Physiologic Effects of Insulin
 Insulin stimulates storage of glycogen in liver and muscle and synthesis of fatty acids and triacylglycerols and
their storage in adipose tissue
o Also stimulates synthesis of proteins in various tissues, some of which contribute to growth of organism
 Difficult to separate effects of insulin on cell growth from those of family of somatomedins (insulin-like growth
factors) IGF-I and IGF-II
 Insulin has paracrine actions within pancreatic islet cells; when insulin released from β-cells, it suppresses
glucagon release from α-cells
Physiologic Effects of Glucagon
 Glucagon – counterregulatory (contrainsular) hormone; synthesized as part of large precursor protein
(proglucagon), which is produced in α-cells of islets of Langerhans in pancreas and L-cells of intestine
o Contains several peptides linked in tandem: glicentin-related peptide, glucagon, glucagon-like peptide 1
(GLP-1), and GLP-2
o Proteolytic cleavage of proglucagon releases various combinations of constituent peptides
 Glucagon cleaved from proglucagon in pancreas and constitutes 30-40% of immunoreactive glucagon in blood;
remaining immunoreactivity caused by other cleavage products of proglucagon released from pancreas and
intestine
 Pancreatic glucagon has plasma half-life of 3-6 minutes and is removed mainly by liver and kidney
 Glucagon promotes glycogenolysis, gluconeogenesis, and ketogenesis by stimulating generation of cAMP in
target cells; liver is major target organ (in part because concentrations of hormone in portal blood higher than in
peripheral circulation)
 Glucagon stimulates insulin release from β-cells of pancreas; pattern of blood flow in pancreatic islet cells is
from β-cells to α-cells, so β-cells may influence α-cell function by endocrine mechanism while influence of α-cells
on βcells is paracrine
Physiologic Effects of Other Counterregulatory Hormones
Somatostatin
 Preprosomatostatin encoded by gene on long arm of chromosome 3; somatostatin (SS-14) is cyclic peptide
produced from 14 amino acids at C-terminus of precursor molecule
 SS-14 releases GH (somatotropin) from anterior pituitary; also inhibits release of insulin
 SS-14 also secreted from D-cells (δ-cells) of pancreatic islets, many areas of CNS outside hypothalamus, and
gastric and duodenal mucosal cells
 SS-14 predominates in CNS and is sole form secreted by δ-cells of pancreas
 In gut, prosomatostatin (SS-28) makes up 70-75% of immunoreactivity (amount of hormone that reacts with
antibodies to SS-14); SS-28 is 7-10x more potent in inhibiting release of GH and insulin than SS-14
 Secretagogues (stimulants for secretion) for somatostatin similar to those that cause secretion of insulin
o Metabolites that increase somatostatin release include glucose, arginine, and leucine
o Hormonse that stimulate somatostatin secretion include glucagon, vasoactive intestinal polypeptide
(VIP), and CCK
o Tolbutamide (sulfonylurea drug that increases insulin secretion) also increases secretion of pancreatic
somatostatin
o Insulin doesn’t influence somatostatin secretion directly
 5 somatostatin receptors identified; all members of G protein coupled-receptor superfamily
o 4/5 receptors don’t distinguish between SS-14 and SS-28
o Somatostatin binds to PM receptors on target cells; activated receptors interact with variety of
intracellular signaling pathways (depending on cell type expressing receptor and which somatostatin
receptor is expressed)
o Pathways include inactivation of adenylate cyclase (via inhibitor G protein), regulation of
phosphotyrosine phosphatases and mitogen-activated protein (MAP) kinases, and alterations of
intracellular ion concentrations (Ca2+ and K+)
 Inactivation of adenylate cyclases reduces production of cAMP, and PKA not activated;
suppresses secretion of GH and TSH from anterior pituitary gland as well as secretion of insulin
and glucagon from pancreatic islets
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Somatostatin reduces nutrient absorption from gut by prolonging gastric emptying time (through decrease in
secretion of gastrin, which reduces gastric acid secretion) by diminishing pancreatic exocrine secretions (i.e.,
digestive enzymes, HCO3-, and water) and by decreasing visceral blood flow
 Somatostatin also suppresses pathologic increase in GH that occurs in acromegaly (caused by GH-secreting
pituitary tumor), DM, and carcinoid tumors (tumors that secrete serotonin)
o Somatostatin also suppresses basal secretion of TSH, TRH, insulin, and glucagon
o Suppressive effect on wide variety of non-endocrine secretions
 Somatostatin and synthetic analogs used clinically to treat variety of secretory neoplasms such as GH-secreting
tumors of pituitary
o Major limitation in clinical use of native somatostatin is its short half-life (less than 3 minutes in
circulation); analogs developed that are resistant to degradation and have longer half-life
 One analog is octreotide with half-life of 110 minutes
Growth Hormone
 GH stimulates growth; many effects mediated by IGFs (somatomedins) produced by cells in response to binding
of GH to PM receptors
 GH has direct effects on fuel metabolism
 Human GH is water-soluble polypeptide with plasma half-life of 20-50 minutes; has 2 intramolecular disulfide
bonds; gene located on chromosome 17
o Secreted by somatotroph cells in lateral areas of anterior pituitary
o Structurally related to PRL and human chorionic somatomammotropin (hCS) from placenta (stimulates
growth of developing fetus)
 hCS has 0.1% of growth-inducing potency of GH
 GH is most abundant trophic hormone in anterior pituitary
 Actions of GH can be classified as those that occur as consequence of hormone’s direct effect on target cells and
those that occur indirectly through ability of GH to generate other factors (particularly IGF-I)
o IGF-I-independent actions of GH exerted primarily in hepatocytes; GH administration followed by early
increase in synthesis of 8-10 proteins, among which are IFG-I, α2-macroglobulin, and serine protease
inhibitors Spi 2.1 and Spi 2.3
o Expression of gene for ornithine decarboxylase (enzyme active in polyamine synthesis and therefore in
regulation of cell proliferation) significantly increased by GH
 Macroadenoma (tumor of >10 mm in diameter) in pituitary gland can compress optic nerve as it crosses above
sella turcica, causing visual problems
o Skeletal and visceral changes because of elevated serum levels of GH and IGF-I
o Therapeutic alternatives include surgery if mass is amenable or lifelong medical therapy with
somatostatin analog such as octreotride
 Could use dopamine agonist that inhibits secretion of GH, such as cabergoline
 Use GH-receptor antagonist, such as pegvisomant
 Can also do stereotactic radiation therapy
o If excessive secretion of GH controlled successfully, some visceral or soft tissue changes of acromegaly
may slowly subside to varying degrees; skeletal changes can’t be reversed
o Can be diagnosed through administration of high glucose; GH levels should fall very low, while GH in
those with pituitary tumors only slightly impacted because tumor autonomously secretes GH
 Muscle and adipocyte PMs contain GH receptors that mediate direct, rapid metabolic effects on glucose and
amino acid transport as well as on lipolysis
o Receptors use associated cytoplasmic tyrosine kinases for signal transduction (such as janus kinases)
o STAT transcription factors activated and, depending on tissue, MAP kinase pathway and/or AKT pathway
also activated
o In adipose tissue, GH has acute insulin-like effects followed by increased lipolysis, inhibition of
lipoprotein lipase, stimulation of hormone-sensitive lipase, decreased glucose transport, and decreased
lipogenesis
o In muscle, GH causes increased amino acid transport, increased nitrogen retention, increased fat-free
(lean) tissue, and increased energy expenditure
 GH receptors present on variety of tissues in which GH increases IGF-I gene expression
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Subsequent rise in IGF-I levels contributes to cell multiplication and differentiation by autocrine or
paracrine mechanisms; these lead to skeletal, muscular, and visceral growth
o Above accompanied by direct anabolic influence of GH on protein metabolism with diversion of amino
acids from oxidation to protein synthesis and shift to positive nitrogen balance
GH stimulates IGF-I gene expression in several extrahepatic sites as well; in acromegalics, rising levels of IGF-I
cause gradual generalized increase in skeletal, muscular, and visceral growth
o As consequence, diffuse increase occurs in bulk of all tissues, especially in acral (mostly peripheral)
tissues of body such as face, hands, and feet
Major influence of GH regulation is hormonal; pulsatile pattern of GH secretion reflects interplay of 2
hypothalamic regulatory peptides
o Release stimulated by GHRH (somatocrinin) produced exclusively in cells of arcuate nucleus
 Full biologic activity resides in first 29 amino acids of N-terminal portion of molecule
 GHRH interacts with specific receptors on PM of somatotrophs
 Both cAMP and calcium-calmodulin stimulate GH release
o GH secretion suppressed by growth hormone release-inhibiting hormone (GHRIH, same as somatostatin)
o IGF-I produced primarily in liver in response to action of GH on hepatocytes feeds back negatively on
somatotrophs to limit GH secretion
o Physiologic factors such as exercise and sleep and many pathologic factors control GH release
o GH release modulated by plasma levels of all metabolic fuels (proteins, fats, and carbs)
 Rising level of glucose in blood suppresses GH release, whereas hypoglycemia increases GH
secretion
 Amino acids, such as arginine, stimulate release of GH when their concentrations rise in blood
 Rising levels of fatty acids blunt GH response to arginine or rapidly dropping blood glucose level
 Prolonged fasting, in which fatty acids mobilized in effort to spare protein, associated with rise
in GH secretion
 Modulators of GH secretion provide basis for clinical suppression and stimulation in patients
with excessive or deficient GH secretion
GH affects uptake and oxidation of fuels in adipose tissue, muscle, and liver; indirectly influences energy
metabolism through actions on islet cells of pancreas
o GH increases availability of fatty acids, which are oxidized for energy
o GH indirectly decreases oxidation of glucose and amino acids
GH increases sensitivity of adipocytes to lipolytic action of catecholamines and decreases sensitivity to lipogenic
action of insulin; leads to release of free fatty acids and glycerol into blood to be metabolized by liver
o GH decreases esterification of fatty acids, reducing triacylglycerol synthesis within fat cell
o GH may impair glucose uptake by both fat and muscle cells by post-receptor inhibition of insulin action
o As result of metabolic effects of GH, clinical course of acromegaly may be complicated by impaired
glucose tolerance or even diabetes mellitus
Lipolytic effects of GH increase free fatty acid levels in blood that bathes muscle; fatty acids used preferentially
as fuel, indirectly suppressing glucose uptake by muscle cells
o Through effects on glucose uptake, rate of glycolysis proportionately reduced
GH increases transport of amino acids into muscle cells, providing substrate for protein synthesis
o Through separate mechanism, GH increases synthesis of DNA and RNA
o Positive effect on nitrogen balance reinforced by protein-sparing effect of GH-induced lipolysis that
makes fatty acids available to muscle as alternative fuel source
When plasma insulin levels low (as in fasting state), GH enhances fatty acid oxidation to acety-CoA; this, in
concert with increased flow of fatty acids from adipose tissue, enhances ketogenesis
o Increased amount of glycerol reaching liver as consequence of enhanced lipolysis acts as substrate for
gluconeogenesis
Hepatic glycogen synthesis stimulated by GH in part because of increased gluconeogenesis in liver
o Glucose metabolism suppressed by GH at several steps in glycolytic pathway
o Major effect of GH on liver is to stimulate production and release of IGFs (somatomedins) that share
structural homologies with proinsulin and have substantial insulin-like growth activity
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Both identical to insulin in half their residues and contain structural domain that is homologous
to C-peptide of proinsulin; more potent than insulin in growth-promoting actions
 IGF-I (somatomedin C) – single chain basic peptide
 IGF-II (somatomedin-A) – slightly acidic
o Broad spectrum of normal cells respond to high doses of insulin by increasing thymidine uptake and
initiating cell propagation; in most instances, IGF-I causes same response as insulin in these cells but at
significantly smaller, more physiologic concentrations
o IGFs exert effects through either endocrine or paracrine/autocrine mechanism
 IGF-I stimulates cell propagation and growth by binding to specific IGF-I receptors on PM of
target cell, rather than binding to GH receptors
 Intracellular portion of PM receptor for IGF-I (but not IGF-II) has intrinsic tyrosine kinase activity
(like receptors for insulin and several other growth factors); tyrosine kinase initiates process of
cellular replication and growth
 Chain of kinases activated, which include several proto-oncogene products
o Most cells of body have mRNA for IGF, but liver has greatest concentration (followed by kidney and
heart); synthesis of IGF-I regulated for most part by GH
o Hepatic production of IGF-II independent of GH levels in blood
o High levels of circulating IGF-I linked to development of breast, prostate, colon, and lung cancer
o Experimental modulation of IGF-I receptor activity can alter growth of different types of tumor cells;
current research aimed at targeting interaction of IGF-I and its receptor to reduce tumor cell
proliferation
Catecholamines: Epinephrine, Norepinephrine, and Dopamine
 Catecholamines – belong to family of bioamines; secretory products of sympathoadrenal system; required for
body to adapt to variety of acute and chronic stresses
o Epinephrine (80-85% of stored catecholamines) synthesized primarily in cells of adrenal medulla
o Norepinephrine (15-20% of stored catecholamines) synthesized and stored in adrenal medulla, various
areas of CNS, and nerve endings of adrenergic nervous system
o Dopamine acts primarily as neurotransmitter and has little effect on fuel metabolism
 Tyrosine is precursor of catecholamines
 Secretion of epinephrine and norepinephrine from adrenal medulla stimulated by variety of stresses (pain,
hemorrhage, exercise, hypoglycemia, and hypoxia); release mediated by stress-induced transmission of nerve
impulses emanating from adrenergic nuclei in hypothalamus
o Impulses stimulate release of neurotransmitter acetylcholine from preganglionic neurons that innervate
adrenomedullary cells
o Acetylcholine depolarizes PMs of cells, allowing rapid entry of extracellular Ca2+ into cytosol
o Ca2+ stimulates synthesis and release of epinephrine and norepinephrine from chromaffin granules into
extracellular space by exocytosis
 Catecholamines act through 2 major types of receptors on target cell PMs: α-adrenergic and β-adrenergic
receptors
o Actions of epinephrine and norepinephrine in liver, adipocytes, skeletal muscle cells, and α-cells and βcells of pancreas directly influence fuel metabolism
o Catecholamines are counterregulatory hormones that have metabolic effects directed toward
mobilization of fuels from storage sites for oxidation by cells to meet increased energy requirements of
acute and chronic stress; simultaneously suppress insulin secretion, which ensures fuel fluxes will
continue in direction of fuel use rather than storage as long as stressful stimulus persists
o Norepinephrine works as neurotransmitter and affects SNS in heart, lungs, blood vessels, bladder, gut,
and other organs
 Effects on heart and blood vessels increase cardiac output and systemic blood pressure,
hemodynamic changes that facilitate delivery of blood-borne fuels to metabolically active
tissues
 Pheochromocytoma – neoplasm of adrenal medulla that secretes excessive quantities of epinephrine and
norepinephrine; catecholamines or their metabolites (such as metanephrines and vanillylmandelic acid (VMA))
may be measured in 24-hour urine collection, or level of catecholamines in blood may be measured
o
Patient who has consistently elevated levels in blood or urine should be considered to have
pheochromocytoma, particularly if patient has signs and symptoms of catecholamine excess such as
excessive sweating, palpitations, tremulousness, and hypertension
o Can digress into impaired glucose tolerance or diabetes mellitus
 Catecholamines have relatively low affinity for both α-receptors and β-receptors
o After binding, catecholamine disassociates from receptor quickly, causing duration of biologic response
to be brief
Glucocorticoids
 Cortisol (hydrocortisone) – major physiologic glucocorticoid (GC) in humans, although corticosterone has some
GC activity; steroid
 GCs raise blood glucose levels; among counterregulatory hormones that protect body from insulin-induced
hypoglycemia
 Synthesis and secretion of cortisol controlled by cascade of neural and endocrine signals linked in tandem in
cerebrocortical-hypothalamic-pituitary-adrenocortical axis
o Cerebrocortical signals to midbrain initiated in cerebral cortex by stressful signals (pain, hypoglycemia,
hemorrhage, and exercise); nonspecific stresses elicit production of monoamines in cell bodies of
neurons of midbrain; those that stimulate synthesis and release of corticotropin-releasing hormone
(CRH) are acetycholine and serotonin
o Neurotransmitters induce production of CRH by neurons originating in paraventricular nucleus
o Neurons discharge CRH into hypothalamic-hypophyseal portal blood to specific receptors on PM of
ACTH-secreting cells (corticotrophs of anterior pituitary)
o Hormone-receptor interaction causes ACTH to be released into general circulation, eventually to
interact with specific receptors for ACTH on PMs of cells in zona fasciculata and zona reticulosum of
adrenal cortex
o Major tropic influence of ACTH on cortisol synthesis is level of conversion of cholesterol to
pregnenolone, from which adrenal steroid hormones derived
 Cortisol secreted from adrenal cortex in response to ACTH; concentration of free cortisol bathes CRH-producing
cells of hypothalamus and ACTH-producing cells of anterior pituitary acting as negative feedback signal that has
regulatory influence on release of CRH and ACTH
o High cortisol levels in blood suppress CRH and ACTH secretion, and low levels stimulate secretion
o In severe stress, negative feedback signal on ACTH secretion exerted by high cortisol levels in blood
overridden by stress-induced activity of higher portions of axis
 GCs have diverse affects that, taken together, promote survival in times of stress
o In many tissues, GCs inhibit DNA, RNA, and protein synthesis and stimulate their degradation
o In response to chronic stress, GCs act to make fuels available, so that when acute alarm sounds and
epinephrine released, organism can fight or flee
o When GCs elevated, glucose uptake by cells of many tissues inhibited, lipolysis occurs in peripheral
adipose tissue, and proteolysis occurs in skin, lymphoid cells, and muscle
o Fatty acids released are oxidized by liver for energy, and glycerol and amino acids serve in liver as
substrates for production of glucose, which is converted to glycogen and stored
 Epinephrine stimulates liver glycogen breakdown, making glucose available as fuel to combat
acute stress
 Mechanism by which GCs exert effects involves binding of steroid to intracellular receptors, interaction of
steroid-receptor complex with GC response elements on DNA, transcription of genes, and synthesis of specific
proteins (for example, induction of phosphoenolpyruvate carboxykinase stimulates gluconeogenesis)
 Excessive secretion of cortisol secondary to excess secretion of ACTH (Cushing disease) or by primary increase of
cortisol production by adrenocortical tumor (Cushing syndrome)
o Taking a fasting plasma cortisol and ACTH level can help differentiate; high ACTH level after fasting
shows cortisol-producing tumor (both high cortisol and ACTH would exist because high ACTH stimulates
production of excessive cortisol)
o Hypercortisolemia causes hyperglycemia
o Muscle wasting and weakness caused by catabolic effect of hypercortisolemia on protein stores, such as
those in skeletal muscle, to provide amino acids as precursors for gluconeogenesis; catabolic action also
results in degradation of elastin (major supportive protein of skin) as well as increased fragility of walls
of capillaries of cutaneous tissues (cause easy bruising and torn subcutaneous tissues in lower abdomen
(striae)); thinning of skin can cause plethora (redness) of facial skin (also caused by cortisol-induced
increase in bone marrow production of RBCs, which enhance redness of subcutaneous tissues
o Patients have central deposition of fat (buffalo hump and moon face) as well as marked increase in neck
and abdominal fat; simultaneously, there is loss of adipose and muscle tissue below elbows and knees,
exaggerating appearance of central obesity
Thyroid Hormone
 Basic steps in synthesis of T3 and T4 involve transport or trapping of I- from blood into thyroid acinar cell against
electrochemical gradient, oxidation of I- to form iodinating species, iodination of tyrosyl residues on protein
(thyroglobulin or Tgb) to form iodotyrosines, and coupling of residues of MIT and DIT in Tgb to form residues of
T3 and T4; proteolytic cleavage of Tgb releases free T3 and T4
o Steps in thyroid hormone synthesis stimulated by TSH (glycoprotein produced by anterior pituitary)
o About 35% of T4 deiodinated at 5’-position to form T3; 43% deiodinated at 5’-position to form inactive
reverse T3; further deiodination or oxidative deamination leads to formation of compounds that have no
biologic activity
 Iodide transport from blood into thyroid acinar cell accomplished through energy-requiring, iodide-trapping
mechanism that requires symport with Na+
o Sodium-iodide symporters (NIS) driven by electrochemical gradient across membrane established by
Na+,K+-ATPase
o For each I- transported across the membrane, 2 Na+ cotransported to facilitate and drive translocation
o Loss of NIS activity leads to congenital I- transport defect
 Once I- enters thyroid follicular cell, it must be transported across apical membrane to react with thyroid
peroxidase and Tgb; apical I- transporter is pendrin and mutations in pendrin lead to Pendred syndrome
o Children with Pendred syndrome display total loss of hearing, goiter, and metabolic defects in Iorganification
 Rate of I- transport influenced by absolute concentration of I- within thyroid cell; internal autoregulatory
mechanism decreases transport of I- when intracellular I- concentration exceeds threshold level
o I--concentrating (trapping) process in PM of thyroid acinar cells creates I- levels several hundred-fold that
in blood, depending on current size of total body I- pool and present need for new hormones
 Oxidation of intracellular I- catalyzed by thyroid peroxidase (located at apical border of thyroid acinar cell) in 2electron oxidation step forming I+ (iodinium ion)
o I+ may react with tyrosine residue in Tgb to form tyrosine quinoid and then 3’-MIT residue
o Second I- may be added to ring by similar mechanism to form 3,5-DIT residue
o Adding iodides called organification of iodide
 Biosynthesis of thyroid hormone proceeds with coupling of MIT and DIT residue to form T3 residue or 2 DIT
residues to form T4 residue; T3 and T4 stored in thyroid follicle as amino acid residues in Tgb
o Under most circumstances T4/T3 ratio in Tgb is about 13:1
o Normally, thyroid gland secretes lots more T4 than T3; additional T3 in circulation is result of deiodination
of 5’-carbon of T4 in peripheral tissues
o T3 is predominant biologically active form of thyroid hormone in body
o Thyroid gland unique in storing large amounts of hormone as amino acid residues in Tgb within colloid
space; storage accounts for low overall turnover rate of T3 and T4 in body
 Plasma half-life of T4 is 7 days, and that of T3 is 1-1.5 days; relatively long plasma half-lives result from binding to
several transport proteins in blood
o Of transport proteins, thyroid-binding globulin (TBG) has highest affinity for hormones and carries 70%
of bound thyroid hormones
o Only 0.03% of total T4 and 0.3% of total T3 in blood are in unbound state; free fraction has biologic
activity because it is only form capable of diffusing across target cell membranes to interact with
intracellular receptors
o Transport proteins serve as large reservoir of hormone that can release additional free hormone as
metabolic need arises
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Thyroid hormones degraded in liver, kidney, muscle, and other tissues by deiodination, which produces
compounds with no biologic activity
Release of thyroid hormones from Tgb controlled by TSH from anterior pituitary; TSH stimulates endocytosis of
Tgb to form endocytic vesicles within thyroid acinar cells
o Lysosomes fuse with vesicles, and lysosomal proteases hydrolyze Tgb, releasing free T4 and T3 into blood
in 10:1 ratio; in various tissues, T4 deiodinated, forming T3, which is active form
o TSH synthesized in thyrotropic cells of anterior pituitary; secretion regulated primarily by balance
between stimulatory action of hypothalamic thyrotropin-releasing hormone (TRH) and inhibitory
(negative feedback) influence of thyroid hormone (primarily T3) at levels higher than critical threshold in
blood bathing pituitary thyrotrophs
o TSH secretion in circadian pattern: surge beginning late in afternoon and peaking before onset of sleep
 TSH secreted in pulsatile fashion, with intervals of 2-6 hours between peaks
o TSH stimulates all phases of thyroid hormone synthesis by thyroid gland, including iodide trapping from
plasma, organification of iodide, coupling of MIT and DIT, endocytosis of Tgb, and proteolysis of Tgb to
release T3 and T4; vascularity of thyroid gland increases as TSH stimulates hypertrophy and hyperplasia
Predominant mechanism of action of TSH mediated by binding of TSH to G protein coupled-receptor on PM of
thyroid acinar cell, leading to increase in concentration of cytosolic cAMP (through Gαs) and Ca2+ (through Gαq)
o Increase in Ca2+ brought about by activation of phospholipase C, eventually leading to activation of MAP
kinase pathway
Tgb (which contains T3 and T4) stored extracellularly in colloid that fills central space of each thyroid follicle
o Each of biochemical reactions that leads to release and eventual secretion of T3 and T4, such as those
that lead to formation in Tgbs, is TSH-dependent
o Rising levels of serum TSH stimulate endocytosis of stored Tgb into thyroid acinar cell
o Lysosomal enzymes cleave T3 and T4 from Tgb
o T3 and T4 secreted into bloodstream in response to rising levels of TSH
As free T3 level in blood bathing thyrotrophs of anterior pituitary gland rises, feedback loop closed; secretion of
TSH inhibited until free T3 levels in systemic circulation fall just below critical level, which once again signals
release of TSH; feedback mechanism ensures uninterrupted supply of biologically active free T3 in blood
o High levels of T3 inhibit release of TRH from hypothalamus
Effects of supraphysiologic concentrations of thyroid hormone on fuel metabolism may not be simple extensions
of physiologic effects; for example, when T3 present in excess, it has severe catabolic effects that increase flow
of amino acids from muscle into blood and eventually to liver
Thyroid hormone increases glycolysis and cholesterol synthesis and increases conversion of cholesterol to bile
salts; through action of increasing sensitivity of hepatocyte to gluconeogenic and glycogenolytic actions of
epinephrine, T3 indirectly increases hepatic glucose production (permissive or facilitatory action)
o Because of ability to sensitize adipocyte to lipolytic action of epinephrine, T3 increases flow of fatty acids
to liver and thereby indirectly increases hepatic triacylglycerol synthesis
o Concurrent increase in flow of glycerol to liver (as result of increased lipolysis) further enhances hepatic
gluconeogenesis
T3 has amplifying or facilitatory effect on lipolytic action of epinephrine on fat cells; also increases availability of
glucose to fat cells, which serves as precursor for fatty acid and glycerol-3-phosphate synthesis
o Major determinant of rate of lipogenesis is not T3 but amount of glucose and insulin available to
adipocyte for triacylglycerol synthesis
In physiologic concentrations, T3 increases glucose uptake by muscle cells; also stimulates protein synthesis and,
therefore, growth of muscle, through stimulatory actions on gene expression
o Thyroid hormone sensitizes muscle cell to glycogenolytic actions of epinephrine
o Glycolysis in muscle increased by action of T3
Thyroid hormone increases sensitivity of β-cells of pancreas to those stimuli that normally produce insulin
release and is required for optimal insulin secretion
Oxidation of fuels convert approximately 25% of potential energy present in foods ingested by humans to ATP;
relative inefficiency of body leads to production of heat as consequence of fuel use; inefficiency in part, allows
homeothermic animals to maintain constant body temperature in spite of rapidly changing environment
conditions; acute response is shivering (secondary to increased SNS activity)
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Thyroid hormone participates in acute cold response by sensitizing SNS to stimulatory effect of cold exposure
o Ability of T3 to increase heat production related to its effects on pathways of fuel oxidation, which both
generate ATP and release energy as heat
 Effects of T3 on SNS increases release of norepinephrine, which stimulates uncoupling protein thermogenin in
brown adipose tissue (BAT), resulting in increased heat production from uncoupling of oxidative
phosphorylation
o Norepinephrine also increases permeability of BAT and skeletal muscle to Na+
o Because increase of intracellular Na+ is potentially toxic to cells, Na+/K+-ATPase stimulated to transport
Na+ out of cell in exchange for K+
o Increased hydrolysis of ATP by Na+/K+-ATPase stimulates oxidation of fuels and regeneration of more
ATP and heat from oxidative phosphorylation
o Over longer time course, thyroid hormone increases level of Na+/K+-ATPase and many enzymes of fuel
oxidation
o Because even at normal room temperature, ATP use by Na+/K+-ATPase accounts for 20% or more of
basal metabolic rate (BMR), changes in activity can cause relatively large increases in heat production
 Thyroid hormone may increase heat production by stimulating ATP use in futile cycles (in which reversible ATPconsuming conversion of substrate to product and back to substrate use fuels, and therefore, produce heat)
 Refertoff disorder – mutation in portion of gene that encodes ligand-binding domain of β-subunit of thyroid
hormone-receptor protein (expressed in all thyroid hormone responsive cells) causes relative resistance to
suppressive action of TSH by thyrotrophs of anterior pituitary
o Gland releases more TSH than normal into blood; elevated TSH causes goiter as well as increase in
secretion of thyroid hormone in blood
o Increase in secretion of thyroid hormone may or may not be adequate to fully compensate for relative
resistance of peripheral tissues to thyroid hormone
o If compensatory increases in secretion of thyroid hormone inadequate, patient may develop signs and
symptoms of hyperthyroidism
 In hypothyroid patients, insulin release may be suboptimal, although glucose intolerance on this basis alone
uncommon
 In hyperthyroidism, degradation and clearance of insulin increased; these with increased demand for insulin
caused by changes in glucose metabolism may lead to varying degrees of glucose intolerance (metathyroid
diabetes mellitus)
o Patient with uncomplicated hyperthyroidism rarely develops significant DM
Gastrointestinal-Derived Hormones that Affect Fuel Metabolism
 Ghrelin (hormone identified as GH secretagogue) linked to appetite stimulation; mechanism is through
activation of AMP-activated protein kinase in hypothalamus
o Activation of protein kinase leads to release of neuropeptide Y, which increases appetite
 Peptides such as gastrin, motilin, pancreatic polypeptide (PP), peptide YY (PYY), and secretin influence fuel
metabolism by indirect effects on synthesis or secretion of insulin or counterregulatory hormones
o Gastrin induces gastric acid secretion, which ultimately affects nutrient absorption and metabolism
o Motilin (secreted by enteroendocrine M-cells of proximal small bowel) stimulates gastric and pancreatic
enzyme secretion, which in turn influences nutrient digestion
o PP from pancreatic islets reduces gastric emptying and slows upper intestinal motility
o PYY from α-cells in mature pancreatic islets inhibits gastric acid secretion
o Secretin (produced by enteroendocrine S-cells in proximal small bowel) regulates pancreatic enzyme
secretion and inhibits gastrin release and secretion of gastric acid
o If digestion or absorption of fuels altered through disturbance in interplay among all the peptides, fuel
metabolism will be altered as well
 Several GI peptides, such as GLP-1 and gastric inhibitory polypeptide/glucose-dependent insulinotropic
polypeptide (GIP), don’t act as direct insulin secretagogues when blood glucose levels normal but do so after
meal large enough to cause increase in blood glucose concentration
o Explains why modest postprandial increase in serum glucose seen in normal subjects has relatively
robust stimulatory effect on insulin release, whereas similar glucose concentration in vitro elicits
significantly smaller increase in insulin release  called incretin effect
o
Accounts for greater β-cell response seen after oral glucose load as opposed to that seen aftger
administration of IV glucose
o Accounts for approximately 50-70% of total insulin secreted after oral glucose administration
 GI tract plays critical role in peripheral energy homeostasis through ability to influence digestion, absorption,
and assimilation of ingested nutrients
 Incretin hormones regulate amount of nutrients ingested through central action as satiety signals
 Both GLP-1 and GIP enhance synthesis and release of insulin as well as exerting positive influence on survival of
pancreatic islet cells
o GLP-1 contributes to regulation of glucose homeostasis by inhibiting secretion of glucagon from α-cells
of pancreas as well as by slowing rate of gastric emptying
o GIP interacts with GIP receptors on adipocytes; interaction coupled to energy storage
 Half-lives of GIP and GLP-1 in circulation are around 2.5 minutes
 Protease DPP-4 found on surface of kidneys, intestine, liver, and many other tissues responsible for inactivating
GIP and GLP-1
 If one wants to increase efficacy of incretins, synthetic incretin mimetics with longer half-lives could be
developed or drugs that inhibit DPP-4, thereby increasing serum half-lives of GIP and GLP-1 (used for treatment
of type 2 DM
o Potent GLP-1 receptor agonists
 Exendin-4 or exenatide (Byetta) isolated from venom of lizard (Heloderma suspectum); must be
administered subcutaneously, but because of relative resistance to enzymatic cleavage by DPP4, its biologic half-life in plasma allows it to be administered only twice daily
 Exenatide has different amino acid configuration that makes it more resistant to DPP-4 action
 Liraglutide – modified version of GLP-1; addition of fatty acid to peptide allows it to bind to
albumin in circulation, protecting it from DPP-4 and allowing single daily dosing
o Orally administered inhibitors of DPP-4; sitagliptin slows rate of catalytic cleavage of GIP and GLP-1 by
DPP-4 and prolongs their half-lives in blood, allowing sitagliptin to be administered twice daily
 Other DPP-4 inhibitors include alogliptin, saxagliptin, and vildagliptin; only sitagliptin and
saxagliptin approved in U.S.
o Glucose-lowering efficacy of above drugs lowers A1C to approximately same extent as other currently
available oral antidiabetic agents (sulfonylureas, metformin, and thiazolidinediones)
Neural Factors that Control Secretion of Insulin and Counterregulatory Hormones
 Pancreatic islet cells innervated by both adrenergic and cholinergic limbs of ANS
 Stimulation of both PNS and SNS increases glucagon secretion
 Insulin secretion increased by vagus nerve fibers and suppressed by sympathetic fibers via α-adrenoreceptors
 SNS regulates pancreatic β-cell function indirectly through stimulation or suppression of secretion of
somatostatin, β2-adrenergic receptor number, and neuropeptides (neuropeptide Y and galanin)
Endocannabinoid System and Energy Homeostasis
 Endocannabinoid system (ECS) – discovered with description of major psychoactive substance in marijuana Δ9tetrahydrocannabinol (Δ9-THC)
 Exogenous ligands (e.g., Δ9-THC) and endogenous ligands (e.g., anandamide (AEA) and 2-arachidonoylglycerol (2AG)) interact with 2 basic receptors of G protein-coupled family of receptors
o CB2 receptor found primarily in cells related to immune function
o CB1 receptor expressed in many tissues, including adipose tissue, muscle, liver, GI tract, pancreas, and
CNS; functions of ECS in brain influence energy metabolism through these
 Ability of cannabinoids to modulate signaling from hypothalamic nuclei to most trophic hormone-producing cells
of anterior pituitary gland
o Ligands modulate rate of secretion of GH, ACTH, LH, FSH, and TSH; all of these trigger release of
hormones from peripheral endocrine organs (IGF-I, cortisol, sex steroids, and thyroid hormone), all of
which directly or indirectly influence nutrient intake and energy use or storage
 CB1 receptor activation induces hyperphagia, particularly for highly palatable foods even in satiated state
o Orexigenic action of endocannabinoids fully inhibited if given CB1-specific antagonists prior to receiving
endocannabinoid
o CB1 receptor blockade decreases reward potential of addictive drugs
o
Most significant reward pathway is part of mesolimbic dopaminergic system in brain; inhibitors of
enzyme fatty acid synthase have significant anorexigenic actions
o Because CB1 receptor activation modulates fatty acid synthase pathway in hypothalamus, inhibition of
hypothalamic expression by CB1 receptor antagonist rimonabant (Acomplia) explains in part
anorexigenic properties of endocannabinoid antagonists in general
 Administration of CB1 receptor antagonists associated with reduction in body weight that persists beyond
duration of anorexigenic action of agent; possibly direct stimulating effect of CB1 receptor antagonists on
energy expenditure
o Expression of CB1 receptors in adipose tissue and capacity of CB1 receptor antagonists to inhibit
cannabinoid-induced lipogenesis suggests ECS operates via peripheral pathways that, when activated,
alter energy balance as well
o CB1 receptor antagonists reduce adipose mass; result of induction of enzymes involved in β-oxidation of
fatty acids as well as enzymes of TCA cycle
o CB1 receptor antagonists increase expression of insulin-responsive glucose transporter 4 (GLUT-4),
suggesting antidiabetogenic action of antagonists
o Chronic administration of CB1 receptor antagonists increases level of adiponectin and increases
production of uncoupling proteins (UCPs); suggests that CB1 receptor blockade may stimulate
thermogenesis and increase oxygen consumption in adipocytes
o ECS plays major role in regulation of energy homeostasis in fat tissue
 Hepatocytes contain twice amount of 2-AG as cells of other peripheral organs; cannabinoid receptor agonist
H4210 stimulates expression of genes that code for lipogenic enzymes such as lipogenic transcription factor
SREBP-1c and its targets acetyl-CoA carboxylase-1 and fatty acid synthase
o Blockade of hepatic ECS protects liver cells from damaging effect of chronically high-fat diet (e.g.,
hepatic steatosis)
 ECS in GI cells may modulate nutrient intake and thereby affect energy homeostasis
o Concentration of AEA in intestinal cells increases sharply when caloric intake significantly restricted; this
together with that which occurs in CNS, may synergize to increase appetite
Diagnosis of Secretory Tumor
 To establish diagnosis of secretory tumor of endocrine gland, one must first demonstrate that basal serum levels
of hormone in question are regularly elevated
 One must also show hypersecretion of hormone (and hence elevated level in peripheral blood) can’t adequately
be inhibited by maneuvers known to suppress secretion from normally functioning glands (show autonomy)
 To ensure both basal and post-suppression levels of specific hormone to be tested will reflect true secretory rate
of suspected endocrine tumor, all known factors that can stimulate synthesis of hormone must be eliminated
 For GH, secretagogues include nutritional factors, patient’s level of activity, level of consciousness, stress level,
and certain drugs
o GH secretion stimulated by high-protein meal or low level of fatty acids or glucose in blood
o Vigorous exercise, stage III to IV sleep, psychologic and physical stress increase GH release
o Levodopa, clonidine, and estrogens also increase GH release
o Suppression test used to demonstrate autonomous hypersecretion of GH involves giving patient oral
glucose load and measuring GH levels subsequently
 Sudden rise in blood glucose suppresses serum GH in normal subjects, but not in acromegaly
o If one attempts to demonstrate autonomous hypersecretion of GH in patient suspected of having
acromegaly, before draing blood for both basal (pre-glucose load) serum GH levels and post-glucose
load serum GH level, one must be certain that patient hasn’t eaten for 6-8 hours, has not done vigorous
exercise for at least 4 hours, remains fully awake during entire testing period (in nonstressed state to
extent possible), and hasn’t taken any drugs known to increase GH secretion for at least 1 week
o If serum tests come up positive, localization procedures (such as MRI of pituitary gland in acromegalic
suspect) performed to further confirm diagnosis
Radioimmunoassays
 Most hormones present in body fluids in picomolar-nanomolar amounts, requiring highly sensitive assays to
determine concentration in blood or urine
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Radioimmunoassays (RIAs) use antibody generated in animals against specific antigen (hormone to be
measured)
Determining concentration of hormone involves incubating plasma or urine sample with antibody and then
quantifying level of antigen-antibody complex formed during incubation by one of several techniques
Class RIA uses very high-affinity antibodies, which have been fixed on inner surface of test tube, Teflon bead, or
magnetized particle
o Standard curve prepared, using set amount of antibody and various known concentrations of unlabeled
hormone to be measured; each tube contains same small, carefully measured amount of radiolabeled
hormone; labeled hormone and unlabeled hormone compete for binding to antibody
o Unknown sample from patient’s blood or urine, containing unlabeled hormone to be measured,
incubated with immobilized antibody in present of same, small, carefully measured amount of
radiolabeled hormone
o Amount of radiolabeled hormone bound to antibody determined, and standard curve used to quantitate
amount of unlabeled hormone in patient’s sample
Immunoradiometric assays (IRMAs) – antibody, rather than antigen to be measured, is radiolabeled
Sensitivity of RIAs can be enhanced using sandwich technique; uses two different monoclonal antibodies
(antibodies generated by single clone of plasma cells rather than multiple clones), each of which recognizes
different specific portion of hormone’s structure
o First antibody, attached to solid support matrix such as plastic culture dish, binds hormone to be
assayed
o After exposure of patient sample to first antibody, excess plasma washed away and second antibody
(which is radiolabeled) incubated with first antibody-hormone complex
o Amount of binding of second (labeled) antibody to first complex proportional to concentration of
hormone in sample
Sandwich technique can be improved further if second antibody is attached to enzyme, such as alkaline
phosphatase; enzyme rapidly converts added colorless substrate into colored product or non-fluorescent
substrate into highly fluorescent product
o Changes can be quantitated if degree of change in color or fluorescence is proportional to amount of
hormone present in patient sample
Less than a nanogram of protein can be measured by enzyme-linked immunosorbent assay (ELISA)