dia care 2001 renal gluconeogenesis

382 DIABETES CARE, VOLUME 24, NUMBER 2, FEBRUARY 2001

To function effectively as a source offuel in the brain, renal medulla, andnucleated blood cells and to supple-ment energy provided to other tissues(e.g., muscle and splanchnic organs) byfree fatty acids and amino acids, glucose isnormally released into the circulation ofhumans who were fasted overnight(postabsorption) at a rate of 1011 mol kg1 min1 (1). This release of glucose isthe result of one of two processes:glycogenolysis and gluconeogenesis.Glycogenolysis involves the breakdown ofglycogen to glucose-6-phosphate and itssubsequent hydrolysis by glucose-6-phos-phatase to free glucose. Gluconeogenesisinvolves the formation of glucose-6-phos-phate from precursors such as lactate, glyc-erol, and amino acids with its subsequenthydrolysis by glucose-6-phosphatase tofree glucose. Liver and skeletal musclecontain most of the bodys glycogen stores.However, because only the liver containsglucose-6-phosphatase, the breakdown ofhepatic glycogen leads to the release ofglucose, whereas the breakdown of muscleglycogen leads to the release of lactate.

This lactate and the lactate generated viaglycolysis of glucose from plasma by bloodcells, the renal medulla, and other tissuescan be absorbed by gluconeogenic organsand re-formed into glucose.

Recent studies using nuclear magneticresonance (NMR) spectroscopy of changesin hepatic glycogen content (2) indicatethat in overnight-fasted normal volunteers,net hepatic glycogenolysis occurred at arate of 5.5 mol kg1 min1 andaccounted for 45 6% of the overall releaseof glucose into the circulation, which wasmeasured isotopically. As indicated earlier,only the liver contains appreciable glycogenand glucose-6-phosphatase, making it theonly organ that can directly release glucoseas a result of glycogen breakdown. Thus,these data represent total glycogenolysisand indicate that 55% of all glucosereleased into the circulation in the postab-sorptive state is a result of gluconeogenesis.It should be pointed out that to a certainextent, this approach may lead to an over-estimation of gluconeogenesis effectsresulting from glycogen cycling and otherconsiderations (3).

Various isotopic methods have beenused to assess the proportion of overallglucose release attributable to gluconeoge-nesis in humans. The ingenious approachdeveloped by Landau et al. (4), which usesthe ratio of enrichments of the C-2 carbonto the C-5 carbon of plasma glucose afteringestion of deuterated water, appears to bethe most widely accepted. Investigatorsusing this approach have found that gluco-neogenesis accounted for 54 2% of allglucose released into the circulation ofovernight-fasted normal volunteers (5).These results are in excellent agreementwith those predicted both from NMR stud-ies of hepatic glycogen depletion (2) andfrom a stable isotope approach using indi-rect calorimetry (51 5%) (6), but they arehigher than those reported using mass iso-topomer distribution analysis during infu-sions of [2-13C]glycerol (36%) (3).

Only two organs in the human bodythe liver and the kidneypossess suffi-cient gluconeogenic enzyme activity andglucose-6-phosphatase activity to enablethem to release glucose into the circulationas a result of gluconeogenesis. As we willlater discussed, a wealth of animal experi-ments performed over the last 60 yearshave provided evidence that both the liverand the kidney release glucose into the cir-culation under a variety of conditions (7).Nevertheless, until quite recently, it wasthought that the liver was the sole site ofgluconeogenesis in normal postabsorptiveindividuals and that the kidney became animportant source of glucose only in acidoticconditions or after prolonged fasting (8). Infact, the literature is replete with publica-tions that refer to isotopic measurements ofthe overall release of glucose into the cir-culation as hepatic glucose output.

However, the concept that the liver isthe sole source of glucose, except in acidoticconditions and after prolonged fasting, hasbeen challenged on several grounds. First,the classic studies of Felig et al. (9), Wahrenet al. (10), and Ahlborg et al. (11) indicatedthat net splanchnic uptake of gluconeogenicprecursors could maximally account foronly 2025% of glucose release (not3655%), assuming that 100% of the netuptake of these precursors were incorpo-rated into glucose by the liver. Indeed, these

From the Department of Medicine (J.E.G., C.M., H.J.W.), the University of Rochester, Rochester, New York;and the University of Tubingen (M.S.), Tubingen, Germany.

Address correspondence to John E. Gerich, MD, University of Rochester School of Medicine, 601 Elm-wood Ave., Box MED/CRC, Rochester, NY 14642. E-mail: [email protected]. Address reprintrequests to Cadmus Journal Services Reprints, P.O. Box 751903, Charlotte, NC 28275-1903.

Received for publication 21 June 2000 and accepted in revised form 3 October 2000.Abbreviations: NMR, nuclear magnetic resonance.A table elsewhere in this issue shows conventional and Systme International (SI) units and conversion

factors for many substances.

Renal GluconeogenesisIts importance in human glucose homeostasis

R E V I E W A R T I C L E

Studies conducted over the last 60 years in animals and in vitro have provided considerable evi-dence that the mammalian kidney can make glucose and release it under various conditions.Until quite recently, however, it was generally believed that the human kidney was not animportant source of glucose except during acidosis and after prolonged fasting. This review willsummarize early work in animals and humans, discuss methodological problems in assessingrenal glucose release in vivo, and present results of recent human studies that provide evidencethat the kidney may play a significant role in carbohydrate metabolism under both physio-logical and pathological conditions.

Diabetes Care 24:382391, 2001

JOHN E. GERICH, MDCHRISTIAN MEYER, MD

HANS J. WOERLE, MDMICHAEL STUMVOLL, MD

R e v i e w s / C o m m e n t a r i e s / P o s i t i o n S t a t e m e n t s

DIABETES CARE, VOLUME 24, NUMBER 2, FEBRUARY 2001 383

Gerich and Associates

values might be overestimations, becauseportal venous lactate, glycerol, and aminoacid levels are generally equal to or lowerthan arterial levels (12). Second, in individ-uals undergoing liver transplantation,endogenous glucose release does not dropto zero after removal of the liver (13,14);indeed, Joseph et al. (13) (Fig. 1) reportedthat 1 h after removal of the liver, endoge-nous glucose release decreases by only50%. Finally, recent studies using a com-bination of net renal glucose balance andisotopic measurements have demonstratedthat the kidney releases significant amountsof glucose in postabsorptive normal volun-teers (7). This article resummarizes andupdates current information on humanrenal glucose metabolism as recentlyreviewed by Meyer and Gerich (7).

EARLY NONHUMAN STUDIES In 1938, Bergman andDrury (15) presented the first evidence thatthe kidney might release glucose and beimportant for maintenance of normal glucosehomeostasis. These investigators used theglucose clamp technique to maintain eugly-cemia in two groups of rabbitsone func-tionally hepatectomized and one functionallyhepatectomized and nephrectomized. Asshown in Fig. 2, functional removal of thekidneys in hepatectomized animals led to anabrupt increase in the amount of glucoserequired to maintain euglycemia, results thatwould be consistent with the hypothesis thatthe kidneys are a source of plasma glucose.

Shortly thereafter, Reinecke (16) repro-duced such results in rats, but also mea-sured arteriorenal venous glucoseconcentrations in the hepatectomized ani-mals. It was found that renal vein glucoselevels exceeded arterial levels as the animalsbecame hypoglycemic, thus demonstrat-ing that under these conditions, the kid-neys released glucose into the circulation.

Several years later, Drury et al. (17) cor-roborated this conclusion using isotopic

methods. These investigators injected 14C-labeled glucose into groups of rats that hadbeen either hepatectomized or hepatec-tomized and nephrectomized. In the formergroup, there was dilution of the plasma glu-cose 14C specific activity as the animalsbecame hypoglycemic, indicating therelease of unlabeled (i.e., endogenouslyproduced) glucose into the circulation fromsome source other than the liver. Dilution ofthe plasma specific activity of the injectedglucose did not occur in hepatectomizedanimals that had been nephrectomized,providing evidence that the source of theendogenous glucose released into the circu-lation after hepatectomy was the kidney.

Four years later, Teng (18) reported thatrenal cortical slices taken from animals withexperimentally induced diabetes releasedglucose at an increased rate, but that treat-ment of the animals with insulin couldreverse this effect. In 1960, using a similarmodel, Landau (19) demonstrated that glu-coneogenesis from pyruvate was increasedmore than twofold by the diabetic kidney.

Near that time, Krebs began a series ofexperiments characterizing the substratesused for renal gluconeogenesis (20), thecapacity of the kidney for gluconeogenesisin different species (21), and variousaspects of the regulation of renal gluco-neogenesis (22,23), including its stimula-tion by free fatty acids (24). Because thekidney had a greater concentration of glu-coneogenic enzymes (in terms of weight)

Figure 1Endogenous glucose release (EGP) before and after removal of the liver in individuals under-going liver transplantation. Reproduced from Joseph et al. (13) with permission.

Figure 2Effect of functional nephrectomy on glucose requirements to maintain euglycemia in hepa-tectomized rabbits. , Functionally nephrectomized-hepatectomized animals; , functionallyhepatectomized animals. Reproduced from Bergman and Drury (15) with permission.


Renal glucose metabolism

than the liver, and because both organshad comparable blood flows (and hencecomparable provision of gluconeogenicprecursors), Krebs hypothesized that thekidney might be as important a gluco-neogenic organ in vivo as the liver (23,25).

Given these data, one may ask why thekidney was not considered an importantsource of glucose in humans. Failure torecognize the limitations of net balanceexperiments and analytical problems areprobably the major reasons.

EARLY HUMAN STUDIES Studies of human renal glu-cose metabolism began in the late 1950s andfocused on measurements of differencesbetween arterial and renal venous glucoseconcentrations. Such experiments yieldedinformation concerning the net glucose bal-ance across the kidney, i.e., the differencebetween the production and the utilizationof glucose by the kidney. As summarized inTable 1, most investigators found little or noarteriovenous differences in glucose con-centrations in nondiabetic overnight-fastedhumans, indicating little or no net glucoserelease by the kidneys. By not taking intoconsideration the fact that the kidney simul-taneously produces and consumes glucose(see below), it was erroneously concludedthat the kidney did not release glucose inpostabsorptive humans.

In 1966, Aber et al. (26) found thatthere was net renal glucose release inpatients with pulmonary disease, whichwas negatively correlated with arterial pH(i.e., the greater the acidosis, the greater thenet renal glucose release). Shortly there-after, Owen et al. (27) demonstrated thatthere was substantial net renal glucoserelease in morbidly obese patients whofasted for 56 weeks. From these observa-tions, there evolved the current textbook

view that the liver was the sole source ofglucose, except after prolonged fasting orunder acidotic conditions. It is worth not-ing, however, that Aber et al. (26) did findnet renal glucose release in nonacidoticpulmonary patients and that Bjrkman etal. (28) found significant net renal glucoserelease in normal volunteers who fasted foronly 60 h. Nevertheless, we must empha-size that net balance measurements under-estimate renal glucose release to the extentthat the kidney takes up glucose.

PHYSIOLOGICAL CONSIDERATIONS The kidneycan be considered two separate organsbecause glucose utilization occurs predom-inantly in the renal medulla, whereas glu-cose release is confined to the renal cortex(2931). This functional partition is a resultof differences in the distribution of variousenzymes along the nephron. For example,cells in the renal medulla have appreciableglucose-phosphorylating and glycolyticenzyme activity, and, like the brain, they areobligate users of glucose (32). These cells,however, lack glucose-6-phosphatase andother gluconeogenic enzymes. Thus,although they can take up, phosphorylate,glycolyse, and accumulate glycogen, theycannot release free glucose into the circula-tion (2931). On the other hand, cells in therenal cortex possess gluconeogenic enzymes(including glucose-6-phosphatase), and thusthey can make and release glucose into thecirculation. But these cells have little phos-phorylating capacity and, under normalconditions, they cannot synthesize appre-ciable concentrations of glycogen (2931).Therefore, the release of glucose by the nor-mal kidney is mainly, if not exclusively, aresult of renal cortical gluconeogenesis,whereas glucose uptake and utilizationoccur in other parts of the kidney.

Because the kidney is both a consumerand producer of glucose, net balance mea-surements do not provide information on theindividual processes of renal glucose pro-duction and utilization. For example, let usassume that the net balance of glucose acrossthe kidney is zero (i.e., arterial and renalvenous glucose concentrations are equiva-lent), as has been commonly observed inpostabsorptive humans. Let us furtherassume that the kidney uses glucose at a rateof 100 mol/min, as has been reported inpostabsorptive humans (33). For the law ofconservation of matter to hold, the kidneymust also release glucose at a rate of 100mol/min. Thus, under these circumstances,the net balance approach will underestimaterenal glucose release. To measure renal glu-cose release in vivo, it is necessary to use acombined isotopicnet balance approach,which permits simultaneous determinationof renal glucose utilization and renal glucoserelease (see below).

One might argue that if the net renalglucose release is negligible, the kidneys arenot important, because their removal orabsence would lead to comparable decre-ments in glucose release and uptake, caus-ing no net overall change in glucosehomeostasis. This, of course, is a theoreticalconstruct that ignores the numerous meta-bolic changes that occur in the anephricstate. It also ignores the fact that renal glu-cose release and renal glucose uptake aredifferentially regulated. But more impor-tantly, it ignores the fact that the calculationof glucose release into the circulation by iso-topic techniques depends on the dilution ofthe infused isotopes specific activity (orenrichment) by the release of unlabeled glu-cose from the liver and kidney, irrespectiveof these organs uptake of glucose. Finally, itignores the consequences in situations otherthan the overnight postabsorptive state.

Table 1Early human net renal glucose balance studies

Reference Study group Finding

Meriel et al., 1958 (82) 15 postabsorptive patients with various disorders No AV differenceAber et al., 1966 (26) 10 postabsorptive patients with pulmonary disease NRGR, correlated with acidosisNieth and Schollmeyer, 1966 (44) 58 postabsorptive patients with renal disease No AV differenceOwen et al., 1969 (27) 5 obese individuals fasted 3541 days NRGR 44% of NSGOBjrkman et al., 1980 (28) 17 60-h fasted normal volunteers NRGR 14% of NSGOBjrkman and Felig, 1982 (83) 6 60-h fasted normal volunteers No AV differenceBjrkman et al., 1989 (84) 5 postabsorptive normal volunteers No AV differenceAhlborg et al., 1992 (49) 6 postabsorptive normal volunteers No AV differenceBrundin and Wahren, 1994 (50) 8 postabsorptive normal volunteers No AV difference

AV, arteriovenous; NRGR, net renal glucose release; NSGO, net splanchnic glucose release.



During such situations (e.g., while fastingand after meal ingestion), differentialchanges in renal glucose release anduptake might be important (see below).For example, after a 60-h fast (34) or dur-ing hypoglycemia (35), renal glucoseuptake decreases while renal glucoserelease increases. Therefore, to say that thekidney is negligible because the net renalglucose balance is negligible in the postab-sorptive state is to clearly underestimatethe potential importance of the kidney.

METHODOLOGICAL CONSIDERATIONS With thecombined isotopicnet balance approach,renal glucose release (RGR) is calculated asthe difference between the net renal glucosebalance (NRGB) and renal glucose uptake(RGU), because NRGB represents the alge-braic sum of RGU and RGR:

RGR = NRGB RGU

Thus, from the example given above, 100mol/min = 0 100 mol/min.

NRGB is calculated as the product ofthe difference between arterial glucose (AG)and renal vein glucose (VG) concentrationsand renal blood flow (RBF), as measured bythe clearance of paraminohippuric acid(36):

NRGB = (AG VG) RBF

RGU is calculated as the product of thefractional extraction of glucose by the kid-ney (FX), the AG, and RBF:

RGU = AG FX RBF

The fractional extraction of glucose by thekidney is calculated from isotopic glucosedata as the difference between the amountof tracer entering the kidney and theamount of tracer leaving the kidney dividedby the amount of tracer entering the kidney.In practice, the amount of tracer enteringand leaving the kidney is usually calculatedas the product of the plasma glucose con-centrations and the respective specificactivities or enrichments, depending onwhether stable or radioactive glucose iso-topes are used. The following equationconsiders the case of using radioactive glu-cose tracers, where GSA stands for glucosespecific activity:

FX =(AGSA AG VGSA VG)

AGSA AG

Because only the kidney and liver releaseglucose into the circulation, use of thiscombined isotopicnet balance approachpermits estimation of hepatic glucoserelease as the difference between overallglucose release (determined with thesame infused isotope used to measurerenal glucose fractional extraction) andrenal glucose release: hepatic glucoserelease = overall glucose release renalglucose release.

Hepatic glucose release can be esti-mated from measurements of splanchnicglucose fractional extraction and net bal-ance made during catheterization of ahepatic vein (37,38). This approach canalso be used to calculate renal glucoserelease; one would first determine thehepatic (splanchnic) glucose release andthen subtract this from the total endoge-nous glucose release to obtain the renal glu-cose release. This approach, as well as thenet renal balanceisotopic approach, hasrecently been used by Ekberg et al. (34).

Because renal blood flow is 1,0001,500 ml/min, arterial-renal venous differ-ences in glucose and tracer concentrationsare relatively small. Consequently, analyticalimprecision in measuring these parameterscan lead to substantial error in calculatingrenal glucose fluxes, including physiologi-cally impossible negative values for renalglucose fractional extraction, uptake, andrelease (34,35). It should be noted thatalthough hepatic blood flow is comparablewith that of the kidney, larger arterial-hepaticvenous differences result in a greater signal-to-noise ratio and generally, but not always(34), obviate this problem. Nevertheless,because the same measurements and equa-tions are used to calculate splanchnic andrenal glucose fractional extraction, uptake,and release, comparable analytical impreci-sion would be expected for determinationsof hepatic and renal glucose release. Thus,the coefficients of variation for both hepaticand renal glucose release have been esti-mated to be 9% (38).

The major assumption with renal stud-ies is that data obtained from one kidneyrepresent half of the total renal glucoserelease. This seems reasonable, althoughcatheter displacement can result in bothdilution of glucose concentrations andincreases in glucose specific activities orenrichments, resulting in underestimationsof renal glucose release. On the other hand,with hepatic studies, one must assume thatdata from one hepatic vein are representa-tive of the whole liver and that portal vein

glucose levels approximate arterial values.The latter is certainly not true after mealingestion and is probably not true in peoplewith diabetes. Furthermore, the coefficientof variation of measurements in differenthepatic veins is 15%, indicating thatresults from the catheterization of onehepatic vein may not be representative ofthe whole liver (39); thus, there may begreater variability with this approach thanwith the renal vein approach.

When faced with physiologicallyimpossible negative fractional extractions ofglucose across the kidney, some investiga-tors have chosen to consider them as zero;other investigators have accepted these dataat face value, whereas some have repeatedsuch measurements as well as those con-sidered to yield unrealistically high frac-tional extractions. The first approach seemsreasonable, but it would introduce somebias favoring increased renal glucoseuptake, which, by use of the equationsdescribed earlier, would lead to the calcu-lation of increased renal glucose release.The second approach is very conservative,but it would have the greatest variance,thus decreasing its power to detect a sig-nificant difference in renal glucose release ifone were present.

In our studies, we chose the thirdapproach: to rerun specific activity or elim-inate an obvious statistical outlier amongthe triplicates of blood glucose concentra-tions if either a negative or an exceedinglyhigh fractional extraction was observed. Werealize that our approach is not founded onany statistical precedent and could lead tobiased or even erroneous results. However,we believe that our use of this approach hasnot led to such results. For example, in oneof our recent experiments (35), 18 of 200samples initially yielded negative fractionalextractions, and 13 yielded unrealisticallyhigh fractional extractions. With ourapproach (i.e., reassaying samples or delet-ing obvious statistical outliers), all high frac-tional extractions were lowered. We foundthat 15 of the negative fractional extrac-tions became less negative, whereas 3became more negative. There were stillseven negative fractional extractions (3.5%of all determinations). The initial averagefractional extraction of all these sampleschanged from 1.4 to 1.8%. However,because of the robustness of the equationsused to calculate renal glucose release (i.e.,changes in glucose concentration producechanges in net balance, which affectchanges in fractional extraction), renal glu-



cose release did not change (1.74 vs. 1.71mol kg1 min1). Nevertheless, in ret-rospect it would have been preferable todetermine glucose specific activity and con-centration measurements with sufficientreplicates, allowing us to apply a statisticallyrecognized approach, such as that proposedby Winer (40), to minimize the effects ofanalytical imprecision.

RENAL GLUCOSE RELEASE IN POSTABSORPTIVE HUMANS Given the analytical difficulties in measur-ing renal and hepatic glucose release inhumans, it is not surprising that widelyvarying results have been reported and thatthe exact contribution of the kidney tooverall glucose release is controversial.Table 2 summarizes the results of all 10studies, which to date have used the com-bined isotopicnet renal balance approachto determine renal glucose release inhumans. Values between 5 and 28% werefound for the contribution of renal glucoserelease to overall glucose release. Theunweighted average (mean SEM) of all ofthese studies is 20 2%, with 95% CIsfrom 8 to 32%.

Although renal glucose release mayhave been overestimated in studies usingzero in place of negative renal glucose frac-tional extraction values, these data taken asa whole clearly indicate that the humankidney releases glucose into the circulationof normal postabsorptive humans. Conse-quently, regardless of the absolute contri-bution of the kidney, it is no longerappropriate to equate whole-body isotopi-cally determined glucose release with

hepatic glucose release, as has been done inthe past (41,42). Isotopic determinations ofendogenous glucose release should bereferred to as endogenous glucose releaseand not hepatic glucose release.

RENAL GLUCONEOGENESIS If one assumes that the average mentionedabove (i.e., 20 2%) approximates therenal contribution to total glucose release,one can draw inferences regarding the rel-ative importance of the liver and kidney asgluconeogenic organs. Current evidenceindicates that in overnight-fasted normalhumans, gluconeogenesis accounts forabout half of all glucose released into thecirculation (2,5). Because all of the glucosereleased by the kidney can reasonably beascribed to gluconeogenesis, it wouldappear that, if renal glucose release accountsfor 20% of overall endogenous glucoserelease, it should be responsible for 40%of all gluconeogenesis.

The studies of Felig et al. (9), Wahren etal. (10), and Ahlborg et al. (11) indicatedthat net splanchnic uptake of gluconeogenicprecursors would maximally allow gluco-neogenesis by the liver to account for only2025% of net splanchnic glucose release.Adding the kidneys contribution to overallgluconeogenesis (based on the combinedisotopicnet renal glucose balance approach[20%]) to that of the liver (based on thenet splanchnic uptake of gluconeogenicprecursors [2025%]) could, within exper-imental error, account for total gluconeoge-nesis, as assessed by methods yielding thehighest values for gluconeogenesis (25).

Table 3 shows the results of our stud-ies regarding the net renal uptake of gluco-neogenic precursors and their potentialcontribution to both renal and overall glu-cose release in postabsorptive normal

volunteers. The net amount of lactate, glu-tamine, glycerol, and alanine taken up bythe kidney could, if wholly converted toglucose, account for 20% of all glucosereleased into the circulation and nearly90% of the glucose released by the kidney.Because these calculations do not includethe net uptake of amino acids other thanglutamine and alanine, they may some-what underestimate the gluconeogenicpotential of the kidney. Nevertheless, if glu-coneogenesis represents 50% of overall glu-cose release in the postabsorptive state,these data indicate that renal gluconeogen-esis could account for 40% of overallgluconeogenesis under these conditions,and they are consistent with independentdeterminations of the contribution of thekidney to overall gluconeogenesis basedon the combined isotopicnet glucose bal-ance experiments of renal glucose release.

Furthermore, these data are also con-sistent with recent studies by Cersosimo etal. (38), who found that renal net uptake oflactate, alanine, and glycerol could accountfor 85% of renal glucose release and 21% ofoverall glucose release. Thus, given theimprecision of the measurements involvedin the determination of both gluconeogen-esis and the release of glucose by the liverand kidney, for practical purposes, onecould consider the kidney as important agluconeogenic organ as the liver in normalpostabsorptive humans.

RENAL GLUCONEOGENIC SUBSTRATES Lactate, glutamine,alanine, and glycerol are the main gluco-neogenic precursors in humans, togetheraccounting for 90% of overall gluconeo-genesis (1). Although considerable humandata are available for renal net balances ofgluconeogenic precursors (27,28,4350),

Table 2Proportion of total glucose releasedue to renal glucose release in normalpostabsorptive humans using the combinedisotopic net balance technique

Reference Proportion

Moller et al., 1999 (85) 21Ekberg et al., 1999 (34) 5Cersosimo et al., 1999 (64) 22Cersosimo et al., 1999 (53) 25Meyer et al., 1998 (77) 17Meyer et al., 1998 (56) 21Stumvoll et al., 1998 (52) 22Stumvoll et al., 1998 (57) 22Meyer et al., 1997 (86) 13Stumvoll et al., 1995 (58) 28Mean SEM 20 2Data are % of total glucose release.

Table 3Relation of net renal uptake of gluconeogenic precursors to overall glucose releaseand renal glucose release in postabsorptive normal volunteers

n Means SEM

Net renal gluconeogenic precursor uptake (mol/min, glucose equivalents) 58Lactate 16 96 11Glutamine 37 22 2Glycerol 10 30 5Alanine 9 7 5

Overall glucose release* (mol/min) 58 825 15Renal glucose release (mol/min) 58 176 9

Data are from references 35, 51, 52, 56, and 58 and other unpublished studies. *Proportion accounted for byrenal precursor uptake is 19% (assuming all precursors taken up were converted to glucose). Proportionaccounted for by renal precursor uptake is 88% (assuming all precursors taken up were converted to glucose).



their actual incorporation into glucose bythe human kidney has been quantitated inonly a few studies (5153). The largeststudy, which comprised 48 subjects, indi-cated that lactate was the most importantrenal gluconeogenic substrate, followed byglutamine and glycerol (51). Renal con-version to glucose of these precursorsaccounted for 50, 70, and 35%, respec-tively, of their overall systemic gluconeoge-nesis. In another study, renal glycerolgluconeogenesis accounted for 17% of itsoverall conversion to glucose (53). Itappears that glutamine is a preferential glu-coneogenic substrate for the kidney,whereas alanine is preferentially used bythe liver (52).

HORMONAL CONTROL OF RENAL GLUCOSE RELEASE Animal and in vitro experiments indicatethat insulin, growth hormone, cortisol, andcatecholamines influence renal glucoserelease (29,30). Recently, using the com-bined isotopic and net balance approach,Cersosimo et al. (54) showed that in dogs,insulin suppressed renal glucose releasewhile stimulating renal glucose uptake.McGuinness et al. (55) demonstrated thatan infusion with cortisol, glucagon, andepinephrine increased renal glucose releasein dogs. Earlier, Teng (18) and Landau

(19) had reported that renal cortical slicesfrom cortisol-treated rats had increasedboth renal glucose release and gluconeo-genesis. Data in humans are limited to theeffects of insulin (53,56), glucagon (57),and epinephrine (58).

In normal postabsorptive humans, twoindependent groups have demonstrated ineuglycemic clamp experiments that physio-logical increases in insulin concentrationssuppress renal glucose release and increaserenal glucose uptake (53,56). The suppres-sion of renal glucose release was comparablewith that of hepatic glucose release (calcu-lated as the difference between total glucoserelease and renal glucose release), whereasrenal glucose uptake accounted for only asmall proportion of total glucose uptake.Cersosimo et al. (38) recently reported thatthe infusion of insulin reduced the renal netuptake of glycerol but not that of alanine andlactate. Similarly, Meyer et al. (56) found thatthe infusion of insulin reduced net renalglycerol uptake, increased net lactate uptake,and did not affect alanine net uptake andglutamine uptake. These observations sug-gest that insulin suppresses renal gluconeo-genesis primarily by intrarenal mechanismsrather than by simply reducing substratedelivery. The process could involve shuntingprecursors away from the gluconeogenicpathway and into the oxidative pathway,

thus compensating for the decreased avail-ability of free fatty acids as an oxidative fuelduring the infusion of insulin.

Because insulin reduces renal free fattyacid uptake (56), and since free fatty acidshave been shown to stimulate renal gluco-neogenesis in vitro (24), insulin suppressionof renal glucose release might be partiallyindirect. Indeed, this would be consistentwith observations that the extrahepatic indi-rect effects of insulin on suppressingendogenous glucose release are mediated bychanges in free fatty acids (59,60).

The infusion of glucagon, whichincreases circulating glucagon levels tothose seen during hypoglycemia, has beenreported to have no effect on renal glucoserelease or uptake (57). On the other hand,the infusion of epinephrine, which pro-duces plasma levels similar to those seenduring hypoglycemia, was found toincrease renal glucose release in a sustainedfashion, so that after 2 h, virtually all of theincrease in systemic glucose release couldbe accounted for by renal glucose release(58) (Fig. 3). These results suggest that cat-echolamines may have more of an effect onrenal gluconeogenesis than they do onhepatic gluconeogenesis. Such an actionwould be consistent with the rich auto-nomic innervation of the kidney.

In the studies by Stumvoll et al. (58),epinephrine augmented renal glutaminegluconeogenesis more than twofold.Because renal glutamine fractional extrac-tion and uptake were increased by only50%, it appears that epinephrine aug-mented renal glutamine gluconeogenesisand perhaps gluconeogenesis from otherprecursors by not merely increasing sub-strate availability. Again, the mechanismmight involve free fatty acids resulting fromthe stimulation of lipolysis by epinephrine.This finding is relevant in view of the studyby Fanelli et al. (61) showing that adrener-gic stimulation of gluconeogenesis duringcounterregulation of hypoglycemia islargely mediated through free fatty acids.

PHYSIOLOGICAL/PATHOPHYSIOLOGICAL IMPLICATIONS Based on availableevidence, it would appear likely that therelease of glucose by the kidney may play asignificant role in the regulation of glucosehomeostasis. Animal and human experi-ments have provided substantial evidencethat the kidney may compensate forimpaired hepatic glucose release in main-taining normoglycemia (1317). Indeed,

Figure 3Effect of epinephrine infusion on overall, renal, and hepatic glucose release in normal volun-teers. , Epinephrine (n = 6); , saline (n = 4). Reproduced from Stumvoll et al. (58) with permission.

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two recent human studies have shown thatduring hepatic transplantation, whenpatients are without a liver, the kidney canincrease its release of glucose to the extentthat it can compensate between 50 and100% of the glucose normally provided bythe liver (13,14) (Fig. 1). This may explainwhy it is extremely uncommon for patientswith extensive hepatic malfunction todevelop hypoglycemia in the absence ofincreases in glucose utilization (e.g., duringsepsis or heart failure) (62).

FASTING As fasting progresses, liverglycogen stores are depleted and gluconeo-genesis becomes the most importantprocess for sustaining the supply of glucoseto the brain and other obligate glucose con-sumers. Several studies (27,28,34) haveshown that the kidney increases its netcontribution to overall glucose releaseunder these circumstances. In the studiesby Ekberg et al. (34), who used the com-bined isotopicnet balance approach, renalglucose release increased 2.5-fold in 60-hfasted subjects compared with overnight(12-h)fasted subjects, whereas hepaticglucose release decreased by 25%. There-fore, one might wonder whether the livercan compensate for the kidney to preservenormoglycemia in patients with renalinsufficiency during prolonged fasting.

HYPOGLYCEMIA COUNTERREGULATION Counter-regulation of hypoglycemia involves both anincreased release of glucose into the circula-tion and decreased tissue glucose uptake(63). In humans, the early increase in glu-cose release is mainly caused by hepaticglycogenolysis, whereas later it is mainly aresult of gluconeogenesis (63). Animal stud-ies cited earlier (16,17) have demonstratedincreased renal glucose release during hypo-glycemia. Recently, two human studies withsimilar experimental designs using thehyperinsulinemic-hypoglycemic clamptechnique have yielded evidence for animportant role of the kidney (35,64). Cer-sosimo et al. (64) reported that during hypo-glycemia (3.6 mmol/l) renal glucose releasedoubled and its contribution to overall sys-temic glucose release increased from 22 to36%. Comparable results were reported byMeyer et al. (35), who found that renal glu-cose release increased threefold duringhypoglycemia (3.2 mmol/l) compared withhyperinsulinemic-euglycemic control exper-iments. Hepatic glucose release (calculatedas the difference between total glucose

release and renal glucose release) increasedonly 1.4-fold above rates observed duringthe control experiments, but absolute incre-ments for hepatic and renal glucose releasewere comparable. Renal glucose uptake dur-ing hypoglycemia was reduced 65%, but itaccounted for only 5% of the overall reduc-tion in tissue glucose uptake.

These studies provide evidence thatthe kidney may play an important role inhuman glucose counterregulation. Con-ceivably, this role of the kidney couldexplain why patients with renal failure havea propensity to develop hypoglycemia (65).Furthermore, patients with type 1 diabeteslose their glucagon response to hypogly-cemia and become dependent on cate-cholamine responses (63). One mighttherefore anticipate that the kidney mayplay a relatively more important role inglucose counterregulation in such individ-uals, because lack of a glucagon responsewould preferentially diminish hepatic glu-cose release.

RENAL GLUCOSE METABOLISM IN THE POSTPRANDIAL STATE Previous discussions of the roleof the kidney in glucose homeostasis haveinvolved the fasting state and hypoglycemia.Another potentially important area is post-prandial glucose metabolism. After mealingestion, endogenous glucose productiondecreases, and the ingested carbohydrateload is taken up by various tissues, mainlythe liver and muscles (42,66). The role ofthe kidney in postprandial glucose metabo-lism has recently been investigated (67).Seemingly, renal glucose release paradoxi-cally increases postprandially and itaccounts for 50% of the endogenous glu-cose release for several hours. These obser-

vations suggest that increased renal glucoserelease may play a role in facilitating efficientliver glycogen repletion by permitting thesubstantial suppression of hepatic glucoserelease. The mechanism responsible for thisincrease in renal glucose release remains tobe determined, but it could involve post-prandial increases in sympathetic nervoussystem activity (68) and increases in theavailability of gluconeogenic precursors(e.g., lactate and amino acids). Renal glu-cose uptake apparently does not play amajor role in postprandial glucose uptake,because it accounted for 10% of the dis-position of the ingested glucose load (67).

ROLE OF THE KIDNEY IN TYPES 1 AND 2 DIABETES Itis well established that in type 1 and type 2diabetes the excessive release of glucose intothe circulation is a major factor responsiblefor fasting hyperglycemia. Increased renalgluconeogenic enzyme activity (6971) andincreased renal glucose release have beenconsistently demonstrated in studies of dia-betic animals (7275). Indeed, Mithieux etal. (71) demonstrated that there were com-parable increases in hepatic and renal glu-cose -6 -phospha ta se ac t i v i t y instreptozotocin-induced diabetic rats.

To date, there have been only two stud-ies in human diabetic subjects (one in type1 diabetes and one in type 2 diabetes)(Fig. 4) that have evaluated renal glucosemetabolism with the combined iso-topicnet renal glucose balance approach(76,77). Both studies showed that renalglucose release was increased by about thesame extent as hepatic glucose release (cal-culated as the difference between overallglucose release and renal glucose release). Aprevious study by DeFronzo et al. (78) had

Figure 4Renal and hepatic glucose release in type 2 diabetes. , Nondiabetic; , diabetic. Repro-duced from Meyer et al. (77) with permission.

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Rel

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used a combined isotopicnet splanchnicbalance approach to measure hepatic glu-cose release in type 2 diabetes. These inves-tigators failed to demonstrate any differencein hepatic glucose release between controlvolunteers and subjects with type 2 dia-betes, despite the fact that the overall glu-cose release (measured isotopically) wasincreased in the diabetic subjects. At facevalue, one might conclude that the dis-crepancy between increased overall glu-cose release and normal hepatic glucoserelease could have been caused wholly byincreased renal glucose release. But thesmall number of subjects studied may haveprovided insufficient statistical power todemonstrate an increase in hepatic glucoserelease. Our own studies (76,77) haveclearly demonstrated an increase in hepaticglucose release in hyperglycemic patientswith types 1 and 2 diabetes.

Because acidosis increases renal gluco-neogenesis but impairs hepatic gluconeo-genesis (79), it is tempting to speculate thatthe kidney may be a major factor in accel-erating gluconeogenesis in diabetic ketoaci-dosis. Moreover, one wonders to whatextent the failure to suppress endogenousglucose release postprandially in diabeticpatients (80) might involve an exaggeratedincrease in renal glucose release.

Interestingly, both of the above com-bined isotopicnet balance studies demon-strated that renal glucose uptake wasincreased in the diabetic subjects. Theseobservations could explain the accumula-tion of glycogen found in diabetic kidneys(81). Therefore, some of the increased renalglucose release found in patients and ani-mals with diabetes may be caused byincreased renal glycogenolysis.

CONCLUSIONS Recent studiesindicate that the human kidney both con-sumes and releases glucose in the postab-sorptive state and that, consequently, it is nolonger appropriate to equate hepatic glucoserelease with overall systemic glucose releasemeasured isotopically. It appears that thekidney may be roughly as important a glu-coneogenic organ as the liver. Renal glucoserelease and uptake are under hormonal con-trol. The kidney plays a role in human glu-cose counterregulation, can compensate atleast partially for impaired hepatic glucoserelease, and contributes to the excessive glu-cose release seen in both types 1 and 2 dia-betes. Further studies are needed to arrive ata consensus on the contribution of the kid-ney to overall glucose release; to evaluate the

effects of substrate availability, pharmaco-logical agents, and additional hormones onrenal glucose release; and to assess the role ofthe kidney in various pathological condi-tions (e.g., renal insufficiency, hepatic failure,sepsis, and aging).

Acknowledgments The present work wassupported in part by National Institutes ofHealth/Division of Research Resources/GeneralClinical Research Center Grants 5M01-RR00044 and National Institute of Diabetes andDigestive and Kidney Diseases 20411. We wishto thank the staff of the General ClinicalResearch Center for their excellent technicalhelp and Mary Little for her superb editorialsupport.

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