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C H A P T E R Gluconeogenesis & the Control of Blood Glucose Owen P. McGuinness, PhD 19 OBJ E C TI VE S Explain the importance of gluconeogenesis in glu...
C H A P T E R Gluconeogenesis & the Control of Blood Glucose Owen P. McGuinness, PhD 19 OBJ E C TI VE S Explain the importance of gluconeogenesis in glucose homeostasis. Describe the pathway of gluconeogenesis, how irreversible enzymes of After studying this chapter, glycolysis are bypassed, and how glycolysis and gluconeogenesis are regulated you should be able to: reciprocally. Explain how plasma glucose concentration is maintained within narrow limits in the fed and fasting states. BIOMEDICAL IMPORTANCE tissue ipoysis reeases gycero. Skeeta musce reeases ac- tate an guconeogenic amino acis. As the fast is extene Guconeogenesis is the process of synthesizing gucose from gycero an amino acis provie an increasing roe in sup- noncarbohyrate precursors. The major substrates are the pying carbon for guconeogenesis. One might think that as a gucogenic amino acis (see Chapter 29), actate, gycero, an fast progresses guconeogenesis increases even more. In fact, propionate. Liver an kiney are the major guconeogenic tissues. it oes not. This is because the gucose emans of periphera The iver is the primary guconeogenic organ. Whie the rena tissues ecrease incuing the brain. This preserves the vita cortex of the kiney may contribute about 10% of whoe boy protein stores. In the fe state guconeogenic suppy oes not guconeogenesis after a short-term fast (18-24 h), the kiney is ecrease, in fact it is eevate. The mix of carbon sources is not a net source of gucose. This is because the rena meua is ifferent. Gycero suppy ecreases because of a ecrease in a consumer of gucose. It is ony with ong-term fasting (~7 ays) ipoysis. Lactate suppy oes not ecrease primariy because that the kiney can suppy net gucose carbon to contribute of the high rates of gycoysis in skeeta musce. Amino aci to gucose homeostasis. The key guconeogenic enzymes are suppy increases as amino acis erive from ietary protein expresse in the sma intestine. Propionate arising from intes- are irecty eivere into the porta vein. During exercise actate tina bacteria fermentation of carbohyrates is a substrate for suppy from working musce heps support the increase gu- guconeogenesis in enterocytes. The intestine is not a net con- coneogenic eman of exercise. sumer of actate an aanine or gycero, the major substrates The transport an uptake of amino acis, gycero, an for guconeogenesis. It is a consumer of gucose in the fasting actate are reguate ifferenty. The iver is extremey effi- state. Thus, any gucose synthesis that occurs ocay is ikey cient at taking up gycero. Greater than 60% of gycero metaboize ocay. eivere to the iver is remove on first pass. This frac- The rate of hepatic guconeogenesis is etermine by tion remains constant in response to increase or ecrease four factors: (1) the avaiabiity of guconeogenic substrates, in insuin, gucagon, an epinephrine which are impor- (2) the capacity of the iver to take up guconeogenic sub- tant reguators of guconeogenesis. In contrast amino aci strates, (3) the quantity an activity of the guconeogenic remova is very sensitive to gucagon an to a esser extent enzymes, an (4) the oxiative capacity of the iver to not ony insuin. Gucagon is a potent stimuator of the transport suppy the energy to support the energy requiring process of of gucogenic amino acis by the iver. About 20% of these guconeogenesis but metaboize the nitrogen from the guco- amino acis are remove on first pass; first pass extraction genic amino acis (Ureagenesis; see Chapter 28). can increase to more than 60% in the presence of an increase Throughout the 24-hour feeing fasting cyce guconeo- in gucagon. Insuin can stimuate amino aci transport but genic precursors are avaiabe. In the fasting state aipose the response is much smaer than that of gucagon. Lactate uptake by the iver is compex because the iver can prouce This was aapte from the 30th eition by Davi A. Bener, PhD & actate uring high rates of gycogen breakown. However, Peter A. Mayes, PhD, DSc in the fasting state the primary river is the avaiabiity of 180 CHAPTER 19 Gluconeogenesis & the Control of Blood Glucose 181 actate. When actate is increase aong with increases in Pyruvate & Phosphoenolpyruvate gucagon the iver can become an efficient consumer of ac- Reversa of the reaction catayze by pyruvate kinase in gyco- tate, supporting the guconeogenic response, for exampe, ysis invoves two enothermic reactions. Mitochonria pyru- as is seen in exercise. vate carboxylase catayzes the carboxyation of pyruvate to In this chapter we wi tak about the guconeogenic path- oxaoacetate, an ATP-requiring reaction in which the vitamin ways an the sites of reguation. These sites are ceary impor- biotin is the coenzyme. Biotin bins CO2 from bicarbonate as tant in fine-tuning how substrates enter an fow through the carboxybiotin prior to the aition of the CO2 to pyruvate (see guconeogenic pathway. However, substrate suppy an sub- Figure 44–14). The resutant oxaoacetate is reuce to maate, strate transport can overrie this reguation by mass action. exporte from the mitochonrion into the cytoso an then For exampe, one might expect that guconeogenesis ecreases oxiize back to oxaoacetate. A secon enzyme, phospho- after a mea as insuin goes up an gucagon eve fas, which enolpyruvate carboxykinase, catayzes the ecarboxyation shou inhibit the guconeogenic enzymes. However, what is an phosphoryation of oxaoacetate to phosphoenopyru- foun is guconeogenesis persists. Deivery an transport of vate using GTP as the phosphate onor. In iver an kiney, substrates are sustaine offsetting the ownreguation of the the reaction of succinate thiokinase in the citric aci cyce enzymes. However, the iver oes not reease the guconeo- (see Chapter 16) prouces GTP (rather than ATP as in other genic-erive carbon; it iverts it into gycogen to augment tissues), an this GTP is use for the reaction of phosphoeno- mea-erive gycogen synthesis (inirect gycogen synthesis; pyruvate carboxykinase. This provies a ink between citric see Chapter 18). aci cyce activity an guconeogenesis, to prevent excessive In isease states associate with hypergycemia (eg, remova (ie, anaperosis an cataperosis have to be equa) of infection an iabetes) guconeogenesis is inappropriatey oxaoacetate for guconeogenesis, which wou impair citric increase. In critically ill patients in response to injury aci cyce activity. an infection guconeogenic suppy is very high (eevate actate, increase ipoysis, increase protein cataboism). Fructose 1,6-Bisphosphate Combine with the unerying insuin resistance an high & Fructose-6-Phosphate gucagon eves it rives guconeogenesis an inuces hyperglycemia, which is associate with poor outcomes. The conversion of fructose 1,6-bisphosphate to fructose- In insuin eficiency (iabetic ketoaciosis) as is seen in 6-phosphate, for the reversa of gycoysis, is catayze by Type 1 iabetes (see Chapter 14), in the absence of insuin fructose 1,6-bisphosphatase. Its presence etermines whether an very high gucagon the unoppose ipoysis an pro- a tissue is capabe of synthesizing gucose (or gycogen) not ony tein cataboism ampifies the hypergycemia. Hypergyce- from pyruvate but aso from triose phosphates (eg, gycero). mia eas to changes in osmoaity of boy fuis, impaire It is present in iver, kiney, an skeeta musce, but is probaby boo fow, intraceuar aciosis, an increase superoxie absent from heart an smooth musce. raica prouction (see Chapter 45), resuting in erange enotheia an immune system function an impaire Glucose-6-Phosphate & Glucose boo coaguation. The conversion of gucose-6-phosphate to gucose is cata- With iver faiure guconeogenesis is impaire an hypogy- yze by glucose-6-phosphatase. It is present in iver an cemia eveops espite the fact that substrate suppy is high an kiney (rena cortex), but absent from musce, which, there- there is severe insuin resistance an very high gucagon eves. In fore, cannot export gucose erive from gycogen into the this case, the inabiity to support energy prouction in the iver boostream. (impaire citric aci cyce fux an ureagenesis; see Chapter 16) starves the guconeogenic pathway of the energy require to sup- Glucose-1-Phosphate & Glycogen port the synthesis of gucose. The breakown of gycogen to gucose-1-phosphate is cata- yze by phosphoryase. Gycogen synthesis invoves a iffer- ent pathway via uriine iphosphate gucose an glycogen GLUCONEOGENESIS INVOLVES synthase (see Figure 18–1). GLYCOLYSIS, THE CITRIC ACID The reationships between guconeogenesis an the gyco- CYCLE, PLUS SOME SPECIAL ytic pathway are shown in Figure 19–1. After transamination or eamination, gucogenic amino acis yie either pyruvate REACTIONS or intermeiates of the citric aci cyce. Therefore, the reac- Thermodynamic Barriers Prevent a tions escribe earier can account for the conversion of both actate an gucogenic amino acis to gucose or gycogen. Simple Reversal of Glycolysis Propionate is a major precursor of gucose in ruminants; Three nonequiibrium reactions in gycoysis (see Chapter 17), it enters guconeogenesis via the citric aci cyce. After catayze by hexokinase, phosphofructokinase, an pyruvate esterification with CoA, propiony-CoA is carboxyate to kinase, prevent simpe reversa of gycoysis for gucose syn- d-methymaony-CoA, catayze bypropionyl-CoA carboxylase, thesis (Figure 19–1). They are circumvente as foows. a biotin-epenent enzyme (Figure 19–2). Methylmalonyl-CoA 182 SECTION IV Metabolism of Carbohydrates FIGURE 19–1 Major pathways and regulation of gluconeogenesis and glycolysis in the liver. Entry points of glucogenic amino acids after transamination are indicated by arrows extended from circles (see also Figure 16–4). The key gluconeogenic enzymes are shown in double- bordered boxes. The ATP required for gluconeogenesis is supplied by the oxidation of fatty acids. Propionate is important only in ruminants. Arrows with wavy shafts signify allosteric effects; dash-shafted arrows, covalent modification by reversible phosphorylation. High concentrations of alanine act as a “gluconeogenic signal” by inhibiting glycolysis at the pyruvate kinase step. racemase catayzes the conversion of d-methymaony-CoA to the sie chain of choestero, an is a (reativey minor) substrate l-methymaony-CoA, which then unergoes isomerization for guconeogenesis. Methymaony-CoA mutase is a vitamin to succiny-CoA catayze by methylmalonyl-CoA mutase. In B12 -epenent enzyme, an in B12 eficiency, methymaonic nonruminants, incuing human beings, propionate arises from aci is excrete in the urine (methylmalonic aciduria). the β-oxiation of o-chain fatty acis that occur in ruminant Gycero is reease from aipose tissue as a resut of ipis (see Chapter 22), as we as the oxiation of isoeucine an ipoysis of ipoprotein triacygycero in the fe state; it may CHAPTER 19 Gluconeogenesis & the Control of Blood Glucose 183 CoA SH Acyl-CoA CO2 + H2O Propionyl-CoA CH3 synthetase CH3 carboxylase CH3 CH2 CH2 H C COO– Mg2+ Biotin COO– CO S CoA CO S CoA ATP AMP + PPi ATP ADP + Pi Propionate Propionyl-CoA D-Methyl- malonyl-CoA Methylmalonyl-CoA racemase COO– Methylmalonyl- CoA mutase CH3 CH2 Intermediates – OOC C H of citric acid cycle CH2 B12 coenzyme CO S CoA CO S CoA L-Methyl- Succinyl-CoA malonyl-CoA FIGURE 19–2 Metabolism of propionate. be use for reesterification of free fatty acis to triacygycero, antagonizes the effect of the gucocorticois an gucagon- or may be a substrate for guconeogenesis in the iver. In the stimuate cAMP, which inuce synthesis of the key enzymes fasting state, gycero reease from ipoysis of aipose tissue of guconeogenesis. triacygycero is use as a substrate for guconeogenesis in the iver an kineys. Covalent Modification by Reversible Phosphorylation Is Rapid GLYCOLYSIS & Glucagon an epinephrine, hormones that are responsive GLUCONEOGENESIS SHARE to a ecrease in boo gucose, inhibit gycoysis an stimu- ate guconeogenesis in the iver by increasing the concentra- THE SAME PATHWAY BUT IN tion of cAMP. This in turn activates cAMP-epenent protein OPPOSITE DIRECTIONS, & ARE kinase, eaing to the phosphoryation an inactivation of RECIPROCALLY REGULATED pyruvate kinase. They aso affect the concentration of fructose 2,6-bisphosphate an therefore gycoysis an guconeogen- Changes in the avaiabiity of substrates are responsibe for esis, as escribe ater. In aition, as mentione gucagon is a most changes in metaboism either irecty or inirecty act- potent stimuator of amino aci transport. ing via changes in hormone secretion. Three mechanisms are responsibe for reguating the activity of enzymes concerne in carbohyrate metaboism: (1) changes in the rate of enzyme Allosteric Modification Is Instantaneous synthesis, (2) covaent moification by reversibe phosphory- In guconeogenesis, pyruvate carboxyase, which catayzes the ation, an (3) aosteric effects. synthesis of oxaoacetate from pyruvate, requires acety-CoA as an allosteric activator. The aition of acety-CoA resuts Induction & Repression of Key Enzymes in a change in the tertiary structure of the protein, ower- ing the Km for bicarbonate. This means that as acety-CoA is Require Several Hours forme from pyruvate, it automaticay ensures the provision The changes in enzyme activity in the iver that occur uner of oxaoacetate by activating pyruvate carboxyase. The acti- various metaboic conitions are iste in Table 19–1. The vation of pyruvate carboxyase an the reciproca inhibition enzymes invove catayze physioogicay irreversibe non- of pyruvate ehyrogenase by acety-CoA erive from the equiibrium reactions. The effects are generay reinforce oxiation of fatty acis expain the action of fatty aci oxia- because the activity of the enzymes catayzing the reactions tion in sparing the oxiation of pyruvate (an hence gucose) in the opposite irection varies reciprocay (see Figure 19–1). an stimuating guconeogenesis. The reciproca reation- The enzymes invove in the utiization of gucose (ie, those of ship between these two enzymes aters the metaboic fate of gycoysis an ipogenesis) become more active when gucose pyruvate as the tissue changes from carbohyrate oxiation avaiabiity is high such as after a mea, an uner these con- (gycoysis) to guconeogenesis uring the transition from the itions the enzymes of guconeogenesis have reativey ow fe to fasting state (see Figure 19–1). A major roe of fatty aci activity. Insuin, secrete in response to increase boo gucose, oxiation in promoting guconeogenesis is to suppy the ATP enhances the synthesis of the key enzymes in gycoysis. It aso that is require for gucose synthesis. 184 SECTION IV Metabolism of Carbohydrates TABLE 19–1 Regulatory & Adaptive Enzymes Associated With Carbohydrate Metabolism Activity in Fasting Carbohydrate and Feeding Diabetes Inducer Repressor Activator Inhibitor Glycogenolysis, glycolysis, and pyruvate oxidation Glycogen synthase ↑ ↓ Insulin, glucose-6- Glucagon phosphate Hexokinase Glucose-6- phosphate Glucokinase ↑ ↓ Insulin Glucagon Phosphofructokinase-1 ↑ ↓ Insulin Glucagon 5′ AMP, fructose- Citrate, ATP, 6-phosphate, glucagon fructose 2,6-bisphosphate, Pi Pyruvate kinase ↑ ↓ Insulin, fructose Glucagon Fructose ATP, alanine, 1,6-bisphosphate, glucagon, insulin norepinephrine Pyruvate dehydrogenase ↑ ↓ CoA, NAD+, insulin, Acetyl-CoA, ADP, pyruvate NADH, ATP (fatty acids, ketone bodies) Gluconeogenesis Pyruvate carboxylase ↓ ↑ Glucocorticoids, Insulin Acetyl-CoA ADP glucagon, epinephrine Phosphoenolpyruvate ↓ ↑ Glucocorticoids, Insulin carboxykinase glucagon, epinephrine Glucose-6-phosphatase ↓ ↑ Glucocorticoids, Insulin glucagon, epinephrine Phosphofructokinase (phosphofructokinase-1) occupies activates gycogen phosphoryase, so increasing gycogenoysis. a key position in reguating gycoysis an is aso subject to A consequence of the inhibition of phosphofructokinase-1 feeback contro. It is inhibite by citrate an by norma intra- by ATP is an accumuation of gucose-6-phosphate, which in ceuar concentrations of ATP an is activate by 5′ AMP. At the turn inhibits further uptake of gucose in extrahepatic tissues norma intraceuar [ATP] the enzyme is about 90% inhibite; by inhibition of hexokinase. Remember gucokinase, which is this inhibition is reverse by 5′AMP (Figure 19–3). present in the iver, is not inhibite by gucose-6-phosphate 5′ AMP acts as an inicator of the energy status of the ce. thus aowing for high rates of gucose entry an iversion to The presence of adenylyl kinase in iver an many other tis- gycogen eposition at the same time aow for guconeogene- sues aows rapi equiibration of the reaction sis-erive carbon to be iverte to gycogen as we. 2ADP ↔ ATP + 5′ AMP Fructose 2,6-Bisphosphate Plays a Thus, when ATP is use in energy-requiring processes, resuting in the formation of ADP, [AMP] increases. A rea- Unique Role in the Regulation of tivey sma ecrease in [ATP] causes a severa fo increase in Glycolysis & Gluconeogenesis in Liver [AMP], so that [AMP] acts as a metaboic ampifier of a sma The most potent positive aosteric activator of phospho- change in [ATP], an hence a sensitive signa of the energy fructokinase-1 an inhibitor of fructose 1,6-bisphosphatase in state of the ce. The activity of phosphofructokinase-1 is thus iver is fructose 2,6-bisphosphate. It reieves inhibition of phos- reguate in response to the energy status of the ce to con- phofructokinase-1 by ATP an increases the affinity for fructose- tro the quantity of carbohyrate unergoing gycoysis prior 6-phosphate. It inhibits fructose 1,6-bisphosphatase by increasing to its entry into the citric aci cyce. At the same time, AMP the Km for fructose 1,6-bisphosphate. Its concentration is uner CHAPTER 19 Gluconeogenesis & the Control of Blood Glucose 185 + 5AMP Relative activity No AMP 0 1 2 3 4 5 ATP (mmol /L) FIGURE 19–3 The inhibition of phosphofructokinase-1 by ATP and relief of inhibition by AMP. The yellow bar shows the normal range of the intracellular concentration of ATP. both substrate (aosteric) an hormona contro (covaent It wou seem obvious that these opposing enzymes are regu- moification) (Figure 19–4). ate in such a way that when those invove in gycoysis are Fructose 2,6-bisphosphate is forme by phosphoryation active, those invove in guconeogenesis are reativey inac- of fructose-6-phosphate by phosphofructokinase-2. The same tive, since otherwise there wou be cycing between phos- enzyme protein is aso responsibe for its breakown, since it phoryate an nonphosphoryate intermeiates, with net has fructose 2,6-bisphosphatase activity. This bifunctional hyroysis of ATP. In fact in the iver futie cycing of carbon enzyme is uner the aosteric contro of fructose-6-phosphate, (1-2%) is present at a ow rate. The avantage is by having both which stimuates the kinase an inhibits the phosphatase. pathways the iver is aowe to rapiy transition from the Hence, when there is an abunant suppy of gucose, the con- fe, faste, or exercising state. In musce both phosphofruc- centration of fructose 2,6-bisphosphate increases, stimuating tokinase an fructose 1,6-bisphosphatase have some activity gycoysis by activating phosphofructokinase-1 an inhibit- at a times, so that there is inee even more wastefu sub- ing fructose 1,6-bisphosphatase. In the fasting state, gucagon strate cycing. This permits the very rapi increase in the rate stimuates the prouction of cAMP, activating cAMP-epenent of gycoysis necessary for musce contraction. At rest the rate protein kinase, which in turn inactivates phosphofructokinase-2 of phosphofructokinase activity is some 10-fo higher than an activates fructose 2,6-bisphosphatase by phosphorya- that of fructose 1,6-bisphosphatase; in anticipation of musce tion. Hence, guconeogenesis is stimuate by a ecrease in the contraction, the activity of both enzymes increases, fructose concentration of fructose 2,6-bisphosphate, which inactivates 1,6-bisphosphatase 10 times more than phosphofructokinase, phosphofructokinase-1 an reieves the inhibition of fructose maintaining the same net rate of gycoysis. At the start of musce 1,6-bisphosphatase. Xyuose 5-phosphate, an intermeiate of the contraction, the activity of phosphofructokinase increases fur- pentose phosphate pathway (see Chapter 20) activates the protein ther, an that of fructose 1,6-bisphosphatase fas, so increasing phosphatase that ephosphoryates the bifunctiona enzyme, so the net rate of gycoysis (an hence ATP formation) as much as increasing the formation of fructose 2,6-bisphosphate an increas- a 1000-fo. ing the rate of gycoysis. This eas to increase fux through gy- coysis an the pentose phosphate pathway an increase fatty aci synthesis (see Chapter 23). THE BLOOD CONCENTRATION OF GLUCOSE IS REGULATED WITHIN Substrate (Futile) Cycles Allow Fine NARROW LIMITS Tuning & Rapid Response In the postabsorptive state, the concentration of boo gucose The contro points in gycoysis an gycogen metaboism is maintaine between 4.5 an 5.5 mmo/L. After the inges- invove a cyce of phosphoryation an ephosphorya- tion of a carbohyrate mea, it may rise to 6.5 to 7.2 mmo/L, tion catayze by gucokinase an gucose-6-phosphatase; an in starvation, it may fa to 3.3 to 3.9 mmo/L. A suen phosphofructokinase-1 an fructose 1,6-bisphosphatase; pyru- ecrease in boo gucose (eg, in response to insuin overose) vate kinase, pyruvate carboxyase, an phosphoenopyruvate causes convusions, because of the epenence of the brain carboxykinase; an gycogen synthase an phosphoryase. on a suppy of gucose. However, much ower concentrations 186 SECTION IV Metabolism of Carbohydrates Glycogen Gucose is forme from two groups of compouns that glucose unergo guconeogenesis (see Figures 16–4 an 19–1): (1) those that invove a irect net conversion to gucose, incuing most Fructose-6-phosphate amino acids an propionate an (2) those that are the pro- Glucagon ucts of the metaboism of gucose in tissues. Thus, lactate, forme by gycoysis in skeeta musce an erythrocytes, is Pi cAMP transporte to the iver an kiney where it reforms gucose, which again becomes avaiabe via the circuation for oxia- cAMP-dependent tion in the tissues. This process is known as the Cori cycle, or protein kinase the lactic acid cycle (Figure 19–5). ADP In the fasting state, there is a consierabe output of aanine ATP from skeeta musce, far in excess of the amount in the musce proteins that are being cataboize. It is forme by transami- Active Inactive Gluconeogenesis F-2,6-pase F-2,6-pase nation of pyruvate prouce by gycoysis of musce gycogen, Glycolysis P Inactive Active an is exporte to the iver, where, after transamination back PFK-2 PFK-2 to pyruvate, it is a substrate for guconeogenesis. This glucose- alanine cycle (see Figure 19–5) provies an inirect way of uti- H2 O Pi izing musce gycogen to maintain boo gucose in the fasting state. The gycero reease by aipose tissue is another source Protein of guconeogenic carbon aong with the actate reease by musce. phosphatase-2 ADP Citrate The ATP require for the hepatic synthesis of gucose from Fructose 2,6 -bisphosphate pyruvate (or gycero) is forme by the oxiation of fatty acis Pi ATP erive from aipose tissue ipoysis. Gucose is aso forme F-1,6-pase PFK-1 from iver gycogen by gycogenoysis (see Chapter 18). H2O ADP Metabolic & Hormonal Mechanisms Fructose 1,6-bisphosphate Regulate the Concentration of Blood Glucose Pyruvate The maintenance of a stabe boo gucose concentration is one of the most finey reguate of a homeostatic mecha- FIGURE 19–4 Control of glycolysis and gluconeogenesis nisms, invoving the iver, extrahepatic tissues, an severa in the liver by fructose 2,6-bisphosphate and the bifunctional hormones. Liver ces are freey permeabe to gucose in either enzyme PFK-2/F-2,6-Pase (6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase). (F-1,6-Pase, fructose 1,6-bisphosphatase; PFK-1, irection (via the GLUT 2 transporter), whereas ces of extra- phosphofructokinase-1 [6-phosphofructo-1-kinase].) Arrows with hepatic tissues (apart from pancreatic β-isets) are reativey wavy shafts indicate allosteric effects. impermeabe, an their uniirectiona gucose transporters are reguate by insuin. As a resut, uptake from the boo- can be toerate if hypogycemia eveops sowy enough for stream is an important, but not rate imiting uner a settings, aaptation to occur. The boo gucose eve in birs is con- (see Chapter 14) eterminant of the utiization of gucose in sieraby higher (14 mmo/L) an in ruminants consieraby extrahepatic tissues. The roe of various gucose transporter ower (~2.2 mmo/L in sheep an 3.3 mmo/L in catte). These proteins foun in ce membranes is shown in Table 19–2. ower norma eves appear to be associate with the fact that ruminants ferment virtuay ietary carbohyrate to short- Glucokinase Is Important in Regulating chain fatty acis, an these argey repace gucose as the main metaboic fue of the tissues in the fe state. Blood Glucose After a Meal Hexokinase has a ow Km for gucose, an in the iver it is satu- rate with ow capacity an acting at a constant rate uner a BLOOD GLUCOSE IS norma conitions. It thus acts to ensure an aequate rate of DERIVED FROM THE DIET, gycoysis to meet the iver’s nees. Gucokinase is an aosteric GLUCONEOGENESIS, & enzyme with a consieraby higher apparent Km (ower affinity) for gucose, so that its activity increases with increase in the con- GLYCOGENOLYSIS centration of gucose in the hepatic porta vein (Figure 19–6). The igestibe ietary carbohyrates yie gucose, gaactose, In the fasting state, gucokinase is ocate in the nuceus. In an fructose that are transporte to the iver via the hepatic response to an increase intraceuar concentration of gu- portal vein. Gaactose an fructose are reaiy converte to cose it migrates into the cytoso, meiate by the carbohyrate gucose in the iver (see Chapter 20). response eement-bining protein (CREBP). It permits hepatic CHAPTER 19 Gluconeogenesis & the Control of Blood Glucose 187 Blood Glucose Liver Muscle Glucose-6-phosphate Glycogen Glycogen Glucose-6-phosphate Urea Pyruvate Lactate Lactate Pyruvate Tra –NH2 n –NH2 tio ns Lactate na am mi ina a Blood ns tio Tra n Pyruvate Alanine Alanine Alanine FIGURE 19–5 The lactic acid (Cori cycle) and glucose-alanine cycles. uptake of arge amounts of gucose after a carbohyrate mea, is prouce by the β ces of the isets of Langerhans in the for gycogen an fatty aci synthesis. Whie the concentration pancreas in response to hypergycemia. The β-iset ces are of gucose in the hepatic porta vein may reach 20 mmo/L after freey permeabe to gucose via the GLUT 2 transporter, a mea, that eaving the iver into the periphera circuation oes an the gucose is phosphoryate by gucokinase. There- not normay excee 8 to 9 mmo/L. Gucokinase is absent from fore, increasing boo gucose increases metaboic fux the iver of ruminants, which have itte gucose entering the through gycoysis, the citric aci cyce, an the genera- porta circuation from the intestines. tion of ATP. The increase in [ATP] inhibits ATP-sensitive At norma periphera boo gucose concentrations K+ channes, causing epoarization of the ce membrane, (4.5-5.5 mmo/L), the iver is a net proucer of gucose. How- which increases Ca2+ infux via votage-sensitive Ca2+ chan- ever, as the gucose eve rises, the output of gucose ceases, nes, stimuating exocytosis of insuin. Thus, the concen- an there is a net uptake (see Figure 14–1). tration of insuin in the boo paraes that of the boo gucose. Other substances causing reease of insuin from the pancreas incue amino acis, nonesterifie fatty acis, Insulin & Glucagon Play a Central Role ketone boies, gucagon, secretin, an the sufonyurea in Regulating Blood Glucose rugs tobutamie an gyburie. These rugs are use In aition to the irect effects of hypergycemia in to stimuate insuin secretion in Type 2 iabetes meitus enhancing the uptake of gucose into the iver, the hormone via the ATP-sensitive K+ channes. Drugs that augment insulin pays a centra roe in reguating boo gucose. It gucagon-ike-peptie signas increase cycic-AMP, which TABLE 19–2 Major Glucose Transporters Tissue Location Functions Facilitative bidirectional transporters GLUT 1 Brain, kidney, colon, placenta, erythrocytes Glucose uptake GLUT 2 Liver, pancreatic β cell, small intestine, kidney Rapid uptake or release of glucose GLUT 3 Brain, kidney, placenta Glucose uptake GLUT 4 Heart and skeletal muscle, adipose tissue Insulin-stimulated glucose uptake GLUT 5 Small intestine Absorption of fructose Sodium-dependent unidirectional transporter SGLT 1 Small intestine and kidney Active uptake of glucose against a concentration gradient 188 SECTION IV Metabolism of Carbohydrates Vmax 100 Hexokinase Tabe 19–1). Both hepatic gycogenoysis an guconeogen- esis contribute to the hyperglycemic effect of gucagon, whose actions oppose those of insuin. Most of the enog- enous gucagon (an insuin) is ceare from the circuation by the iver (Table 19–3). Activity 50 Glucokinase Other Hormones Affect Blood Glucose The anterior pituitary gland secretes hormones that ten to eevate boo gucose an therefore antagonize the action of 0 5 10 15 20 25 insuin. These are growth hormone, arenocorticotropic hor- Blood glucose (mmol/L) mone (ACTH), an possiby other “iabetogenic” hormones. Growth hormone secretion is stimuate by hypogycemia; it FIGURE 19–6 Variation in glucose phosphorylating activity ecreases gucose uptake in musce. Some of this effect may of hexokinase and glucokinase with increasing blood glucose concentration. The Km for glucose of hexokinase is 0.05 mmol/L and be inirect, since it stimuates mobiization of nonesterifie of glucokinase is 10 mmol/L. fatty acis from aipose tissue, which themseves inhibit gu- cose utiization. The glucocorticoids (11-oxysterois) are secrete by the arena cortex, an are aso synthesize in an potentiate gucose-stimuate insuin secretion. Epineph- unreguate manner in aipose tissue. They act to increase rine an norepinephrine bock the reease of insuin. Insu- guconeogenesis as a resut of enhance hepatic cataboism in acts to ower boo gucose immeiatey by enhancing of amino acis, ue to inuction of aminotransferases (an gucose transport into aipose tissue an musce by recruit- other enzymes such as tryptophan ioxygenase) an key ment of gucose transporters (GLUT 4) from the interior enzymes of guconeogenesis. In aition, gucocorticois of the ce to the pasma membrane. Athough it oes not inhibit the utiization of gucose in extrahepatic tissues. In a affect gucose transport activity in the iver, it irecty aug- these actions, gucocorticois act in a manner antagonistic ments iver gucose uptake an gycogen eposition ikey to insuin. A number of cytokines secrete by macrophages through effects on gucokinase an gycogen synthase an infitrating aipose tissue aso have insuin antagonistic phosphoryase activity. Insuin an other hormones mou- actions; together with gucocorticois secrete by aipose ate ong-term uptake as a resut of their actions on tran- tissue, this expains the insuin resistance that commony scriptiona signas to change an entire enzyme portfoio occurs in obese peope. controing gycoysis, gycogenesis, an guconeogenesis Epinephrine is secrete by the arena meua because (see Chapter 18 an Tabe 19–1). of stressfu stimui (fear, excitement, hemorrhage, hypoxia, Glucagon is the hormone prouce by the α ces of hypogycemia, etc.) an eas to gycogenoysis in iver an the pancreatic isets in response to hypogycemia. In the musce owing to stimuation of phosphoryase via generation iver, it stimuates gycogenoysis by activating gycogen of cAMP. In musce, gycogenoysis resuts in increase gyco- phosphoryase. Unike epinephrine, gucagon oes not ysis an actate reease, whereas in iver, it resuts in the reease have an effect on musce phosphoryase. Gucagon aso of gucose into the boostream. Epinephrine is a potent stim- enhances guconeogenesis from amino acis an actate. In uator of guconeogenesis because of the robust increase in a these actions, gucagon acts via generation of cAMP (see substrate suppy. TABLE 19–3 Tissue Responses to Insulin & Glucagon Liver Adipose Tissue Muscle Increased by insulin Fatty acid synthesis Glucose uptake Glucose uptake Glycogen synthesis Fatty acid synthesis Glycogen synthesis Protein synthesis Protein synthesis Fatty acid synthesis Decreased by insulin Ketogenesis Lipolysis Gluconeogenesis Increased by glucagon Glycogenolysis Lipolysis Gluconeogenesis Ketogenesis CHAPTER 19 Gluconeogenesis & the Control of Blood Glucose 189 FURTHER CLINICAL ASPECTS which wou normay be reease from aipose tissue, is avaiabe for guconeogenesis. Glucosuria Occurs When the Renal Threshold for Glucose Is Exceeded The Ability to Utilize Glucose May Be When the boo gucose concentration rises above about Ascertained by Measuring Glucose 10 mmo/L, the kiney aso exerts a (passive) reguatory effect. Gucose is continuousy fitere by the gomerui, but is nor- Tolerance may competey reabsorbe in the rena tubues by active Gucose toerance is the abiity to reguate the boo gucose transport. The capacity of the tubuar system to reabsorb gu- concentration after the aministration of a test ose of gucose cose is imite to a rate of about 2 mmo/min, an in hyper- (normay 1 g/kg boy weight) (Figure 19–7). The norma gycemia (as occurs in poory controe iabetes meitus), gucose toerance is etermine by the timing of an quan- the gomeruar fitrate may contain more gucose than can be tity of insuin secrete an the abiity of tissues to respon to reabsorbe, resuting in glucosuria when the renal threshold insuin. If a person gains weight, they become insuin resistant. for gucose is exceee. Thus a common cinica presentation Most peope who gain weight o not become gucose intoer- of iabetes is unexpaine weight oss an frequent urina- ant because their beta ces compensate an make aitiona tion. The weight oss is ue to the voume oss an subsequent insuin to maintain norma gucose toerance. However, their ehyration ue to osmotic iuresis in the kiney combine risk of eveoping iabetes increases. Cinicay, the gucose with the oss of gucose caories in the urine. toerance test is primariy use to etect gestationa iabetes. To etermine average boo gucose in a person cinicians measure gycosyation status (see Chapter 15) of hemogobin Hypoglycemia May Occur During (HbA1c), which correates with the person’s average gucose Pregnancy & in the Neonate over a 2 to 3 month perio. If it is (norma 6.5%) more than 6.5%, it is iagnostic of there is a risk of materna, an possiby feta, hypogyce- iabetes. mia, particuary if there are ong intervas between meas Diabetes mellitus (type 1, or insuin-epenent ia- or at night. Furthermore, premature an ow-birth-weight betes meitus [IDDM]) is characterize by impaire gu- babies are more susceptibe to hypogycemia, since they have cose toerance as a resut of ecrease secretion of insuin itte aipose tissue to provie nonesterifie fatty acis. The because of progressive estruction of pancreatic β-iset ces. enzymes of guconeogenesis may not be fuy eveope at this Gucose toerance is aso impaire in Type 2 iabetes mei- time, an guconeogenesis is anyway epenent on a suppy tus (noninsuin-epenent iabetes [NIDDM]) as a resut of of nonesterifie fatty acis for ATP formation. Litte gycero, reuce sensitivity of tissues to insuin action combine with 18 16 14 Plasma glucose (mmol /L) 12 10 Diabetic 8 6 4 Normal 2 0 0 1 2 3 Time after glucose load (h) FIGURE 19–7 Glucose tolerance test. Blood glucose curves of a normal and a diabetic person after oral administration of 1 g of glucose/kg body weight. Note the initial raised concentration in the fasting diabetic (>7 mM); so by definition they are diabetic without measuring glucose tolerance. If baseline glucose is in the normal range, a criterion of normal tolerance is the return to the baseline value within 2 hours. 190 SECTION IV Metabolism of Carbohydrates an impaire secretion of insuin. Insuin resistance associate met by oxiation of fatty acis. Whie this is ogica, controe with obesity (an especiay abomina obesity) eaing to the energy baance stuies emonstrate that energy expeniture is eveopment of hyperipiemia, then atheroscerosis an cor- in fact not increase. In the en a caorie is a caorie. Weight oss onary heart isease, as we as overt iabetes, is known as the occurs because they eat ess caories. The rapi weight oss com- metabolic syndrome. Impaire gucose toerance aso occurs mony seem with these iets is most ikey ue to the fact that in conitions where the iver is amage, in some infections, ow carbohyrate iets ecrease gycogen stores, which have 3 g an in response to some rugs, as we as in conitions that of water per gram of gycogen. The biggest chaenge is that stay- ea to hyperactivity of the pituitary gan or arena cortex ing on these or other extreme iets is neary impossibe. because hormones secrete by these gans antagonize the action of insuin. SUMMARY Aministration of insuin (as in the treatment of iabetes Guconeogenesis is the process of synthesizing gucose or meitus) owers the boo gucose concentration an increases gycogen from noncarbohyrate precursors. It is of particuar its utiization an storage in the iver an musce as gycogen. importance when carbohyrate is not avaiabe from the iet. An excess of insuin may cause hypoglycemia, resuting in The main substrates are amino acis, actate, gycero, an convusions an even eath uness gucose is aministere propionate. prompty. Hypogycemia upon fasting can be observe in The pathway of guconeogenesis in the iver an kiney pituitary or arenocortica insufficiency. It is ue to a ecrease utiizes those reactions in gycoysis that are reversibe pus in the antagonism to insuin an the ower guconeogenic four aitiona reactions that circumvent the irreversibe capacity of the iver. nonequiibrium reactions. Since gycoysis an guconeogenesis share the same pathway Think Otherwise: Very Low but operate in opposite irections, their activities are reguate Carbohydrate Diets Promote reciprocay. The iver reguates the boo gucose concentration after Weight Loss a mea because it contains the high Km gucokinase that Very ow carbohyrate iets, proviing ony 20 g per ay of promotes increase hepatic utiization of gucose an is carbohyrate or ess (compare with a esirabe intake of responsive to insuin. 100-120 g/ay), but permitting unimite consumption of fat Insuin is secrete as a irect response to hypergycemia; it an protein, have been promote as an effective regime for stimuates the iver to store gucose as gycogen an increases weight oss. Such iets are counter to a avice on a pruent iet uptake of gucose into extrahepatic tissues. composition for heath. Since there is a continua eman for Gucagon is secrete as a response to hypogycemia an gucose, there wi be a consierabe amount of guconeogenesis activates both gycogenoysis an guconeogenesis in the iver, from amino acis; the associate high ATP cost must then be causing reease of gucose into the boo.
