testes, Uterus, Retinas
impacts of thyroid hormone on specific tissues
Calorigenic: increased O2 consumption, BMP, teat dissipation, panting sweating, beta adrenergic receptors, cutaneous vasodilation, increased cardiac output
Body temperature increased: uncouple oxidation from phosphorylation in brown fat (neonates, arousal from hibernation)
CHO metabolism- provide more glucose: increased GH, cortisol, glucagon, epinephrine, gluconeogenesis and glycogenolysis, and intestinal carbohydrate absorption
Lipid metabolism- provide more fatty acids: increased lipolysis (synergistic with epinephrine), beta oxidation, hepatic ketogenesis, triglyceride synthesis, hepatic LDL-receptor synthesis, hepatic LDL-receptor synthesis, cholesterol clearance
Bone: maintain growth and epiphyseal closure
Brain: increased fetal brain development, synapse formation, and myelination
Hyperthyroidism
most common endocrinopathy in older cats.
Common cause- TG tumors (or too high or too low iodide diet
symptoms of hyperthyroidism
weak and nervous, poor hair coat, diarrhea, vomiting, goiter, weight loss, increased nail growth, heat intolerant, goiter, vomiting
Treatment of hyperthyroidism
Methimazole (inhibits T4 formation), surgery for resection of tumor, radioactive I to target cancer in thyroid gland since thyroid hormone traps iodide
Hypothyroidism
Most common endocrine disorder in dogs, rare in cats (but note iatrogenic condition caused by treatment of hyperthyroidism) and other domestic animals
Tertiary hypothyroidism
will increase in HSH after administering TRH
secondary hypothyroidism
with no increase in TSH after administering TRH
Primary hypothyroidism
with no increase in T4 after administering TH,
Majority of dog cases
Signs of hypothyroidism
Slow onset, subtle signs- frequently noted at advanced stages
Loss of appetite, lethargy, obesity, constipation, hypercholesterolemia, bradycardia, course hair coat, bilateral alopecia
Treatment of hypothyroidism
replacement therapy with synthetic thyroxine- levothyroxine
Cretinism
congenital hypothyroidism
Presents with poor hair growth, lethargy, difficulty walking, impaired cognitive abilities, severely retarded bone maturation and mild osteopenia on radiographs
treated with levothyroxine
breeds with a predisposition to hypothyroidism
Golden retriever, Doberman pincher, Great Dane, Cocker Spaniel, Dachshund, Irish Setter, Shetland sheep dog, Airedale, Boxer, Miniature schnauzer, Poodle, Pomeranian
Endocrine pancreas
islets of Langerhans and cells that secrete insulin and glucagon
insulin and glucagon
(poly?)Peptides, secreted by pancreatic islets of Langerhans
Function: rapid and powerful regulators of metabolism. Regulate: disposition of nutrient inputs from meals, flow of endogenous substrates during fasting, both effects achieved via actions on liver, adipose tissue, and muscle mass
Insulin and glucagon are often secreted reciprocally
Insulin
acts on insulin-sensitive tissues: muscle, liver, adipocytes
primary hormone involved with energy storage
Anabolic- increases storage of glucose, fatty acids and amino acids.
Opposed by counter-regulatory hormones: glucagon, cortisol, epinephrine (catecholamines), growth hormone
Direct relationship between plasma concentration of glucose and insulin secretion
Insulin secretion begins before elevation of glucose levels, due to anticipatory signals from parasympathetic nervous system
discovered in 1921 by Banting and Best
Glucagon
Mobilizes fuels
deficiency: virtually unknown, compensated for my other hormones that mobilize fuels
Acts on the liver
exocrine pancreas
gland that secretes digestive enzymes in the GI tract
Within the exocrine portion of the gland are distributed small groups of endocrine cells- the islets of Langerhans
Duct cells secrete aqueous NaHCO3 solution that neutralizes acid contents in intestine
Acinar cells secrete digestive enzymes
Diabetes mellitus
discovered in experiments in 1880 when Oscar Sarcofsky removed the pancreas of animals, urine was ketotic
common endocrine insulin-related disorder in dogs and cats (high incidence)
literally “syphon” or “running through” and “sweet”
1/200 incidence in dogs, 2nd most common endocrinopathy after hypothyroidism
Most common in cats together with hyperthyroidism (1/50-400)
Rare in other domestic species
Results from insulin deficiency or diminished response to insulin
characterized by persistent hyperglycemia, resulting in glucosuria
become glucose intolerant,
reduced entry of glucose into insulin-sensitive tissues (adipocytes and muscle), and the increased entry of glucose into insulin-insensitive tissue
In absence of insulin, fuel breakdown and anti-insulin hormones predominate, yielding elevated levels of glucose, ketoacids, amino acids and free fatty acids
isolation of insulin or glucagon
difficult because the the proteases secreted by the exocrine pancreas
Ligated duct to kill the cells secreting proteases to isolate insulin
Islets of Langerhans
Porcine pancreas contains ~1,000,000 islets, each containing several hundred cells
The islet tissue can not regenerate (similar to the CNS), if they are damage/lost, this is permanent
Cell types:
alpha is 20%, secretes glucagon
beta is 80%, secretes insulin
delta is 1-5%, secretes somatostatin
also 1-2% Pancreatic polypeptide cells
impact of insulin and glucagon on liver
Major target of these hormones, when they are secreted into portal blood of liver.
Liver receives high concentrations of these hormones and also of nutrients brought in from the gut
Reach peripheral tissue through hepatic vein and peripheral arteries
chemical structure of insulin
Polypeptide, two chains connected by disulfide bridges,
function of the c peptide is unknown, present on proinsulin
Circulatory half-life is 3-5 minutes
Recombinant form of human insulin is available
Factors regulating insulin release
Increased by nutrients
Autonomic NS: increased by vagal and beta adrenergic receptors, decreased by alpha adrenergic receptors, Sympathetic inhibits release of insulin and parasympathetic stimulates production of insulin
Increased release by glucagon (priming of insulin between meals. storage of glucose after high protein meals) and enteric hormones (glucagon-like peptide, gastric inhibitory polypeptide, gastrin, CCK)
Decreased release due to insulin, somatostatin, amylin and pancreastatin and catecholamines
Secretion of insulin is controlled by the supply of nutrients and insulin stimulates the nutrient uptake, use, and storage
- Meal increases Concentration of nutrients in plasma (glucose aminoacids free fatty acids ketoacids)
- high levels of nutrients stimulate insulin secretion
- Stimulates uptake of nutrients and their use and storage
- Decreases to normal levels
- Normal or low levels inhibit insulin secretion
Insulin receptors
enzyme-linked receptor
- Binding of insulin to the alpha subunit
- autophosphorylates the beta subunit
- which in turn induces the tyrosine kinase activity
- The tyrosine kinase phosphorylates other enzymes that mediate effects on glucose transport and protein, fat and carbohydrate metabolism
Example of insulin action: it increases glucose uptake by adipose tissue by stimulating incorporation of glucose transporters in the cell membrane
Cells use glucose for energy metabolism
Glucose enters cells via glucose transporters (GLUTs) found in the membrane.
Levels of glucose in plasma are elevated.
Elevated glucose stimulates insulin secretion.
Insulin stimulates cells in the adipose tissue and in muscle to incorporate more GLUTs into their membranes
Glucose enters these cells to be used and stored
As a consequence, the concentration of glucose drops to normal levels
number of carrier proteins is the limiter of facilitated diffusion
Glucose stored as glycogen in muscle, metabolized in adipocytes
Insulin causes translocation of stored glucose transporters onto the cell membrane (not GLUT 2)
GLUT 4
regulated by insulin, facilitates glucose diffusion into cells of adipose tissue and muscle
GLUT 2
There is no uptake of glucose in the liver.
mediates glucose diffusion to and from hepatocytes. In hepatocytes, insulin stimulates phosphorylation of intracellular glucose to maintain a high concentration gradient
GLUT 3
mediates entry of glucose in neurons. It is insulin independent
Neurons are not insulin sensitive
effects of insulin action
insulin increases fuel storage (glycogenesis, lipogenesis, protein synthesis, fatty acid esterification) and decreases/ inhibits fuel breakdown (glycogenolysis, gluconeogenesis, ketogenesis, proteolysis)
synthesis and secretion of glucagon
29 aminoacid peptide, derived from preproglucagon
Preproglucagon synthesized in pancreas, GI tract, brain
Glucagon is synthesized and secreted in response to a lowering of plasma glucose levels- it regulate hepatic glucose and free fatty acid metabolism
Circulatory half-life= 3-6 min, degraded by kidney and liver
Different hormones are produced depending on where cleavage occurs
Nutrients regulate glucagon secretion and glucagon regulates flow of fuels
High amino acids and low glucose stimulate release of glucagon
High amino acids important for carnivores with low carbohydrates and high protein meals
Insulin inhibits glucagon
Glucagon stimulates glycogenolysis, stimulates use of aminoacids used in hepatic gluconeogenesis which makes glucose
Glucagon stimulates lipolysis in adipose tissue (minor effect)
FFAs in liver converted into ketoacids
Note: most of the actions of glucagon are opposite to those of insulin
Factors controlling glucagon release
stimulated by high amino acids, or low glucose, FFAs or ketone bodies.
parasympathetic system stimulates release, sympathetic system inhibits release
Effects of glucagon action
stimulates fuel break down and inhibits fuel storage
etiology of diabetes mellitus in humans
Type 1: insulin-dependent diabetes mellitus (juvenile DM). Destruction of pancreatic beta cells (immunological) causing low levels of insulin. Treatment requires replacement therapy with insulin
Usually die by autoimmune process
Type 2: non-insulin-dependent diabetes mellitus (adult onset DM). combined alteration of insulin sensitivity and insulin secretion. Treated with dietary therapy, oral hypoglycemic agents and insulin. Lack of adequate response to insulin causing insulin insensitivity then decreased secretion of insulin
diabetes mellitus in dogs
1/200 incidence, more frequent in small breeds (eg. dachshund and poodle), More resistant are German shepherds, cocker spaniels, collies and boxers
Age of onset is 8-9 years and more frequent in females
1. Hypoinsulinemic (similar to DM type 1, most frequent). Different degrees of ketosis.
2. Hyperinsulinemic (similar to DM type 2) less frequent. Elevated level of growth hormone, mild clinical signs (ketosis)
diabetes mellitus in cats
1/ 50-400, age of onset is 9 years, more frequent in males
analog of human DM type 2 (decrease in insulin sensitivity and altered insulin secretion) is most common
Possible causes of diabetes mellitus
- Genetic predisposition
- Pancreatic injury: eg inflammation (pancreatitis in dogs or amyloidosis in cats) or autoantibodies kill beta cells (most common cause of human DM 1 and canine hypoinsulinemia)
- Hormone-induced beta cell exhaustion: by cells that mobilize fuels eg. Growth hormone and acromegaly
- Target tissue insensitivity
- Dyshormonogenesis in insulin
Signs of DM in dogs
Cataracts, Weight loss Depression, ketoacidosis, hyperglycemia, hepatomegaly, polydipsia, anorexia, ketonuria, glycosuria, polyuria, cystitis
Results from malfunction of the carbohydrate, protein and lipid metabolism. This is caused by the lack of effects of insulin and by unchecked action of anti-insulin hormones
cells sensitive to glucose toxicity
endothelial cells in retina: retinopathy (cataracts)
Mesangial cells of the kidney: nephropathy
Peripheral neurons and Schwann cells: neuropathy
cascade of pathological processes in diabedes
Malfunction of the carbohydrate, protein and lipid metabolism.
Related to lack of insulin and to the checked action of anti-insulin hormones (glucagon, growth hormone, cortisol, catecholamines)
dehydration, hyperglycemia,
Peripheral circulatory failure causes adrenal stimulation, lipolysis, insulin resistance)
treatments of diabetes mellitus
complex combinations of:
- Weight loss: hormones produced by adipose tissue are associated with insulin insensitivity (eg resistin)
- Dietary manipulations: restriction of carbohydrate intake, switch to high-protein and high-fiber and complex carbohydrates
- Hypoglycemic agents: increase insulin secretion (eg Sulfonylureas block K channels and are depolarizing beta cells), increase insulin sensitivity (eg. Metformin stimulates synthesis of enzymes controlled by insulin), decrease glucose absorption in GI tract (eg alpha-glucosidase inhibitors)
- Insulin administration (this is used for type 1)
physiological functions of calcium
muscle contraction, hormone and neurotransmitter release, second messenger, coagulation, structural component of bone, many others
control of plasma level
controlled by homeostatic mechanisms:
Vitamin D and parathormone increase Ca plasma level
Calcitonin decreases Ca plasma level
regulation of calcium homeostatisis
- calcium absorption in GI tract
- storage in bone
- excretion by kidney
combined action of parathormone, vitamin D and calcitonin
concentration and mass values for calcium
Normal concentration in ECF: 5 mEq/liter, because it is a divalent cation (~2.5 mmol/L),
ECF concentration is 1000 times higher than free cytoplasmic concentration
In plasma 50% of Ca is ionized, 40% is bound to proteins and 10% is complexed with other ions like phosphate
1g consumed in diet 0.5g absorbed in GI tract but 0.3 g secreted back= 0.8 g excreted in feces
From the ECF, 10g filtered to kidneys and 9.8 g is reabsorbed and 0.2 g excreted in urine
0.3g can be accreted from ECF to form the bone and 0.3 g resorbed from bone to ECF
storage of calcium
stored in endoplasmic/ sarcoplasmic reticulum in cells
99% of calcium is stored in bone
PTH
parathormone, protein, secreted by chief cells of parathyroid gland
Secretion triggered by a decrease in serum ionized Ca
Drop in Ca detected by calcium sensing receptor in membranes of chief cells
Increases Ca levels by stimulating bone resorption and Ca renal reabsorption
effects of PTH
elevates the serum ionized Ca concentration by stimulating bone resorption
Main effect is stimulation of osteoclasts, which are bone cells responsible for bone resorption
Note: the primary function of osteoblasts (active bone lining cells) and osteocytes (trapped bone lining cells) is bone accretion. However, they also participate in bone resorption. These cells have receptors for PTH
Additional functions of PTH
increase renal vitamin D activation
increase renal Ca reabsorption
decrease renal PO4 reabsorption
activation of vitamin D in kidney by PTH
increases vitamin D’s stimulation of calcium absorption in gut
1. Dietary calcium is absorbed by duodenal mucosal cells
2. Activity of mucosal cells is strongly stimulated by vitamin D
3. PTH stimulates vitamin D formation in the kidney and in this way it indirectly stimulates absorption of calcium in the gut
sodium antiporter pumps Ca out of the mucosal cells into the blood
Vitamin D synthesis
1,25(OH)2D3, dihydroxycalciferol, Cholesterol in keratinocytes in the skin is exposed to UV light to make 7-dehydrocholesterol then D3 (cholecalciferol)
Cats and dogs have low levels, rely more on D3 in food.
D3 is used as a food supplement and rodenticide (both of these found on a farm). Ingestion can produce D3 toxicosis and hypercalcemia
D3 in liver made into 25(OH)D3, which is made into Vitamin D (1,25(OH)2D3) in the kidney through stimulation by PTH
Main functions of vitamin D
main effect: increase Ca and PO4 intestinal absorption
increase Ca and PO4 renal reabsorption
increase bone resorption
all lead to increased Ca and PO4 in plasma
Vitamin D deficiency and toxicosis
toxicosis: hypercalcemia
deficit: rickets or osteomalacia
Calcitonin
role in decreasing Ca level and the regulation of its secretion
32 amino-acid peptide
secreted by parafollicular cells in thyroid gland in the response to hypercalcemia (uncommon)
Triggers: high plasma Ca, Gastrin (GI hormone)
Inhibits cells that secrete gastrin, decreasing HCl and Ca ions in stomach
Main functions: decrease of Ca intestinal absorption, resorption from bone, and renal reabsorption
Most likely protects bones of mother against loss of Ca during pregnancy
hypercalcemia
Primary hyperparathyroidism (eg tumor), Vitamin D toxicosis Decreased neuromuscular excitability, Ca has the ability to block sodium channels. Low calcium makes depolarization easier Bones: dissolution of bone, pain, and fractures Groans: constipation, anorexia, dyspepsia Stones: nephrocalcinosis, kidney stones, PU/PD, metabolic acidosis Moans: fatigue, myalgia, muscle weakness, joint pain Overtones: depression, memory loss, confusion, lethargy, and coma Treatment: volume expansion, loop diuretics (change Ca reabsorption in kidney, dilute plasma and volume expansion
hypocalcemia
primary hypoparathyroidism, renal failure
Increased neuromuscular excitability. High calcium makes depolarization more difficult
Coagulopathies, Eclampsia, Milk fever
Pregnant or lactating bitches or cows. Demand for milk calcium depletes calcium in mother’s plasma
Treatment: iv administration of calcium gluconate, oral calcium, vitamin D
Melatonin
secreted by pineal gland (epiphysis), neuroendocrine transducer organ involved in the control of photoperiodism.
Controls reproduction in seasonal breeders
Don’t confuse with melatonin with melanocyte stimulating hormone
Note: pineal gland called third eye, seat of soul by Descartes, contains DMT (dimethyltryptophan) which has role in dreams
synthesis of melatonin
depends on light exposure, synthesized from tryptophan in Pinealocytes
antigonadal in most species (except goat and sheep) influences reproductive cycle of seasonal breeders, most likely via regulation of GnRH
Light (increasing duration of daylight) inhibits melatonin secretion and this activates gonads in long-day breeders
Reproduction of long day breeders is suppressed by darkness and by melatonin, meaning animals can be induced to breed by the exposure to artificial light
When light enters eye, signals are sent to suprachiasmatic nucleus, signals sent to brain stem then superior cervical ganglion
Photoperiodism and reproductive cycle of seasonal breeders
Short day breeders: goat, sheep
Long day breeders: cat and horse
Nonseasonal breeders: cow, pig, human, house, monkey, rat, guinea pig
Other physiological effects of melatonin
Photoperiodic regulation of reproduction, puberty, stress response, hibernation, free radicals, thyroid
antagonizes alpha MSH in Melanophores
Melatonin also exhibits circadian rhythmicity (high at night) and entrains circadian clock in the suprachiasmatic nucleus. Circadian clock needs adjustment all the time by melatonin
Erythropoietin
EPO, Glycoprotein, produced by fetal liver and adult kidney (peritubular capillary endothelial cells)
Stimulates erythropoiesis and Fe uptake in small intestine.
Erythropoiesis occurs in fetal liver and adult bone marrow
Lack of EPO causes anemia
Anemia in animals treated using human recombinant EPO
Control of EPO production
controlled by PO2 of blood perfusing the kidney and it stimulates erythropoiesis
Main triggers: decrease renal blood flow, cardiopulmonary disease, decreased hemoglobin concentration, hemorrhage, high altitude, hypotension,
stimulate peritubular capillary endothelial cells to secrete erythropoietin
EPO is abused for blood doping in gray hounds, and racing horses)
Cats and dogs: renal disease causes decreased EPO and anemia. Treatment: human EPO, Iron supplementation, transfusion
