Physiology_Levy

Physiology_Levy. Production of new HCO3 − as a result of titratable acid excretion is depicted in Fig. 37.6 . Because of HCO3 − reabsorption by the proximal tubule and loop of Henle, fluid reaching the distal tubule and collecting duct normally contains little HCO3 − . Thus when H+ is secreted it will combine with non-HCO3 − buffers (primarily Pi) and be excreted as titratable acid. Because the H+ was produced inside the cell from hydration of CO2, a HCO3 − is also produced. This HCO3 − is returned to the ECF as new HCO3 − . As noted, Pi excretion increases with acidosis. However, even with increased Pi available for titratable acid formation, this response is insufficient to generate the required amount of new HCO3 − . The remainder of new HCO3 − generation occurs as a result of NH4 + generation and excretion. NH4 + is produced by the kidneys, and its synthesis and subsequent excretion adds HCO3 − to ECF. Importantly, this process is regulated in response to the acid-base requirements of the body.


Physiology_Levy

Physiology_Levy. NH4 + is produced by the kidneys, and its synthesis and subsequent excretion adds HCO3 − to ECF. Importantly, this process is regulated in response to the acid-base requirements of the body. NH4 + is produced in the kidneys via metabolism of glutamine. Essentially the kidneys metabolize glutamine, excrete NH4 + , and add HCO3 − to the body. However, formation of new HCO3 − via this process depends on the kidneys’ ability to excrete NH4 + in urine. If NH4 + is not excreted in urine but instead enters the systemic circulation, it is converted into urea by the liver. This conversion process generates H+ , which is then buffered by HCO3 − . Thus production of urea from renal-generated NH4 + consumes HCO3 − and negates formation of HCO3 − through synthesis and excretion of NH4 + by the kidneys. However, normally the kidneys excrete NH4 + in urine and thereby produce new HCO3 − . The process by which the kidneys excrete NH4 + is complex.


Physiology_Levy

Physiology_Levy. The process by which the kidneys excrete NH4 + is complex. Fig. 37.7 illustrates the essential features of this process. NH4 + is produced from glutamine in the cells of the proximal tubule, a process termed ammoniagenesis. Each glutamine molecule produces two molecules of NH4 + and the divalent anion 2-oxoglutarate2− . Metabolism of this anion ultimately provides two molecules of HCO3 − . HCO3 − exits the cell across the basolateral membrane and enters the peritubular blood as new HCO3 − . NH4 + exits the cell across the apical membrane and enters the tubular fluid. The primary mechanism for NH4 + secretion into the tubular fluid involves the Na+/H+ antiporter, with NH4 + substituting for H+ . In addition, some NH3 can diffuse out of the cell into the tubular fluid, where it is protonated to NH4 + .


Physiology_Levy

Physiology_Levy. A significant portion of the NH4 + secreted by the proximal tubule is reabsorbed by the loop of Henle. The TAL is the primary site of this NH4 + reabsorption, with NH4 + substituting for K+ on the 1Na+/1K+/2Cl− symporter. In addition the lumen-positive transepithelial voltage in this segment drives paracellular reabsorption of NH4 + . 678 SECTION7Berne & Levy Physiology •Fig. 37.6 GeneralschemeforexcretionofH+withnon-HCO3−urinarybuffers(titratableacid).Theprimaryurinarybufferisphosphate(HPO42−).AH+-secretingintercalatedcellisshown.Forsimplicity,onlytheH+-ATPaseisdepicted.H+secretionbytheH+,K+-ATPasealsotitratesluminalbuffers.ATP,adenosinetriphosphate;CA,carbonicanhydrase.Tubular fluid Blood Cl– CO2 + H2O Buffer + H+ H-Buffer H˜ATP CA HCO3 – HCO3 – The NH4 + reabsorbed by the TAL of the loop of Henle accumulates in the medullary interstitium. From there it is then secreted into the tubular fluid by the collecting duct.


Physiology_Levy

Physiology_Levy. The NH4 + reabsorbed by the TAL of the loop of Henle accumulates in the medullary interstitium. From there it is then secreted into the tubular fluid by the collecting duct. The cells of the collecting duct express two NH3 membrane transporters known as Rhesus (Rh) glycoproteins (RhBG and RhCG). RhBG is present in the basolateral membrane of H+-secreting intercalated cells and principal cells, and RhCG is present in both the apical and basolateral membranes of these cells. As depicted in Fig. 37.7 , NH3 is transported across the collecting duct, a process traditionally termed nonionic diffusion. The secreted NH3 is protonated in the tubule lumen as a result of intercalated H+ secretion. Because the apical membrane has a low permeability to NH4 + it is effectively trapped in the tubular lumen, a process traditionally termed diffusion trapping.


Physiology_Levy

Physiology_Levy. H+ secretion by the collecting duct is critical for excretion of NH4 + . If collecting duct H+ secretion is inhibited, the NH4 + reabsorbed by the TAL of Henle’s loop will not be excreted in the urine. Instead it will be returned to the systemic circulation, where as described previously, it will be converted to urea by the liver and consume HCO3 − in the process. Thus new HCO3 − is produced during the metabolism of glutamine by cells of the proximal tubule. However, the overall process is not complete until the NH4 + is excreted (i.e., production of urea from NH4 + by the liver is prevented). Thus NH4 + excretion in urine can be used as a marker of glutamine metabolism in the proximal tubule.


Physiology_Levy

Physiology_Levy. AssessingNH4+ excretionbythekidneysisdoneindirectlybecauseassaysofurineNH4+ arenotroutinelyavailable.Considerforexamplethesituationofmetabolicacidosis,whereintheappropriaterenalresponseistoincreasenetacidexcretion.Accordingly,littleornoHCO3− willappearinurine,urinewillbeacidic,andNH4+ excretionwillbeincreased.Toassessthis,andespeciallytheamountofNH4+ excreted,the“urinarynetcharge”or“urineaniongap”canbecalculatedbymeasuringurinaryconcentrationsofNa+ ,K+ ,andCl−: TheconceptofurineaniongapduringametabolicacidosisassumesthatthemajorcationsinurineareNa+ ,K+ ,andNH4+ andthatthemajoranionisCl− (withurinepH< 6.5,virtuallynoHCO3− ispresent).AsaresulttheurineaniongapwillyieldanegativevaluewhenNH4+ isbeingexcreted.Indeed,theabsenceofaurineaniongaportheexistenceofapositivevalueindicatesarenaldefectinNH4+ productionandexcretion. gBoth RhBG and RhCG transport NH3. There is some evidence that RhBG may also transport some NH4 + .


Physiology_Levy

Physiology_Levy. gBoth RhBG and RhCG transport NH3. There is some evidence that RhBG may also transport some NH4 + . •Fig. 37.7 Production,transport,andexcretionofNH4+bythenephron.GlutamineismetabolizedtoNH4+andHCO3−intheproximaltubule.TheNH4+issecretedintothelumen,andtheHCO3−enterstheblood.ThesecretedNH4+isreabsorbedinHenle’sloop,primarilybythethickascendinglimb,andaccumulatesinthemedullaryinterstitium.NH3issecretedbythecollectingductviarhesusglycoproteins,andH+secretiontrapsNH4+inthelumen.ForeachmoleculeofNH4+excretedintheurine,amoleculeof“new”HCO3−isaddedbacktotheECF.CA,carbonicanhydrase.Tubular fluid Tubular fluid CO2 + H2O NH4 + NH4 + 2NH4 + NH4 + NH3 NH3 NH4 + NH4 + NH3 + H+ NH4 + NH4 + NH4 + NH4 + H˜NH3HCO3 – Blood Blood Na+ Na+ H+H+ Glutamine A= 2HCO3 – CA In the net, one new HCO3 − is returned to the systemic circulation for each NH4 + excreted in the urine.


Physiology_Levy

Physiology_Levy. In the net, one new HCO3 − is returned to the systemic circulation for each NH4 + excreted in the urine. An important feature of the renal NH4 + system is that it is regulated by systemic acid-base balance. As already described, cortisol levels increase with acidosis, as does angiotensin II secretion into the lumen of the proximal tubule. Both cortisol and angiotensin II stimulate ammoniagenesis (i.e., NH4 + production from glutamine). During systemic acidosis, the enzymes in the proximal tubule cell responsible for metabolism of glutamine are stimulated. This involves synthesis of new enzyme and requires several days for complete adaptation. With increased levels of these enzymes, NH4 + production is increased, allowing enhanced production of new HCO3 − . Conversely, glutamine metabolism is reduced with alkalosis. Acidosis also increases the abundance of RhBG and RhCG in the collecting duct. Thus the ability to secrete NH4 + is also enhanced. Response to Acid-Base Disorders


Physiology_Levy

Physiology_Levy. Response to Acid-Base Disorders The pH of the ECF is maintained within a very narrow range (7.35–7.45). Inspection of Eq. 37.3 shows that the pH of hFor simplicity of presentation in this chapter, the value of 7.40 for body fluid pH is used as normal, even though the normal range is from 7.35 to 7.45. Similarly the normal range for PCO2 is 35 to 45 mm Hg. However, a PCO2 of 40 mm Hg is used as the normal value. Finally, a value of 24 mEq/L is considered a normal ECF [HCO3 −], even though the normal range is 22 to 28 mEq/L. ECF varies when either [HCO3 −] or PCO2 are altered. As already noted, disturbances of acid-base balance that result from a change in [HCO3 −] of ECF are termed metabolic acid-base disorders, whereas those resulting from a change in PCO2 are termed respiratory acid-base disorders. The kidneys are primarily responsible for regulating [HCO3 −], whereas the lungs regulate PCO2.


Physiology_Levy

Physiology_Levy. When an acid-base disturbance develops, the body uses several mechanisms to defend against the change in ECF pH. These defense mechanisms do not correct the acid-base disturbance but merely minimize the change in pH imposed by the disturbance. Restoration of the blood pH to its normal value requires correction of the underlying process or processes that produced the acid-base disorder. The body has three general mechanisms to defend against changes in body fluid pH produced by acid-base disturbances: (1) extracellular and intracellular buffering, (2) adjustments in blood PCO2 via alterations in the ventilatory rate of the lungs, and (3) adjustments in RNAE. The first line of defense against acid-base disorders is extracellular and intracellular buffering. The response of the extracellular buffers is virtually instantaneous, whereas the response to intracellular buffering is slower and can take several minutes.


Physiology_Levy

Physiology_Levy. Metabolic disorders that result from addition of nonvolatile acid or alkali to body fluids are buffered in both the extracellular and intracellular compartments. The HCO3 − buffer system is the principal ECF buffer. When nonvolatile acid is added to body fluids (or alkali is lost from the body), HCO3 − is consumed during the process of neutralizing the acid load, and the [HCO3 −] of ECF is reduced. Conversely, when nonvolatile alkali is added to body fluids (or acid is lost from the body), H+ is consumed, causing more HCO3 − to be produced from the dissociation of H2CO3. Consequently, [HCO3 −] increases.


Physiology_Levy

Physiology_Levy. Although the HCO3 − buffer system is the principal ECF buffer, Pi and plasma proteins provide additional extracellular buffering. The combined action of the buffering processes for HCO3 − , Pi, and plasma protein accounts for approximately 50% of the buffering of a nonvolatile acid load and 70% of a nonvolatile alkali load. The remainder of the buffering under these two conditions occurs intracellularly. Intracellular buffering involves movement of H+ into cells (during buffering of nonvolatile acid) or movement of H+ out of cells (during buffering of nonvolatile alkali). H+ is titrated inside the cell by HCO3 − , Pi, and the histidine groups on proteins. Bone represents an additional source of extracellular buffering. However, with acidosis, buffering by bone results in its demineralization.


Physiology_Levy

Physiology_Levy. Bone represents an additional source of extracellular buffering. However, with acidosis, buffering by bone results in its demineralization. When respiratory acid-base disorders occur, the pH of body fluid changes as a result of alterations in PCO2. Virtually all buffering in respiratory acid-base disorders occurs intracellularly. When PCO2 rises (respiratory acidosis), CO2 moves into the cell, where it combines with H2O to form H2CO3. H2CO3 then dissociates to H+ and HCO3 − . Some of the H+ is buffered by cellular proteins, and HCO3 − exits the cell and raises the ECF [HCO3 −]. This process is reversed when PCO2 is reduced (respiratory alkalosis). Under this condition the hydration reaction (H2O + CO2 ↔ H2CO3) is shifted to the left by the decrease in PCO2. As a result the dissociation reaction (H2CO3 ↔ H++ HCO3 −) also shifts to the left, thereby reducing the ECF [HCO3 −].


Physiology_Levy

Physiology_Levy. The lungs are the second line of defense against acid-base disorders. As indicated by the Henderson-Hasselbalch equation (see Eq. 37.2 ), changes in PCO2 alter the blood pH: a rise decreases the pH, and a reduction increases the pH. The ventilatory rate determines the PCO2. Increased ventilation decreases PCO2, whereas decreased ventilation increases it (Fig. 37.8 ). The blood PCO2 and pH are important regulators of the ventilatory rate. Chemoreceptors located in the brainstem (ventral surface of the medulla) and periphery (carotid and aortic bodies) sense changes in PCO2 and [H+] and alter the ventilatory rate appropriately. Thus when metabolic acidosis occurs, a rise in the [H+] (decrease in pH) stimulates the ventilatory rate. Conversely, during metabolic alkalosis, a decreased [H+] (increase in pH) reduces the ventilatory rate. With maximal hyperventilation, the PCO2 can be reduced to approximately •Fig. 37.8 EffectofventilatoryrateonalveolarPCO2andthusarterialbloodPCO2.


Physiology_Levy

Physiology_Levy. 10 mm Hg. Because hypoxia, a potent stimulator of ventilation, also develops with hypoventilation, the degree to which the PCO2 can be increased is limited. In an otherwise normal individual, hypoventilation cannot raise the PCO2 above 60 mm Hg. The respiratory response to metabolic acid-base disturbances may be initiated within minutes but may require several hours to complete.


Physiology_Levy

Physiology_Levy. The third and final line of defense against acid-base disorders involves the kidneys. In response to an alteration in plasma pH and PCO2, the kidneys make appropriate adjustments in the excretion of RNAE. The renal response may require several days to reach completion because it takes hours to days to increase the synthesis and activity of the proximal tubule enzymes involved in NH4 + production. In the case of acidosis (increased [H+] or PCO2), the secretion of H+ by the nephron is stimulated and the entire filtered load of HCO3 − is reabsorbed. Titratable acid excretion is increased and production and excretion of NH4 + is also stimulated, and thus RNAE is increased ( Fig. 37.9). The new HCO3 − generated during the process of net acid excretion is added to the body, and the plasma [HCO3 −] increases.


Physiology_Levy

Physiology_Levy. Fig. 37.9). The new HCO3 − generated during the process of net acid excretion is added to the body, and the plasma [HCO3 −] increases. When metabolic alkalosis exists (decreased [H+]), the filtered load of HCO3 − is increased (plasma [HCO3 −] is elevated). With respiratory alkalosis (decreased PCO2), plasma [HCO3 −] is decreased and thus the filtered load is decreased. In both conditions, secretion of H+ by the nephron is inhibited. As a result, HCO3 − excretion is increased. At the same time, excretion of both titratable acid and NH4 + is decreased. Thus RNAE is decreased and HCO3 − appears in urine. Also, some HCO3 − is secreted into urine by the HCO3 −-secreting intercalated cells of the distal tubule and collecting duct. With enhanced excretion of HCO3 − , plasma [HCO3 −] decreases. •Fig. 37.9 Responseofthenephrontoacidosis.Pi,phosphate;PTH,parathyroidhormone;Rhbg&Rhcg,rhesusglycoproteins;RNAE,renalnetacidexcretion;TA,titratableacid;V,urineflowrate.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Table 37.1 summarizes the primary alterations and the subsequent compensatory or defense mechanisms of the various simple acid-base disorders. In all acid-base disorders the compensatory response does not correct the underlying disorder but simply reduces the magnitude of the change in pH. Correction of the acid-base disorder requires treatment of its cause. Types of Acid-Base Disorders Metabolic acidosis is characterized by a decreased ECF [HCO3 −] and pH. It can develop via the addition of nonvolatile acid to the body (e.g., diabetic ketoacidosis), the loss of nonvolatile base (e.g., HCO3 − loss caused by diarrhea), or failure of the kidneys to excrete titratable acid and NH4 + (e.g., renal failure). As previously described, the buffering of H+ occurs in both the ECF and ICF compartments. When the pH falls, the respiratory centers are stimulated and the ventilatory rate is increased (respiratory compensation).


Physiology_Levy

Physiology_Levy. Finally, in metabolic acidosis, RNAE is increased. This occurs via elimination of all HCO3 − from urine (enhanced reabsorption of filtered HCO3 −) and via increased titratable acid and NH4 + excretion (enhanced production of new HCO3 −). If the process that initiated the acid-base disturbance is corrected, the enhanced RNAE will ultimately return the pH and [HCO3 −] to normal. After correction of the pH, the ventilatory rate also returns to normal. Metabolic alkalosis is characterized by an increased ECF [HCO3 −] and pH. It can occur via the addition of nonvolatile base to the body (e.g., ingestion of antacids), as a result of volume contraction (e.g., hemorrhage), or more commonly from loss of nonvolatile acid (e.g., loss of gastric HCl because of prolonged vomiting). Buffering occurs predominantly in the ECF and to a lesser degree in the Respiratoryacidosis↓ Respiratoryalkalosis↑ ECF,extracellularfluid;ICF,intracellularfluid;RNAE,renalnetacidexcretion


Physiology_Levy

Physiology_Levy. Albuminisanegativelychargedmacromolecule,anditmakesaconsiderablecontributionto“unmeasuredanions.”Asaresulttheaniongapmustbeadjustedinpatientswhohaveanabnormalserum[albumin].Foreach1g/dLchangeinserum[albumin],theaniongapneedstobeadjustedinthesamedirectionby2.5mEq/L. ICF. The increase in the pH inhibits the respiratory centers, which reduces the ventilatory rate, thus the PCO2 is elevated (respiratory compensation). The renal compensatory response to metabolic alkalosis is to increase excretion of HCO3 − by reducing its reabsorption along the nephron. Normally this occurs quite rapidly (minutes to hours) and effectively. Enhanced renal excretion of HCO3 − eventually returns the pH and [HCO3 −] to normal, provided the underlying cause of the initial acid-base disturbance is corrected. When the pH is corrected, the ventilatory rate also returns to normal.


Physiology_Levy

Physiology_Levy. Respiratory acidosis is characterized by an elevated PCO2 and reduced ECF pH. It results from decreased gas exchange across the alveoli as a result of either inadequate ventilation (e.g., drug-induced depression of the respiratory centers) or impaired gas diffusion (e.g., pulmonary edema, such as occurs in cardiovascular and lung disease). In contrast to the metabolic disorders, buffering during respiratory acidosis occurs almost entirely in the ICF compartment. The increase in PCO2 and the decrease in pH stimulate both HCO3 − reabsorption by the nephron and titratable acid and NH4 + excretion (renal compensation). Together these responses increase RNAE and generate new HCO3 − . The renal compensatory response takes several days to occur. Consequently, respiratory acid-base disorders are commonly divided into acute and chronic phases. In the acute phase the time for the renal compensatory response is not sufficient, and the body relies on ICF buffering to minimize the change in pH. In


Physiology_Levy

Physiology_Levy. divided into acute and chronic phases. In the acute phase the time for the renal compensatory response is not sufficient, and the body relies on ICF buffering to minimize the change in pH. In the chronic phase, renal compensation occurs. Correction of the underlying disorder returns the PCO2 to normal and RNAE decreases to its initial level.


Physiology_Levy

Physiology_Levy. Respiratory alkalosis is characterized by a reduced PCO2 and an increased ECF pH. It results from increased gas exchange in the lungs, usually caused by increased ventilation from stimulation of the respiratory centers (e.g., via drugs or disorders of the central nervous system). Hyperventilation also occurs at high altitude and as a result of anxiety, pain, or fear. Buffering is primarily in the ICF compartment. As with respiratory acidosis, respiratory alkalosis has both acute and chronic phases reflecting the time required for renal compensation to occur. The acute phase of respiratory alkalosis reflects intracellular buffering, whereas the chronic phase reflects renal compensation. With renal compensation, the elevated pH and reduced PCO2 inhibit HCO3 − reabsorption by the nephron and reduce titratable acid and NH4 + excretion. As a result of these effects, RNAE is reduced. Correction of the underlying disorder returns the PCO2 to normal, and renal excretion of acid then increases


Physiology_Levy

Physiology_Levy. reduce titratable acid and NH4 + excretion. As a result of these effects, RNAE is reduced. Correction of the underlying disorder returns the PCO2 to normal, and renal excretion of acid then increases to its initial level.


Physiology_Levy

Physiology_Levy. Analysis of Acid-Base Disorders Analysis of an acid-base disorder is directed at identifying the underlying cause so appropriate therapy can be initiated. The patient’s medical history and associated physical findings often provide valuable clues about the nature and origin of an acid-base disorder. In addition, analysis of an arterial blood sample is frequently required. Such an analysis is straightforward if approached systematically. For example, consider the following data: pH = . The acid-base disorder represented by these values or any other set of values can be determined using the following three-step approach: 1.


Physiology_Levy

Physiology_Levy. The acid-base disorder represented by these values or any other set of values can be determined using the following three-step approach: 1. Examination of the pH. When pH is considered first, the underlying disorder can be classified as either an acidosis or an alkalosis. The defense mechanisms of the body cannot correct an acid-base disorder by themselves. Thus even if the defense mechanisms are completely operative, the change in pH indicates the acid-base disorder. In the example provided, the pH of 7.35 indicates acidosis. 2. Determination of metabolic versus respiratory disorder. Simple acid-base disorders are either metabolic or


Physiology_Levy

Physiology_Levy. 2. Determination of metabolic versus respiratory disorder. Simple acid-base disorders are either metabolic or Role of the Kidneys in the Regulation of Acid-Base Balance respiratory. To determine which disorder is present the clinician must next examine the ECF [HCO3 −] and PCO2. As previously discussed, acidosis could be the result of a decrease in [HCO3 −] (metabolic) or an increase in PCO2 (respiratory). Alternatively, alkalosis could be the result of an increase in ECF [HCO3 −] (metabolic) or a decrease in PCO2 (respiratory). For the example provided, the ECF [HCO3 −] is reduced from normal (normal = 24 mEq/L), as is the PCO2 (normal = 40 mm Hg). The disorder must therefore be metabolic acidosis; it cannot be a respiratory acidosis because the PCO2 is reduced. 3. Analysis of a compensatory response. Metabolic disorders result in compensatory changes in ventilation and thus in PCO2, whereas respiratory disorders result in compensatory changes in RNAE and thus in ECF [HCO3 −] (


Physiology_Levy

Physiology_Levy. Table 37.2 ). In an appropriately compensated metabolic acidosis, the PCO2 is decreased, whereas it is elevated in compensated metabolic alkalosis. With respiratory acidosis, compensation results in an elevation of the [HCO3 −]. Conversely, ECF [HCO3 −] is reduced in response to respiratory alkalosis. In this example, the PCO2 is reduced from normal, and the magnitude of this reduction (10 mm Hg decrease in PCO2 for an 8 mEq/L decrease in ECF [HCO3 −]) is as expected (see Table 37.2 ). Therefore the acid-base disorder is a simple metabolic acidosis with appropriate respiratory compensation. A mixed acid-base disorder reflects the presence of two or more underlying causes for the acid-base disturbance. For example, consider the following data: pH = .6 96


Physiology_Levy

Physiology_Levy. When the three-step approach is followed, it is evident that the disturbance is an acidosis that has both a metabolic component (ECF [HCO3 −] < 24 mEq/L) and a respiratory component (PCO2 > 40 mm Hg). Thus this disorder is mixed. Mixed acid-base disorders can occur, for example, in an individual who has a history of a chronic pulmonary disease such as emphysema (i.e., chronic respiratory acidosis) and who develops an acute gastrointestinal illness with diarrhea. Because diarrhea fluid contains HCO3 − , its loss from the body results in the development of metabolic acidosis.


Physiology_Levy

Physiology_Levy. A mixed acid-base disorder is also indicated when a patient has abnormal PCO2 and ECF [HCO3 −] values but the pH is normal. Such a condition can develop in a patient who has ingested a large quantity of aspirin. Salicylic acid (active ingredient in aspirin) produces metabolic acidosis and at the same time stimulates the respiratory centers, causing hyperventilation and respiratory alkalosis. Thus the patient has a reduced ECF [HCO3 −] and a reduced PCO2. (NOTE: The PCO2 is lower than would occur with normal respiratory compensation of a metabolic acidosis.) 1.


Physiology_Levy

Physiology_Levy. The kidneys maintain acid-base balance through excretion of an amount of acid equal to the amount of nonvolatile acid produced by metabolism and the quantity ingested in the diet (termed renal net acid excretion [RNAE]). The kidneys also prevent loss of HCO3 − in urine by reabsorbing virtually all the HCO3 − filtered at the glomeruli. Both reabsorption of filtered HCO3 − and excretion of acid are accomplished by secretion of H+ by the nephrons. Acid is excreted by the kidneys in the form of titratable acid (primarily as Pi) and NH4 + . Both titratable acid and NH4 + excretion result in generation of new HCO3 − , which replenishes the ECF HCO3 − lost during neutralization of nonvolatile acids. 2. The body uses three lines of defense to minimize the impact of acid-base disorders on body fluid pH: (1) ECF and ICF buffering, (2) respiratory compensation, and (3) renal compensation.


Physiology_Levy

Physiology_Levy. 2. The body uses three lines of defense to minimize the impact of acid-base disorders on body fluid pH: (1) ECF and ICF buffering, (2) respiratory compensation, and (3) renal compensation. Curthoys NP. Renal ammonium ion production and excretion. In: Alpern RJ, et al., eds. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology. 5th ed. Waltham, MA: Elsevier; 2013. Dubose TD Jr. Disorders of acid-base balance. In: Taal MW, et al., eds. Brenner and Rector’s The Kidney. 9th ed. Philadelphia: Saunders; 2012. Hamm LL, et al. Cellular mechanisms of renal tubule acidification. In: Alpern RJ, et al., eds. Seldin and Giebisch’s The Kidney: Physiology and Pathophysiology. 5th ed. Waltham, MA: Elsevier; 2013. Weiner ID, Verlander JW. Renal acidification mechanisms. In: Taal MW, et al., eds. Brenner and Rector’s The Kidney. 9th ed. Philadelphia: Saunders; 2012. Berend K, et al. Physiological approach to assessment of acid-base disturbances. N Engl J Med. 2014;371:1434-1445. 3.


Physiology_Levy

Physiology_Levy. Berend K, et al. Physiological approach to assessment of acid-base disturbances. N Engl J Med. 2014;371:1434-1445. 3. Metabolic acid-base disorders result from primary alterations in ECF [HCO3 −], which in turn results from addition of acid to or loss of alkali from the body. In response to metabolic acidosis, pulmonary ventilation is increased, which decreases PCO2. The pulmonary response to metabolic acid-base disorders occurs in a matter of minutes. RNAE is also increased, but this takes several days. An increase in ECF [HCO3 −] causes alkalosis. This rapidly (minutes to hours) decreases pulmonary ventilation, which elevates PCO2 as a compensatory response. RNAE is also decreased, but this takes several days. 4.


Physiology_Levy

Physiology_Levy. 4. Respiratory acid-base disorders result from primary alterations in PCO2. Elevation of PCO2 produces acidosis, and the kidneys respond with an increase in RNAE. Conversely, a reduction of PCO2 produces alkalosis, and RNAE is reduced. The kidneys respond to respiratory acid-base disorders over several hours to days. Breton S, Brown D. Regulation of liminal acidification by the V-ATPase. Physiology (Bethesda). 2013;28:318-329. Brown D, Wagner CA. Molecular mechanisms of acid-base sensing in the kidney. J Am Soc Nephrol. 2012;23:774-780. Curthoys NP, Moe OW. Proximal tubule function and response to acidosis. Clin J Am Soc Nephrol. 2014;9:1627-1638. Hamm LL, et al. Acid-base homeostasis. Clin J Am Soc Nephrol. 2015;10:2232-2242. Levin LR, Buck J. Physiological roles of acid-base sensors. Annu Rev Physiol. 2015;77:347-362. Roy A, et al. Collecting duct intercalated cell function and regulation. Clin J Am Soc Nephrol. 2015;10:305-324.


Physiology_Levy

Physiology_Levy. Roy A, et al. Collecting duct intercalated cell function and regulation. Clin J Am Soc Nephrol. 2015;10:305-324. Seifter JL. Integration of acid-base and electrolyte disorders. N Engl J Med. 2014;371:1821-1831. Weiner ID, Verlander JW. Ammonia transport in the kidney by rhesus glycoproteins. Am J Physiol Renal Physiol. 2014;306:F1107-F1120. SECTION 8The Endocrine and Reproductive Systems BRUCE A. WHITE AND JOHN R. HARRISON Chapter 39 Hormonal Regulation of Energy Metabolism Introduction to the Endocrine System Chapter 40 Hormonal Regulation of Calcium and Phosphate Metabolism Chapter 41 The Hypothalamus and Pituitary Gland The Thyroid Gland The Adrenal Gland Chapter 44 The Male and Female Reproductive Systems Upon completion of this chapter, the student should be able to answer the following questions: 1. Name the major endocrine glands and their hormonal product or products. 2.


Physiology_Levy

Physiology_Levy. Upon completion of this chapter, the student should be able to answer the following questions: 1. Name the major endocrine glands and their hormonal product or products. 2. Map out and differentiate a simple endocrine negative feedback loop and one involving the hypothalamus, anterior pituitary and peripheral endocrine gland, and list the major endocrine glands under each type of feedback loop. 3. Define a releasing hormone and a tropic hormone. 4. Explain the chemical nature and the characteristics of protein/peptide hormones, catecholamine hormones, steroid hormones, and iodothyronines (thyroid hormones). Include such characteristics as site of regulation (synthesis or secretion), circulating form of hormone, subcellular localization of hormone receptor, and metabolic clearance. 5. Integrate the concept of peripheral conversion with the function/action of a secreted hormone. 6. Integrate the intracellular steps associated with a hormone response in a target cell.


Physiology_Levy

Physiology_Levy. 5. Integrate the concept of peripheral conversion with the function/action of a secreted hormone. 6. Integrate the intracellular steps associated with a hormone response in a target cell. he ability of cells to communicate with each other is an underpinning of human biology. As discussed in , cell-to-cell communication exists at various levels of complexity and distance. Endocrine signaling involves (1) the regulated secretion of an extracellular signaling molecule, called a hormone, into the extracellular fluid; (2) diffusion of the hormone into the vasculature and its circulation throughout the body; and (3) diffusion of the hormone out of the vascular compartment into the extracellular space and binding to a specific receptor within cells of a target organ. Because of the spread of hormones throughout the body, one hormone often regulates the activity of several target organs. Conversely, cells frequently express receptors for multiple hormones.


Physiology_Levy

Physiology_Levy. The endocrine system is a collection of glands whose function is to regulate multiple organs within the body to (1) meet the growth and reproductive needs of the organism and (2) respond to fluctuations within the internal environment, including various types of stress. The endocrine system comprises the following major glands ( Fig. 38.1 Endocrine tissues of the pancreas Parathyroid glands Pituitary gland (in association with hypothalamic nuclei) Gonads (testes or ovaries) These endocrine glands synthesize and secrete bioactive hormones and, with the exception of gonads, which perform both endocrine and gametogenic functions, are dedicated to hormone production ( Table 38.1 ). A transitory organ, the placenta, also performs a major endocrine function. In addition to dedicated endocrine glands, there are endocrine cells within organs whose primary function is not endocrine (see


Physiology_Levy

Physiology_Levy. In addition to dedicated endocrine glands, there are endocrine cells within organs whose primary function is not endocrine (see Table 38.1 ). These include cells within the heart that produce atrial natriuretic peptide, liver cells that produce insulin-like growth factor type 1 (IGF-1), cells within the kidney that produce erythropoietin, and numerous cell types within the gastrointestinal tract that produce gastrointestinal hormones. There also exist collections of cell bodies (called nuclei) within the hypothalamus that secrete peptides, called neurohormones, into capillaries associated with the pituitary gland. A third subset of the endocrine system is represented by numerous cell types that express intracellular enzymes, ectoenzymes, or secreted enzymes that modify inactive precursors or less active hormones into highly active hormones (see


Physiology_Levy

Physiology_Levy. Table 38.1). An example is the generation of angiotensin II from the inactive polypeptide angiotensinogen by two subsequent proteolytic cleavages (see ). Another example is activation of vitamin D by two subsequent hydroxylation reactions in the liver and kidneys to produce the highly bioactive hormone 1,25-dihydroxyvitamin D (vitamin D). Configuration of Feedback Loops Within the Endocrine System The predominant mode of a closed feedback loop among endocrine glands is negative feedback. In a negative feedback loop, a hormone acts on one or more target organs to induce a change (either a decrease or increase) in circulating levels of a specific component, and the change in this component then inhibits secretion of the hormone. Negative feedback loops confer stability by keeping a physiological parameter (e.g., blood glucose level) within a normal range. There are also a few examples of positive feedback


Physiology_Levy

Physiology_Levy. CHAPTER 38 Introduction to the Endocrine System 687 • Fig. 38.1 Glands of the endocrine system. in endocrine regulation. A closed positive feedback loop, in which a hormone increases levels of a specific component and this component stimulates secretion of the hormone, confers instability. Under the control of positive feedback loops, something has got to give; for example, positive feedback loops control processes that lead to rupture of a follicle through the ovarian wall or expulsion of a fetus from the uterus. There are two basic configurations of negative feedback loops within the endocrine system: a physiological response–driven feedback loop (referred to simply as a response-driven feedback loop) and an endocrine axis–driven feedback loop ( Fig. 38.2).


Physiology_Levy

Physiology_Levy. The response-driven feedback loop is observed in endocrine glands that control blood glucose levels (pancreatic islet cells), blood Ca++ and Pi levels (parathyroid glands, kidneys), blood osmolarity and volume (hypothalamus/posterior pituitary gland), and blood Na+ , K+ , and H+ levels (zona glomerulosa of the adrenal cortex and atrial cells). In the response-driven configuration, secretion of a hormone is stimulated or inhibited by a change in the level of a specific extracellular parameter (e.g., an increase in blood glucose level stimulates insulin secretion). Alterations in hormone levels lead to changes in the physiological characteristics of target organs (e.g., decreased hepatic gluconeogenesis, increased uptake of glucose by muscle) that directly regulate the parameter (in this case, blood glucose level) in question. The change in the parameter (decreased blood glucose level) then inhibits further secretion of the hormone (i.e., insulin secretion drops as blood glucose level


Physiology_Levy

Physiology_Levy. blood glucose level) in question. The change in the parameter (decreased blood glucose level) then inhibits further secretion of the hormone (i.e., insulin secretion drops as blood glucose level falls).


Physiology_Levy

Physiology_Levy. Much of the endocrine system is organized into endocrine axes; each axis consists of the hypothalamus, the pituitary gland, and the peripheral endocrine glands (see


Physiology_Levy

Physiology_Levy. Fig. 38.2 ). Thus the endocrine axis–driven feedback loop involves a three-tiered configuration. The first tier is represented by hypothalamic neuroendocrine neurons that secrete releasing hormones. Releasing hormones stimulate (or, in a few cases, inhibit) the production and secretion of tropic hormones from the pituitary gland (second tier). Tropic hormones stimulate the production and secretion of hormones from peripheral endocrine glands (third tier). The peripherally produced hormones—namely, thyroid hormone, cortisol, sex steroids, and IGF-1—typically have pleiotropic actions (e.g., multiple phenotypic effects) on numerous cell types. However, in endocrine axis–driven feedback, the primary feedback loop involves feedback inhibition of pituitary tropic hormones and hypothalamic releasing hormones by the peripherally produced hormone. In contrast to response-driven feedback, the physiological responses to the peripherally produced hormone play only a minor role in regulation of


Physiology_Levy

Physiology_Levy. hormones by the peripherally produced hormone. In contrast to response-driven feedback, the physiological responses to the peripherally produced hormone play only a minor role in regulation of feedback within endocrine axis–driven feedback loops. From a clinical perspective, endocrine diseases are described as primary, secondary, or tertiary diseases (e.g., secondary hyperthyroidism, tertiary hypogonadism). Primary disease is a lesion in the peripheral endocrine gland; secondary disease is a lesion in the anterior pituitary gland; and tertiary disease is a lesion in the hypothalamus.


Physiology_Levy

Physiology_Levy. An important aspect of the endocrine axes is the ability of descending and ascending neuronal signals to modulate release of the hypothalamic releasing hormones and thereby control the activity of the axis. A major neuronal input to releasing hormone–secreting neurons comes from another region of the hypothalamus called the suprachiasmatic nucleus (SCN). SCN neurons impose a daily rhythm, called a circadian rhythm, on the secretion of hypothalamic releasing hormones and the endocrine axes that they control ( Fig. 38.3). SCN neurons represent an intrinsic circadian clock, as evidenced by the fact that they demonstrate a spontaneous peak of electrical activity at the same time every 24 to 25 hours. The 24-to 25-hour cycle can be “entrained” by the normal environmental light-dark cycle created by the earth’s rotation, so that the periodicity of the clock appears to be environmentally controlled ( Fig. 38.4 Hormones Produced to a Significant Degree by Peripheral Conversion


Physiology_Levy

Physiology_Levy. Fig. 38.4 Hormones Produced to a Significant Degree by Peripheral Conversion LungsAngiotensinIIKidney1,25-DihydroxyvitaminD(vitaminD)Adipose,mammaryglands,otherorgansEstradiol-17β Liver,sebaceousgland,otherorgansTestosteroneGenitalskin,prostate,otherorgans5-Dihydrotestosterone(DHT)ManyorgansTriiodothyronine •Fig. 38.2 Physiologicalresponse–drivenandendocrineaxis–drivennegativefeedbackloops.Endocrine gland Pituitary gland Releasing hormone Peripheral endocrine gland Hormone Hormone Negative feedback Negative feedback Circulating component (e.g., blood glucose) Tropic hormone Physiological effects Physiological effects Hypothalamic neuroendocrine neurons Target organ(s) Target organs ENDOCRINE AXIS–DRIVEN NEGATIVE FEEDBACK PHYSIOLOGICAL RESPONSE–DRIVEN NEGATIVE FEEDBACK


Physiology_Levy

Physiology_Levy. Neural input is generated from specialized light-sensitive retinal cells that are distinct from rods and cones and from signals to the SCN via the retinohypothalamic tract. Under constant conditions of light or dark, however, the SCN clock becomes “free running” and slightly drifts away from a 24-hour cycle each day. The pineal gland forms a neuroendocrine link between the SCN and various physiological processes that require circadian control. This tiny gland, close to the hypothalamus, synthesizes the hormone melatonin from the neurotransmitter serotonin, of which tryptophan is the precursor. The rate-limiting enzyme for melatonin synthesis is N-acetyltransferase. The amount and activity of this enzyme in the pineal gland vary markedly in a cyclic manner, which accounts for the cycling of melatonin secretion and its plasma levels. Synthesis of melatonin is inhibited by light and markedly stimulated by darkness (see


Physiology_Levy

Physiology_Levy. Fig. 38.4 ). Thus melatonin may transmit the information that nighttime has arrived, and body functions are regulated accordingly. Melatonin feedback to the SCN at dawn or dusk may also help evoke day-night entrainment of the SCN 24to 25-hour clock. Melatonin has numerous other actions, including induction of sleep.


Physiology_Levy

Physiology_Levy. Another important input to hypothalamic neurons and the pituitary gland is stress, either as systemic stress (e.g., hemorrhage, inflammation) or as processive stress (e.g., fear, anxiety). Major medical or surgical stress overrides the circadian clock and causes a pattern of persistent and exaggerated hormone release and metabolism that mobilizes endogenous fuels, such as glucose and free fatty acids, and augments their delivery to critical organs. Growth and reproductive processes, in contrast, are suppressed. In addition, cytokines released during inflammatory or immune responses, or both, directly regulate the release of hypothalamic releasing hormones and pituitary hormones. Chemical Nature of Hormones


Physiology_Levy

Physiology_Levy. Chemical Nature of Hormones Hormones are classified biochemically as proteins/peptides, catecholamines, steroid hormones, or iodothyronines. The chemical nature of a hormone determines (1) how it is synthesized, stored, and released; (2) how it is transported in blood; (3) its biological half-life and mode of clearance; and (4) its cellular mechanism of action. Protein and peptide hormones can be grouped into structurally related molecules that are encoded by gene families. Protein/peptide hormones obtain their specificity from their primary amino acid sequence and from posttranslational modifications, especially glycosylation. Because protein/peptide hormones are destined for secretion outside the cell, their synthesis and processing are differently from those of proteins destined to remain within the cell or to be continuously added to the membrane (


Physiology_Levy

Physiology_Levy. Fig. 38.5 ). These hormones are synthesized on the polyribosome as larger preprohormones or prehormones. The nascent peptides have at their N-terminus a group of 15 to 30 amino acids called the signal peptide. The signal peptide interacts with a ribonucleoprotein particle, which ultimately directs the growing peptide chain through a pore •Fig. 38.4 Originofcircadianrhythmsinendocrineglandsecretion,metabolicprocesses,andbehavioralactivity.(ModifiedfromTurekFW.Recent Prog Horm Res. 1994;49:43.) a membrane-bound secretory vesicle that is subsequently released into the cytoplasm. The carbohydrate moiety of glycoproteins is added in the Golgi apparatus. Most hormones are produced as prohormones. Prohormones harbor the peptide sequence of the active hormone within their primary sequence. However, prohormones are inactive or less active and require the action of endopeptidases to trim away the neighboring inactive sequences.


Physiology_Levy

Physiology_Levy. D Plasma ACTH Protein/peptide hormones are stored in the gland as membrane-bound secretory vesicles and are released by exocytosis through the regulated secretory pathway. Thus these hormones are not continually secreted. Rather, they are secreted in response to a stimulus through a mechanism of stimulus-secretion coupling. Regulated exocytosis requires energy, Ca++ , an intact cytoskeleton (microtubules, microfilaments), and the presence of coat proteins that specifically deliver secretory vesicles to the cell membrane.


Physiology_Levy

Physiology_Levy. The ultrastructure of protein hormone–producing cells is characterized by abundant rough endoplasmic reticulum and Golgi membranes and the presence of secretory vesicles •Fig. 38.3 Acircadianpacemakerdirectsnumerousendocrineand bodyfunctions,eachwithitsowndailyschedule.Thenighttimerise inplasmamelatoninmaymediatecertainothercircadianpatterns.ACTH,adrenocorticotropichormone.(DatafromSchwartzWJ.Adv Intern Med. 1994;38:81.) in the membrane of the endoplasmic reticulum located on the cisternal (i.e., inner) surface of the endoplasmic reticular membrane. Removal of the signal peptide by a signal peptidase generates a hormone or prohormone, which is then transported from the cisternae of the endoplasmic reticulum to the Golgi apparatus, where it is packaged into ( Fig. 38.6


Physiology_Levy

Physiology_Levy. Fig. 38.6 Protein/peptide hormones are soluble in body fluids and, with the notable exceptions of IGFs and growth hormone, circulate in blood predominantly in an unbound form and therefore have short biological half-lives. Protein hormones are removed from blood primarily by endocytosis and lysosomal degradation of hormone-receptor complexes (see the section “ Cellular Responses to Hormones”). Many protein hormones are small enough to appear in urine in a physiologically active form. For example, follicle-stimulating hormone and luteinizing hormone are present in urine.


Physiology_Levy

Physiology_Levy. Fig. 38.5 Schematic Representation of Peptide Hormone Synthesis. Inthenucleus,theprimarygenetranscript,amessengerRNAprecursormolecule,undergoesexcisionofintrons,splicingofexons,cappingofthe5′ end,andadditionofpolyadenylation(poly-A)atthe3′ end.TheresultantmaturemessengerRNAentersthecytoplasm,whereitdirectsthesynthesisofapreprohormonepeptidesequenceonribosomes.Inthisprocess,theN-terminussignalisremoved,andtheresultantprohormoneistransferredvectoriallyintotheendoplasmicreticulum.TheprohormoneundergoesfurtherprocessingandpackagingintheGolgiapparatus.Afterfinalcleavageoftheprohormonewithinthegranules,theycontainthehormoneandcopeptidesreadyforsecretionbyexocytosis.NH2,amidogen. Fig. 38.6 Ultrastructure of a Protein Hormone–Producing Cell. Notethepresenceofsecretoryvesiclesandroughendoplasmicreticulumintheproteinhormone–secretingcell.(FromKierszenbaumAL.Histology and Cell Biology: An Introduction to Pathology. 2nded.Philadelphia:Mosby;2007.) •Fig. 38.7 Chemicalstructuresofcatecholamines.


Physiology_Levy

Physiology_Levy. Proteins/peptides are readily digested in the gastrointestinal tract if administered orally. Hence they must be administered by injection or, in the case of small peptides, through a mucous membrane (sublingually or intranasally). Because proteins/peptides do not cross cell membranes readily, they signal through membrane receptors (see Catecholamines are synthesized by the adrenal medulla and neurons and include norepinephrine, epinephrine, and dopamine (


Physiology_Levy

Physiology_Levy. Fig. 38.7 ). The primary hormonal products of the adrenal medulla are epinephrine and, to a lesser extent, norepinephrine. Catecholamines obtain their specificity through enzymatic modifications of the amino acid tyrosine. Catecholamines are stored in secretory vesicles that are part of the regulated secretory pathway. They are copackaged with adenosine triphosphate, Ca++, and proteins called chromogranins. Chromogranins play a role in the biogenesis of secretory vesicles and in the organization of components within the vesicles. Catecholamines are soluble in blood and circulate either unbound or loosely bound to albumin. They are similar to protein/peptide hormones in that they do not cross cell membranes readily and hence produce their actions through cell membrane receptors. Catecholamines have short biological half-lives (1 to 2 minutes) and are removed from blood primarily by cell uptake and enzymatic modification.


Physiology_Levy

Physiology_Levy. Steroid hormones are made by the adrenal cortex, ovaries, testes, and placenta. Steroid hormones from these glands belong to five categories: progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens. Progestins,


Physiology_Levy


Physiology_Levy

Physiology_Levy. mineralocoricoids, and glucocorticoids are 21-carbon steroids, whereas androgens are 19-carbon steroids and estrogens are 18-carbon steroids ( Table 38.2 ). Steroid hormones also include the active metabolite of vitamin D (see ), which is a secosteroid (i.e., one of the rings has an open conformation).


Physiology_Levy

Physiology_Levy. Table 38.2 ). Steroid hormones also include the active metabolite of vitamin D (see ), which is a secosteroid (i.e., one of the rings has an open conformation). Gonadotropinsarepituitaryhormones,whichareluteinizinghormoneandfollicle-stimulatinghormone.Thesehormonesareheterodimersthatconsistofacommonα subunitandauniqueβ subunit(see ).Theurineofpostmenopausalwomenisanexcellentsourceofgonadotropinsbecausepostmenopausalserumgonadotropinlevelsarehighasaresultofthelossofnegativefeedbackbyovariansteroids(see ),andthehormonesarefilteredandexcretedasintactmoleculesinurine.Athirdgonadotropinistheplacentalhormonehumanchorionicgonadotropin(hCG;see ),whichhasthesamecommonα subunitandanhCG-specificβ subunit.Itisanextremelystablehormone,andbloodhCGlevelsdoubleevery2daysduringthefirsttrimester.Accordingly,urinarylevelsofhCGalsoincreaserapidly.Pregnancy tests arebasedonimmunologicaldetectioninurineofthehCGspecificβ subunitaspartoftheintacthCGheterodimer.


Physiology_Levy

Physiology_Levy. Steroid hormones are synthesized by a series of enzymatic modifications of cholesterol, and a cyclopentanoperhydrophenanthrene ring (or a derivative thereof) serves as their core (


Physiology_Levy

Physiology_Levy. Fig. 38.8 ). The enzymatic modifications of cholesterol are of three general types: hydroxylation, dehydrogenation/ reduction, and lyase reactions. The purpose of these modifications is to produce a cholesterol derivative that is sufficiently unique to be recognized by a specific receptor. Thus progestins bind to the progesterone receptor, mineralocorticoids bind to the mineralocorticoid receptor, glucocorticoids bind to the glucocorticoid receptor, androgens bind to the androgen receptor, estrogens bind to the estrogen receptor, and the active vitamin D metabolite binds to the vitamin D receptor. The complexity of steroid hormone action is increased by the expression of multiple forms of each receptor. In addition, there is some degree of nonspecificity between steroid hormones and the receptors to which they bind. For example, glucocorticoids bind to the mineralocorticoid receptor with high affinity, and progestins, glucocorticoids, and androgens can all interact with the


Physiology_Levy

Physiology_Levy. and the receptors to which they bind. For example, glucocorticoids bind to the mineralocorticoid receptor with high affinity, and progestins, glucocorticoids, and androgens can all interact with the progesterone, glucocorticoid, and androgen receptors to some degree. As discussed later, steroid hormones are hydrophobic and pass through cell membranes easily. Accordingly, classic steroid hormone receptors are localized intracellularly and act by regulating gene expression. There is mounting evidence of the presence of plasma membrane and juxtamembrane steroid hormone receptors that mediate rapid, nongenomic actions of steroid hormones.


Physiology_Levy

Physiology_Levy. Steroidogenic cell types are defined as cells that can convert cholesterol to pregnenolone, which is the first reaction common to all steroidogenic pathways. Steroidogenic cells have some capacity for cholesterol synthesis but often obtain cholesterol from cholesterol-rich lipoproteins (low-density lipoproteins and high-density lipoproteins). Pregnenolone is then further modified by several enzymatic reactions. Because of their hydrophobic nature, steroid hormones and precursors can leave the steroidogenic cell easily and thus are not stored. Therefore, steroidogenesis is regulated at the level of uptake, storage, and mobilization of cholesterol and at the level of steroidogenic enzyme gene expression and activity. Steroids are not regulated at the •Fig. 38.8 A, Structureofcholesterol,theprecursorofsteroidhormones.B, Structureofsteroidhormones.


Physiology_Levy

Physiology_Levy. Mitochondria with tubular cristae Nucleus •Fig. 38.9 Ultrastructure of a Steroidogenic Cell. Notetheabundanceoflipiddroplets,smoothendoplasmicreticulum,andmitochondriawithtubularcristae.(FromKierszenbaumAL.Histology and Cell Biology: An Introduction to Pathology. 2nded.Philadelphia:Mosby;2007.) level of secretion of the preformed hormone. A clinical implication of this mode of secretion is that high levels of steroid hormone precursors are easily released into blood when a steroidogenic enzyme within a given pathway is inactive or absent. The ultrastructure of steroidogenic cells is distinct from proteinand catecholamine-secreting cells. Steroidogenic enzymes reside within the inner mitochondrial membrane or the membrane of the smooth endoplasmic reticulum. Thus steroidogenic cells typically contain extensive mitochondria and smooth endoplasmic reticulum ( Fig. 38.9 ). These cells also contain lipid droplets, which represent a store of cholesterol esters.


Physiology_Levy

Physiology_Levy. An important feature of steroidogenesis is that steroid hormones often undergo further modifications (apart from those involved in deactivation and excretion) after their release from the original steroidogenic cell. For example, estrogen synthesis by the ovary and placenta requires at least two cell types to complete the conversion of cholesterol to estrogen. This means that one cell secretes a precursor and a second cell converts the precursor to estrogen. There is also considerable peripheral conversion of active steroid hormones. For example, the testes secrete little estrogen. However, adipose, muscle, and other tissues express the enzyme for converting testosterone (a potent androgen) to estradiol-17β (a potent estrogen). Thus the overall production of a particular steroid hormone is equivalent to the sum of the secretion of this steroid hormone from a steroidogenic cell type and peripheral conversion of other steroids to the particular steroid hormone (


Physiology_Levy

Physiology_Levy. Fig. 38.10 ). Peripheral conversion can produce (1) a more active but similar class of hormone (e.g., conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D); (2) a less active hormone that can be reversibly activated by another tissue (e.g., conversion of cortisol to cortisone in the kidneys, followed by conversion of cortisone to cortisol in abdominal adipose tissue); or (3) a different class of hormone (e.g., conversion of testosterone to estrogen). Peripheral conversion of steroids plays an important role in several endocrine disorders (see Because of their nonpolar nature, steroid hormones are not readily soluble in blood. Therefore, steroid hormones circulate bound to transport proteins, including albumin, but also the specific transport proteins sex hormone– binding globulin and corticosteroid-binding globulin (see the section “


Physiology_Levy

Physiology_Levy. Transport of Hormones in the Circulation ”). Excretion of hormones from the body typically involves inactivating modifications, followed by glucuronide or sulfate conjugation in the liver, which is often coupled to biliary excretion. These modifications also increase the water solubility of the steroid and decrease its affinity for transport proteins, thereby allowing the inactivated steroid hormone to be excreted by the kidneys. Steroid compounds are absorbed fairly readily in the gastrointestinal tract and may therefore be administered orally. Thyroid hormones are iodothyronines (Fig. 38.11 ) that are made by the coupling of iodinated tyrosine residues through an ether linkage. Their specificity is determined by the thyronine structure, as well as by where the thyronine is iodinated. Thyroid hormones cross cell membranes by •Fig. 38.10 Peripheralconversionofsteroidhormones.


Physiology_Levy

Physiology_Levy. 3,5,3˜5˜-Tetraiodothyronine (thyroxine, or T4) 3,5,3˜-Triiodothyronine (T3) •Fig. 38.11 Structureofthyroidhormones,whichareiodothyronines. transport systems. They are stored extracellularly in the thyroid as an integral part of the glycoprotein molecule thyroglobulin. Thyroid hormones are sparingly soluble in blood and aqueous fluids and are transported in blood that is bound (>99%) to serum-binding proteins. A major transport protein is thyroid hormone–binding globulin. Thyroid hormones have long half-lives (7 days for thyroxine; 18 hours for triiodothyronine). Thyroid hormones are similar to steroid hormones in that the thyroid hormone receptor is intracellular and acts as a transcription factor. In fact, the thyroid hormone receptor belongs to the same gene family that includes steroid hormone receptors and vitamin D receptor. Thyroid hormones can be administered orally; the amount absorbed intact is sufficient for this to be an effective mode of therapy.


Physiology_Levy

Physiology_Levy. Transport of Hormones in the Circulation A significant fraction of steroid and thyroid hormones is transported in blood that is bound to plasma proteins that are produced in a regulated manner by the liver. Protein and polypeptide hormones are generally transported free in blood. The concentrations of bound hormone, free hormone, and plasma transport protein are in equilibrium. If free hormone levels drop, hormone will be released from the transport proteins. This relationship may be expressed as follows: Equation 38.1 where [H] = concentration of free hormone, [P] = concentration of plasma transport protein, [HP] = concentration of bound hormone, and K = the dissociation constant.


Physiology_Levy

Physiology_Levy. Equation 38.1 where [H] = concentration of free hormone, [P] = concentration of plasma transport protein, [HP] = concentration of bound hormone, and K = the dissociation constant. Free hormone is the biologically active form for action on the target organ, feedback control, and clearance by cellular uptake and metabolism. As a consequence, when hormonal status is evaluated, sometimes free hormone levels must be determined in addition to total hormone levels. This is particularly important because hormone transport proteins themselves are regulated by altered endocrine and disease states.


Physiology_Levy

Physiology_Levy. Protein binding serves several purposes. It prolongs the circulating half-life of the hormone. Many hormones cross cell membranes readily and would either enter cells or be excreted by the kidneys if they were not protein bound. The bound hormone represents a reservoir of hormone and, as such, can serve to buffer acute changes in hormone secretion. Some hormones, such as steroids, are sparingly soluble in blood, and protein binding facilitates their transport. Cellular Responses to Hormones


Physiology_Levy

Physiology_Levy. Cellular Responses to Hormones Hormones are also referred to as ligands, in the context of ligand-receptor binding, and as agonists, in that their binding to the receptor is transduced into a cellular response. Receptor antagonists typically bind to a receptor and lock it in an inactive state, in which the receptor is unable to induce a cellular response. Loss or inactivation of a receptor results in hormonal resistance. Constitutive activation of a receptor leads to unregulated, hormone-independent activation of cellular processes.


Physiology_Levy

Physiology_Levy. Hormones regulate essentially every major aspect of cellular function in every organ system. Hormones control the growth of cells, ultimately determining their size and competency for cell division. Hormones regulate the differentiation of cells and their ability to survive or to undergo programmed cell death. They influence cellular metabolism, the ionic composition of body fluids, and cell membrane potential. Hormones orchestrate several complex cytoskeleton-associated events, including cell shape, migration, division, exocytosis, recycling/endocytosis, and cell-cell and cell-matrix adhesion. Hormones regulate the expression and function of cytosolic and membrane proteins, and a specific hormone may determine the level of its own receptor or the receptors for other hormones.


Physiology_Levy

Physiology_Levy. Although hormones can exert coordinated, pleiotropic control on multiple aspects of cell function, any given hormone does not regulate every function in every cell type. Rather, a single hormone controls a subset of cellular functions in only the cell types that express receptors for that hormone. Thus selective receptor expression determines which cells respond to a given hormone. Moreover, the differentiated state of a cell determines how it responds to a hormone. Thus the specificity of hormonal responses resides in the structure of the hormone itself, the receptor for the hormone, and the cell type in which the receptor is expressed. Serum hormone concentrations are typically extremely low (10−11 to 10−9 mol/L). Therefore, a receptor must have high affinity, as well as specificity, for its cognate hormone.


Physiology_Levy

Physiology_Levy. How does hormone-receptor binding get transduced into a cellular response? Hormone binding to a receptor induces conformational changes in the receptor. These changes are collectively referred to as a signal. The signal is transduced into the activation of one or more intracellular messengers. Messenger molecules then bind to effector proteins, which in turn modify specific cellular functions. The combination of hormone-receptor binding (signal), activation of messengers (transduction), and regulation of one or more effector proteins is referred to as a signal transduction pathway (also called simply a signaling pathway), and the final outcome is referred to as the cellular response. Signaling pathways are usually characterized by the following properties: 1.


Physiology_Levy

Physiology_Levy. Signaling pathways are usually characterized by the following properties: 1. Multiple, hierarchical steps in which “downstream” effector proteins are dependent on and driven by “upstream” receptors, transducers, and effector proteins. This means that loss or inactivation of one or more components within the pathway leads to general resistance to the hormone, whereas constitutive activation or overexpression of components can drive a pathway in an unregulated manner. 2. Amplification of the initial hormone-receptor binding. Amplification can be so great that maximal response to a hormone is achieved when the hormone binds to a small percentage of receptors. 3.


Physiology_Levy

Physiology_Levy. 2. Amplification of the initial hormone-receptor binding. Amplification can be so great that maximal response to a hormone is achieved when the hormone binds to a small percentage of receptors. 3. Activation of multiple pathways, or at least regulation of multiple cell functions, from one hormone-receptor binding event. For example, binding of insulin to its receptor activates three separate signaling pathways. Even in fairly simple pathways (e.g., glucagon activation of adenylate cyclase), divergent downstream events allow the regulation of multiple functions (e.g., post-translational activation of glycogen phosphorylase and increased phosphoenolpyruvate carboxykinase gene transcription). 4.


Physiology_Levy

Physiology_Levy. Antagonism by constitutive and regulated negative feedback reactions. This means that a signal is dampened or terminated (or both) by opposing reactions and that loss or gain of function of opposing components can cause hormone-independent activation of a specific pathway or hormone resistance. As discussed in , hormones signal to cells through membrane or intracellular receptors. Membrane receptors have rapid effects on cellular processes (e.g., enzyme activity, cytoskeletal arrangement) that are independent of the synthesis of new protein. Membrane receptors can also rapidly regulate gene expression through either mobile kinases (e.g., cyclic adenosine monophosphate–dependent protein kinase [PKA], mitogen-activated protein kinases [MAPKs]) or mobile transcription factors (e.g., signal transducer and activator of transcription proteins [STATs], Mothers against decapentaplegic homologs [Smads]). Steroid hormones have slower, longer term effects that involve chromatin remodeling and


Physiology_Levy

Physiology_Levy. transducer and activator of transcription proteins [STATs], Mothers against decapentaplegic homologs [Smads]). Steroid hormones have slower, longer term effects that involve chromatin remodeling and changes in gene expression. Increasing evidence indicates that steroid hormones have rapid, nongenomic effects as well, but these pathways are still being elucidated.


Physiology_Levy

Physiology_Levy. The presence of a functional receptor is an absolute requirement for hormone action, and loss of a receptor produces essentially the same symptoms as loss of hormone. In addition to the receptor, there are fairly complex pathways involving numerous intracellular messengers and effector proteins. Accordingly, endocrine diseases can arise from abnormal expression or abnormal activity, or both, of any of these signal transduction pathway components. Finally, hormonal signals can be terminated in several ways, including hormone/receptor internalization, phosphorylation/ dephosphorylation, proteosomal destruction of receptor, and generation of feedback inhibitors.


Physiology_Levy

Physiology_Levy. Endocrinediseasescanbebroadlycategorizedashyperfunctionorhypofunctionofaspecifichormonalpathway.Hypofunctioncanbecausedbylackofactivehormoneorbyhormone resistance asaresultofinactivationofhormonereceptorsorpostreceptordefects.Testicular feminization syndrome isadramaticformofhormoneresistanceinwhichtheandrogenreceptorismutatedandcannotbeactivatedbyandrogens.Inpatientsinwhomthediagnosisisnotmadebeforepuberty,thetestisbecomeshyperstimulatedbecauseofabrogationofthenegativefeedbackbetweenthetestisandthepituitarygland.Theincreasedandrogenlevels 1. Endocrine signaling involves (1) regulated secretion of an extracellular signaling molecule, called a hormone, into the extracellular fluid; (2) diffusion of the hormone into the vasculature and circulation throughout the body; and (3) diffusion of the hormone out of the vascular compartment into the extracellular space and binding to a specific receptor within cells of a target organ. 2.


Physiology_Levy

Physiology_Levy. 2. The endocrine system is composed of the endocrine tissue of the pancreas, the parathyroid glands, the pituitary gland, the thyroid gland, the adrenal glands, and the gonads (testes or ovaries). 3. Negative feedback represents an important control mechanism that confers stability on endocrine systems. Hormonal rhythms are imposed on negative feedback loops. 4. Protein/peptide hormones are produced on ribosomes and stored in endocrine cells in membrane-bound secretory granules. They typically do not cross cell Bae YJ, Kratzsch J. Corticosteroid-binding globulin: modulating mechanisms of bioavailability of cortisol and its clinical implications. Best Pract Res Clin Endocrinol Metab. 2015;29:761-772.


Physiology_Levy

Physiology_Levy. Bae YJ, Kratzsch J. Corticosteroid-binding globulin: modulating mechanisms of bioavailability of cortisol and its clinical implications. Best Pract Res Clin Endocrinol Metab. 2015;29:761-772. havenodirectbiologicaleffectasaresultofthereceptordefect.However,theandrogensareperipherallyconvertedtoestrogens.Thusaffectedindividualsaregeneticallymale(i.e.,46,XY)buthaveastronglyfeminizedexternalphenotype,afemalesexualidentity,andusuallyasexualpreferenceformen(i.e.,heterosexualinrelationtosexualidentity).Treatmentinvolvesremovalofthehyperstimulatedtestes(whichresideintheabdomenandposeariskforcancer),estrogenreplacementtherapy,andcounselingforthepatientand,ifoneexists,thepartner/spousetoaddressinfertilityandsocial/psychologicaldistress. membranes readily and act through cell membrane– associated receptors. 5. Catecholamines are synthesized in the cytosol and secretory granules and do not readily cross cell membranes. They act through cell membrane– associated receptors. 6.


Physiology_Levy

Physiology_Levy. 5. Catecholamines are synthesized in the cytosol and secretory granules and do not readily cross cell membranes. They act through cell membrane– associated receptors. 6. Steroid hormones are not stored in tissues and generally cross cell membranes relatively readily. They act through intracellular receptors. 7. Thyroid hormones are synthesized in follicular cells and stored in follicular colloid as thyroglobulin. They cross cell membranes and associate with nuclear receptors. 8. Some hormones act through membrane receptors, and their responses are mediated by rapid intracellular signaling pathways. 9. Other hormones bind to nuclear receptors and act by directly regulating gene transcription.


Physiology_Levy

Physiology_Levy. 9. Other hormones bind to nuclear receptors and act by directly regulating gene transcription. Vija L, Ferlicot S, Paun D. Testicular histological and immunohistochemical aspects in a post-pubertal patient with 5 alpha-reductase type 2 deficiency: case report and review of the literature in a perspective of evaluation of potential fertility of these patients. BMC Endocr Disord. 2014;14:43. Upon completion of this chapter the student should be able to answer the following questions: 1. Explain the different requirements for and utilization by different cells of fuels during the digestive phase as opposed to the interdigestive and fasting phases. 2. Integrate the structure, synthesis, and secretion of insulin with circulating fuel levels, especially glucose. 3. Utilize the different signaling pathways regulated by insulin to link insulin to itscellular effects at the molecular level. 4.


Physiology_Levy

Physiology_Levy. 3. Utilize the different signaling pathways regulated by insulin to link insulin to itscellular effects at the molecular level. 4. Integrate the structure, synthesis, and secretion of glucagon with the levels of circulating fuels, insulin, and catecholamines. 5. Map out and integrate the actions of insulin on the utilization and storage of glucose, free fatty acids (FFAs), and amino acids (AAs) by hepatocytes, skeletal muscle, and adipocytes during the digestive phase. 6. Map out and integrate the actions of counterregulatory hormones (glucagon, catecholamines) on the utilization of glucose, the sparing of glucose, and the utilization of FFAs and AAs by hepatocytes, skeletal muscle, and adipocytes during the interdigestive and fasting phases. 7. Integrate the changes in fuel utilization and hormonal signaling in hepatocytes during the interdigestive and fasting phases that allow for and promote hepatic glucose production and ketogenesis. 8.


Physiology_Levy

Physiology_Levy. 8. Compare signaling pathways that have orexigenic and anorexigenic actions via the hypothalamus. 9. Link several pathologies related to metabolism, especially those caused by the absolute or relative absence of insulin and by obesity. Continual Energy Supply and Demand: The Challenge


Physiology_Levy

Physiology_Levy. There are an estimated 40 trillion cells in the human body, not including the approximately 40 trillion nonhuman cells that comprise the human microbiome. All these cells must continually perform work to stay alive. This work includes maintenance of cellular composition and structural integrity, along with the integrated synthesis and breakdown (i.e., turnover) of macromolecules and organelles. This work also involves the functions of cells that contribute to the human body as a whole (e.g., contraction of the muscle fibers of the diaphragm). Additional work is required of cells when the human body is engaged in a variety of activities, including (but not limited to) manual labor, exercise, and outdoor play; body growth spurt and maturation of the reproductive systems at puberty; pregnancy and breastfeeding; combating a serious infection or cancer; and the healing of damaged tissues/organs (e.g., a broken bone or healing from surgery). On average the resting metabolic rate of a


Physiology_Levy

Physiology_Levy. and breastfeeding; combating a serious infection or cancer; and the healing of damaged tissues/organs (e.g., a broken bone or healing from surgery). On average the resting metabolic rate of a relaxed, awake, stationary, healthy adult human accounts for about 70% of their total energy expenditure each day (


Physiology_Levy

Physiology_Levy. Fig. 39.1 To perform this work, cells need fuels, along with the capability to convert fuels into potential chemical energy in the form of adenosine triphosphate (ATP). Cells then convert the energy within ATP into chemical and mechanical work (see


Physiology_Levy

Physiology_Levy. Fig. 39.1 ). This means that the need for ATP is immediate and unending, and consequently all living cells must continually synthesize ATP. In fact, humans produce about the equivalent of their body weight in ATP daily. This places a demand on the body to continually supply fuel in some form to all cells. All fuel originates from the diet, but humans do not eat in a nonstop manner all day long. Thus the constant cellular demand for fuels to make ATP and perform work is paired with an intermittent intake of fuels. Diet-derived fuels are oxidized for ATP, but some are also stored for future use, and some are converted to other fuels that can be used by other cell types, depending on the metabolic phase, type of fuel, and cell type in question.


Physiology_Levy

Physiology_Levy. In trying to make sense of energy metabolism, it is important to organize one’s thinking around the following: 1. Metabolic phases. Metabolic phases refer to the hourly and daily differences in fuel usage and energy metabolism, which are dictated largely by the abundance or scarcity of certain fuels and orchestrated by phase-specific hormones. In general there are three metabolic phases ( Fig. 39.2 ): (1) the digestive or absorptive phase, which occurs during the 2 to 3 hours it takes to digest a meal; (2) the interdigestive or postabsorptive phase, which normally occurs between meals; and (3) the Sources of fuels 1. 2. Diet—Release of stored fuel during postabsorptive stage (especially during sleep on a daily basis, or during a fast or prolonged exercise)


Physiology_Levy

Physiology_Levy. Sources of fuels 1. 2. Diet—Release of stored fuel during postabsorptive stage (especially during sleep on a daily basis, or during a fast or prolonged exercise) ATP constant amount universal not stored Structural integrity Differentiated function Growth and division Response to stimuli and stress Output 60%–70% = Resting metabolic rate 25%–30% = Movement Glucose, FFAs, AAs, ketone bodies EnergyOxidation of fuels 60% Heat 40% •Fig. 39.1 Overviewofenergymetabolism.


Physiology_Levy

Physiology_Levy. •Fig. 39.2 Bloodglucoselevelsduringthethreemetabolicphases:D,digestivephase;F,fastingphase;I,interdigestivephase.B,break-fast;D,dinner;L,lunch.Red arrow indicatestheupperlimitfornormalfastingglucose;green arrow indicatesthelowerlimitfornormalfastingglucose.FFB150100BloodGlucose(mg/dL)50LDDDDII fasting phase, which most commonly occurs between the last snack before bedtime and breakfast. (In fact, physicians refer to a blood value as “fasting,” e.g., “fasting blood glucose,” if the patient abstains from eating after midnight and has blood drawn about 8 AM; prolonged fasting and starvation are more extreme forms of fasting.) Physical exertion, which imposes a heightened energy demand, is another type of metabolic phase that occurs with some frequency and regularity for some individuals. This chapter primarily compares how metabolism differs between the digestive phase and the fasting phase, and how different hormones orchestrate these metabolic differences.


Physiology_Levy

Physiology_Levy. 2, Metabolic actions of hepatocytes, adipocytes, and skeletal myocytes. All cells are involved in energy metabolism, but these three cell types have a profound impact on whole-body metabolism. Key features with respect to metabolism of these three cell types are listed in Table 39.1 3, Insulin and the counterregulatory hormones. Metabolism during the digestive phase is orchestrated almost entirely by insulin. During the fasting phase, insulin drops to low levels, and this alone allows for some of the metabolic adaptions associated with fasting. In addition, glucagon and catecholamines (epinephrine, norepinephrine) stimulate metabolic pathways that integrate the body’s response to an absence of ingested and absorbed fuels. These hormones are referred to as counterregulatory hormones based on their opposition to insulin. Growth hormone (see ) also contribute somewhat to fasting-phase metabolism. Integrated Overview of Energy Metabolism


Physiology_Levy

Physiology_Levy. Integrated Overview of Energy Metabolism Fuels enter the body from the diet during the digestive phase. Our diet includes both monomeric and polymeric forms (the latter are converted into monomeric forms during digestion and absorption) of the following fuels: (1) monosaccharides, including glucose, fructose, and galactose; (2) long-chain free fatty acids (referred to in this chapter as simply FFAs); and (3) amino acids (AAs). The diet may also include other fuels such as ethanol. Glucose,fed•UtilizationforATPphase•Storageasglycogen Glucose,fasting•Breakdownofglycogenandphasereleaseofglucoseintoblood FFA/TG,fedphase•MakeFFAsfromglucosebyDNL FFA/TG,fasting•UtilizationforATPphase•UtilizationtoproduceKBs SecretionofVLDLAAs,fedphase•Utilizationformultipleanabolic pathwaysAAs,fastingphase•Utilizationforgluconeogenesis UtilizationforketogenesisKBs,fedphase•ShouldbeabsentKBs,fastingphase•SynthesisfromFFAsandsome


Physiology_Levy

Physiology_Levy. UtilizationforketogenesisKBs,fedphase•ShouldbeabsentKBs,fastingphase•SynthesisfromFFAsandsome AA,aminoacid;ATP,adenosinetriphosphate;DNL,denovolipogenesis;FFA,freefattyacid;G3P,glycerol-3-phosphate;KB,ketonebody;TG,triglyceride;VLDL,verylow-densitylipoprotein. During the digestive phase, absorbed fuels are partitioned and used for different purposes. Insulin (discussed in detail later) regulates essentially every aspect of metabolism during the digestive phase. Glucose is the primary fuel used for energy (i.e., ATP production) during the digestive phase ( Fig. 39.3A ). Glucose is considered a universal fuel in that most cells can perform the following: 1. 2. “trap” and “activate” imported glucose by converting glucose into glucose-6-phosphate (G6P) through the activity of one or more hexokinases. G6P cannot pass through GLUT transporters (“trapping”) and is now a substrate for several enzymatic pathways (“activation”). 3.


Physiology_Levy

Physiology_Levy. metabolize G6P to pyruvate via the glycolytic pathway, which yields a small amount of ATP without requiring mitochondria or O2. Cells without mitochondria ferment pyruvate to lactate and export lactate as waste. Most cells import pyruvate into mitochondria, convert it to acetyl CoA by pyruvate dehydrogenase, and then condense acetyl CoA with oxaloacetate to form citrate. Citrate is cycled through the tricarboxylic acid (TCA) cycle back to oxaloacetate. This metabolism of pyruvate through the TCA cycle releases CO2 as waste and generates guanosine triphosphate (GTP) along with flavin adenine dinucleotide hydride (FADH2) and nicotine adenine dinucleotide hydride (NADH). FADH2 and NADH are used by the electron transport system and oxidative phosphorylation to ultimately generate relatively large amounts of ATP through a process that is absolutely dependent on O2. Cells with no or very few mitochondria (e.g., erythrocytes, lens cells of the eye) are absolutely dependent on glucose for


Physiology_Levy

Physiology_Levy. large amounts of ATP through a process that is absolutely dependent on O2. Cells with no or very few mitochondria (e.g., erythrocytes, lens cells of the eye) are absolutely dependent on glucose for energy. Additionally the brain can only use glucose under normal conditions, in that it has essentially no capacity for oxidation of FFAs and only marginal capacity for the use of lactate, ketone bodies (KBs), and AAs as fuels. Thus in all metabolic phases, maintenance of blood glucose above a certain minimal threshold is absolutely necessary to avoid central nervous system (CNS)-related symptoms, beginning with those caused by a hypoglycemia-activated autonomic response (e.g., nausea, sweating, cardiac arrhythmias). If blood glucose continues to fall, progression to symptoms caused by neuroglycopenia (e.g., cognitive dysfunction, loss of coordinated motor function, and ultimately even coma


Physiology_Levy

Physiology_Levy. RBCCNSDietG6PG6P GLY HEPATOADIPOSKM2,4,5 11 2,3 2,4,5 8 7,82,4,52,3,4,5 6 G6P G6P G3G1 1 1 1 G2 G4-mG4-mG4-m ATP A. Digestive Phase ATP ATP TG G’OL3P G6P TG GlucoseATP 6 ATP GLY ATP G6P AAs G’OL ATP ATP13 TG 11 11 12 12 FFA A,4,5 GLY ATP RBCSKMG6P KBs CNS2,4,5112 3 HEPATOFFA 9 11 10 KBs A,4,5 A,4,5 B,4,5 G4-iG4-i B,4,5 ADIPOB,4,5 GLY G6P LACT ATP G6P Glucose PROT G4-iG4-i G1G1 G3G3 G2G2 B. Fasting Phase •Fig. 39.3 A, Overview of glucose utilization during the digestive phase. GLUTtransporters:G1,GLUT1;G2,GLUT2;G3,GLUT3;G4-m,functionalGLUT4localizedtocellmembrane.Celltypes:ADIPO,adipocyte;CNS,centralnervoussystemneuronsandglia;HEPATO,hepatocyte;RBC,redbloodcell;SKM,skeletalmyocyte.Metabolites:G6P,glucose-6-phosphate;GLY,glycogen;G’OL3P,glycerol-3-phosphate;TG,triglyceride.Metabolicreactions/pathways:1,hexokinase/glucokinase;2,glycolysis;3,lactatedehydrogenase;4,TCAcycle±


Physiology_Levy

Physiology_Levy. pyruvatedehydrogenase;5,oxidativephosphorylation;6,glycogensynthesis;7,denovolipogenesis;8,esterificationofFFAstoG’OL3PtoformTG.B, Overview of energy metabolism during the fasting phase. GLUTtransporters:seelegendforA,plus:G4-I,inactiveGLUT4withintracellularlocalization.Celltypes:seelegendforAMetabolites:seelegendforA,plus:AAs,aminoacids;FFA,freefattyacid;G’OL,glycerol;KBs,ketonebodies;LACT,lactate;PROT,protein.Metabolicreactions/pathways:seelegendforA,plus:9,glycogenolysis;10,gluconeogenesis;11,G6Pase;12,ketogenesis;13,proteolysis;A,β-oxidation;B,ketolysis.


Physiology_Levy

Physiology_Levy. and death) can occur. This means that whole-body metabolism during the interdigestive and fasting phases must meet the challenge of maintaining blood glucose above 60 mg/ dL (see Fig. 39.2 , green arrow). On the other hand, glucose levels must be maintained below a certain maximal threshold (i.e., fasting blood glucose < 100 mg/dL) to avoid glucose-induced side reactions (both enzymatic and nonenzymatic) as well as osmotic imbalances that lead to multiple forms of damage to cell function (see Fig. 39.2 , red arrow).


Physiology_Levy


Physiology_Levy

Physiology_Levy. glucose tolerance, andvaluesat125mg/dLandaboveareevidenceofdiabetes mellitus.


Physiology_Levy

Physiology_Levy. Glucose is consumed by erythrocytes and the brain continually throughout all metabolic phases. In contrast, hepatocytes, skeletal myocytes, and adipocytes primarily use glucose during the digestive phase only. Insulin stimulates glycolysis and entry of pyruvate (end product of glycolysis) into the TCA cycle and oxidative phosphorylation for ATP production in hepatocytes, skeletal myocytes, and adipocytes (see Table 39.1). Hepatocytes express the GLUT2 isoform of the glucose transporter, which is not regulated by insulin for its insertion into the cell membrane. In contrast, skeletal myocytes and adipocytes express the GLUT4 isoform. Newly synthesized GLUT4 exists in an intracellular inactive state with GLUT4 storage vesicles (G4-i in Fig. 39.3B ). Insulin induces translocation of GLUT4 to the cell membrane, where it can function as an active glucose transporter (G4-m in Fig. 39.3A).


Physiology_Levy

Physiology_Levy. Fig. 39.3B ). Insulin induces translocation of GLUT4 to the cell membrane, where it can function as an active glucose transporter (G4-m in Fig. 39.3A). After its phosphorylation to G6P by glucokinase, hepatocytes convert some of the imported glucose into the storage form, glycogen, during the digestive phase (see Fig. 39.3A ). Similarly, skeletal muscle converts some of the G6P from imported glucose into glycogen. Hepatocytes can only store a finite amount of glucose as glycogen. Hepatocytes also convert excess glucose into FFAs through the process of de novo lipogenesis (DNL). These FFAs are typically esterified to glycerol-3-phosphate (G3P) to form triglyceride (TG), which accumulates as intrahepatic TG during the digestive phase (see Fig. 39.3A ). As discussed later for insulin signaling, an excessive accumulation of intrahepatic TG (i.e., fatty liver, hepatic steatosis) can result in insulin resistance.


Physiology_Levy

Physiology_Levy. Fig. 39.3A ). As discussed later for insulin signaling, an excessive accumulation of intrahepatic TG (i.e., fatty liver, hepatic steatosis) can result in insulin resistance. During the digestive phase, AAs are used in multiple anabolic pathways to regenerate degraded molecules, including other AAs, proteins, nucleotides and nucleic acids, glutathione, and complex lipids.


Physiology_Levy

Physiology_Levy. FFAs represent the most efficient fuel type in terms of ATP molecules made per carbon of fuel. However, utilization of FFAs competes effectively with glucose utilization in the mitochondria. High FFA levels during the digestive phase would promote a greater magnitude and duration of the glucose surge, thereby contributing to hyperglycemia. Thus most of the FFAs in an average meal are prevented from entering the circulation by their reesterification into TG and packaging into chylomicrons within the intestinal enterocyte. Chylomicrons are secreted, enter lymphatic vessels, and ultimately enter the blood. Once in the general circulation, chylomicrons convey the FFAs (as TG) to the adipose tissue where they are released from chylomicronassociated TG through lipolysis, imported by adipocytes, and reesterified as intracellular TG for storage (discussed in detail later).


Physiology_Levy

Physiology_Levy. During the digestive phase, hepatocytes, skeletal myocytes, and adipocytes function largely independently of each other. In contrast the actions of these three cell types become highly integrated during the fasting phase to maintain adequate blood glucose levels while providing alternative energy substrates for each cell type (see Fig. 39.3B Table 39.1


Physiology_Levy

Physiology_Levy. Fig. 39.3B Table 39.1 As stated earlier, cells without mitochondria (e.g., erythrocytes) and cells of the CNS require glucose for ATP production during all metabolic phases, and thus the body must maintain blood glucose above 60 mg/dL even days or weeks after the last ingestion of food (an exception to this rule is that the brain can use KBs [discussed later] during a prolonged fasting phase). Two general processes contribute to maintenance of blood glucose during the fasting phase: hepatic glucose production and glucose sparing. Hepatic glucose production is in turn based on two metabolic pathways. The first is the rapid catabolic process of glycogenolysis (pathway 9 in Fig. 39.3B ). Hepatocytes express the enzyme glucose-6-phosphatase (G6Pase) (pathway 11 in Fig. 39.3B ), allowing them to convert G6P back to glucose, which can then exit the cell through a bidirectional GLUT transporter. Release of glucose derived from glycogenolysis is relatively short Source of blood


Physiology_Levy

Physiology_Levy. Source of blood DietaryGluconeogenesis0 Breakfast 12.00 24.00Glycogenolysis •Fig. 39.4 Relativecontributionsofthethreesourcesofbloodglucoserelativetomealsandtimeofday.Theinsetboxstressesreplacementofglycogenolysiswithgluconeogenesisduringthefastingphase(i.e.,sleep).(AdaptedfromBaynesJW,DominiczakJH[eds].Medical Biochemistry. 3rded.Philadelphia:Mosby/Elsevier;2009.) lived because the liver glycogen supply becomes exhausted by about 8 hours. The second metabolic contribution to hepatic glucose production during the fasting phase is the gradual pathway of gluconeogenesis (pathway 10 in Fig. 39.3B ). The onset of gluconeogenesis during fasting is slower than glycogenolysis, but gluconeogenesis continues essentially nonstop throughout a fasting phase (


Physiology_Levy

Physiology_Levy. Fig. 39.3B ). The onset of gluconeogenesis during fasting is slower than glycogenolysis, but gluconeogenesis continues essentially nonstop throughout a fasting phase ( Fig. 39.4 ). Gluconeogenesis requires precursors, especially lactate, “gluconeogenic” AAs, and glycerol. How are these precursors supplied during the fasting phase? Lactate is continually produced by erythrocytes. Lactate is also produced by glycolytic skeletal muscle fibers during exercise (exercise tends to occur more frequently during the interdigestive and fasting phases as opposed to “on a full stomach”), although much of this lactate is utilized by aerobic skeletal muscle and cardiac muscle during exercise. But additionally the overall anabolism of the digestive phase switches over to a general catabolism during the fasting phase (see Fig.


Physiology_Levy

Physiology_Levy. Fig. 39.3B ). TGs within adipocytes undergo lipolysis to FFAs and glycerol, and there is a general net proteolysis with the release of AAs during the fasting state. The glycerol and gluconeogenic AAs are released from cells and circulate to the liver, where they are subsequently used for gluconeogenesis. Thus gluconeogenesis requires an integration of catabolic pathways in adipocytes and skeletal myocytes with anabolic gluconeogenesis in hepatocytes. Gluconeogenesis eventually supplants glycogenolysis and can continue as long as precursors flow into the liver.


Physiology_Levy

Physiology_Levy. Glucose sparing represents the other general process that contributes to maintenance of adequate circulating glucose levels during the fasting phase. Glucose sparing means the switching of fuel utilization from glucose to a nongluconeogenic fuel in most cell types, but especially in skeletal muscle, which represents the potentially largest single consumer of glucose. First, the uptake of glucose by skeletal muscle and adipocytes is greatly reduced because the GLUT4 transporter isoform exists in an intracellular CHAPTER 39 Hormonal Regulation of Energy Metabolism Fig. 39.3B) during the fasting phase. Thus alternative fuels need to be delivered to skeletal muscle and adipocytes. The nongluconeogenic fuels (i.e., cannot be used for gluconeogenesis by the liver) are FFAs and KBs. FFAs are Fig. 39.3B are also released after packaging of intrahepatic TGs into cussed later). KBs are produced by hepatocytes from acetyl CoA, which in turn originates from FFAs and ketogenic


Physiology_Levy

Physiology_Levy. Fig. 39.3B are also released after packaging of intrahepatic TGs into cussed later). KBs are produced by hepatocytes from acetyl CoA, which in turn originates from FFAs and ketogenic AAs, both of which become abundant during the fasting phase. Thus glucose sparing depends on catabolic adipocyte metabolism, which results in lipolysis of stored TGs and release of FFAs. FFAs are imported by hepatocytes, which use FFAs to produce acetyl CoA. Protein degradation in available for ketogenesis. High levels of intramitochondrial acetyl CoA in the hepatocyte not only provides ample carbons for ATP synthesis but serves to: (1) inhibit conver sion of pyruvate to acetyl CoA, (2) promote conversion of pyruvate to oxaloacetate for gluconeogenesis, and (3) promote synthesis of KBs (see


Physiology_Levy

Physiology_Levy. Fig. 39.3B ). After several days of fasting, the CNS can start using KBs for energy, thereby further sparing glucose for erythrocytes. Many other cell types with mitochondria use KBs along with FFAs for ATP production, especially skeletal muscle. The hormones that drive glycogenolysis, gluconeogen esis, lipogenesis, and hepatic ketogenesis as well as VLDL production by the liver during the fasting phase are glucagon and catecholamines. In the presence of low glucose, insulin levels fall, and that removes the inhibition by insulin of the secretion of another pancreatic hormone, glucagon. Thus diminished blood glucose causes a rise in the circulating glucagon-to-insulin ratio. Hepatocytes are the primary target organ of glucagon, which directly drives glyco genolysis, gluconeogenesis, FFA oxidation, and ketogenesis by the hepatocyte ( Fig. 39.5B).


Physiology_Levy

Physiology_Levy. Fig. 39.5B). from sympathetic innervation and epinephrine from the ) can reinforce the actions of glucagon. Adipocytes also express the glucagon receptor, as well as the β2-and β3-adrenergic receptors that respond to catecholamines in response to hypoglycemia, exertion, or certain stresses. Skeletal muscle is not a target of glucagon but does respond to catecholamines stimulation through β2-adrenergic receptors. Skeletal muscle is very responsive to intracellular Ca++ , which increases during physical exertion/movement, and to an increase in the intracellular adenosine monophosphate (AMP):ATP ratio, which activates AMP kinase.


Physiology_Levy

Physiology_Levy. Finally, it is important to understand that the pathways upregulated during the fasting phase are opposed by insulin-dependent pathways that are most active during the digestive phase (discussed later). Thus attenuation of insulin signaling also contributes to the ability of hepatocytes, skeletal myocytes, and adipocytes to display an integrated response to the metabolic challenges of the fasting phase. •Fig. 39.5 TheisletsofLangerhans(endocrinepancreas)fromrat.A, Pancreashistologyshowingexocrineaciniwheredigestiveenzymesareproducedtobedeliveredtotheduodenumviathepancreaticduct,andanendocrineisletwhereinsulinandglucagonareproducedanddeliveredtothecirculationuponuptakebyarichcapillarybed.B, Stainingofendocrineisletforinsulinwithinbetacells;thesearethemostnumerouscelltypeandareprimarilylocatedcentrallywithintheislet.C, Stainingofendocrineisletforglucagonwithalphacells;thesearemuchlessnumerousthanbetacellsandareprimarilylocatedalongtheperipheryoftheislet.


Physiology_Levy

Physiology_Levy. •Fig. 39.6 ProinsulinisprocessedbyprohormoneconvertasesintoamatureinsulinmoleculewithtwopeptidestrandslinkedbyH-bondsandaCpeptide.Botharesecretedinequimolarratios.(FromWhiteBA,PorterfieldSP[eds].Endocrine and Reproductive Physiology. 4thed.Philadelphia:Mosby/Elsevier;2013.)C peptide C peptide Insulin B B Converting enzymes Proinsulin “folded” S-S bonds formed Endoplasmic reticulum Golgi Secretory granule A A S S S S S S S S S S S S The islets of Langerhans constitute the endocrine pancreas ( Fig. 39.6 ). Approximately 1 million islets making up about 1% to 2% of the pancreatic mass are spread throughout the exocrine pancreas (see ). The islets are composed of several cell types, each producing a different hormone. Beta cells make up about three-fourths of the cells of the islets and produce the hormone insulin (see Fig. 39.5B ). Alpha cells account for about 10% of islet cells and secrete glucagon (see


Physiology_Levy

Physiology_Levy. Fig. 39.5B ). Alpha cells account for about 10% of islet cells and secrete glucagon (see Fig. 39.5C ). Other endocrine cell types reside within islets, but their respective hormone products are of marginal or unclear importance and thus will not be discussed further. Blood flow to the islets is somewhat autonomous from blood flow to the surrounding exocrine pancreatic tissue. Blood flow through the islets passes from beta cells, which predominate in the center of the islet, to alpha and delta cells, which predominate in the periphery (see Fig. 38.5B-C ). Consequently the first cells affected by circulating insulin are the alpha cells, in which insulin inhibits glucagon secretion.


Physiology_Levy

Physiology_Levy. Fig. 38.5B-C ). Consequently the first cells affected by circulating insulin are the alpha cells, in which insulin inhibits glucagon secretion. Insulin is the primary anabolic hormone that dominates regulation of metabolism during the digestive phase. Insulin is a protein hormone that belongs to the gene family that includes insulinlike growth factors I and II (IGF-I, IGF-II) and relaxin. The insulin gene encodes preproinsulin. Insulin is synthesized as preproinsulin, which is converted to proinsulin as the hormone enters the endoplasmic reticulum. Proinsulin is packaged in the CHAPTER 39 Hormonal Regulation of Energy Metabolism 705 4 (-) ATP of cell membrane • Fig. 39.7 Glucose is the primary stimulus of insulin secretion and is enhanced by sulfonylurea drugs as well as GLP-1 analogues/DPP-4 inhibitors. See text for explanation of numbered steps in glucose-stimulated insulin secretion (GSIS).


Physiology_Levy

Physiology_Levy. Golgi apparatus into membrane-bound secretory granules. Proinsulin contains the AA sequence of insulin plus the C (connecting) peptide. The proteases that cleave proinsulin (proprotein convertases) are packaged with proinsulin within secretory vesicles. Proteolytic processing clips out the C peptide and generates the mature hormone, which consists of two chains, an α chain and a β chain, connected by two disulfide bridges (


Physiology_Levy

Physiology_Levy. Fig. 39.7). A third disulfide bridge is contained within the α chain. Insulin is stored in secretory granules in zinc-bound crystals. On stimulation, the granule’s contents are released to the outside of the cell by exocytosis. Equimolar amounts of mature insulin and C peptide are released, along with small amounts of proinsulin. C peptide has no known biological activity but is useful in assessing endogenous insulin production. C peptide is more stable in blood than insulin (making it easier to assay) and helps distinguish endogenous insulin production from injected insulin, insofar as the latter has been purified from C peptide.