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Renal Gluconeogenesis
Its importance in human glucose homeostasis
JOHN E. GERICH, MD HANS J. WOERLE, MD Various isotopic methods have been
CHRISTIAN MEYER, MD MICHAEL STUMVOLL, MD used to assess the proportion of overall
glucose release attributable to gluconeoge-
nesis in humans. The ingenious approach
developed by Landau et al. (4), which uses
the ratio of enrichments of the C-2 carbon
Studies conducted over the last 60 years in animals and in vitro have provided considerable evi- to the C-5 carbon of plasma glucose after
dence that the mammalian kidney can make glucose and release it under various conditions. ingestion of deuterated water, appears to be
Until quite recently, however, it was generally believed that the human kidney was not an
the most widely accepted. Investigators
important source of glucose except during acidosis and after prolonged fasting. This review will
summarize early work in animals and humans, discuss methodological problems in assessing using this approach have found that gluco-
renal glucose release in vivo, and present results of recent human studies that provide evidence neogenesis accounted for 54 ± 2% of all
that the kidney may play a significant role in carbohydrate metabolism under both physio- glucose released into the circulation of
logical and pathological conditions. overnight-fasted normal volunteers (5).
These results are in excellent agreement
Diabetes Care 24:382–391, 2001 with those predicted both from NMR stud-
ies of hepatic glycogen depletion (2) and
from a stable isotope approach using indi-
o function effectively as a source of This lactate and the lactate generated via rect calorimetry (51 ± 5%) (6), but they are
EARLY NONHUMAN
STUDIES — In 1938, Bergman and
Drury (15) presented the first evidence that
the kidney might release glucose and be
important for maintenance of normal glucose
homeostasis. These investigators used the
glucose clamp technique to maintain eugly-
cemia in two groups of rabbits—one func-
tionally hepatectomized and one functionally
hepatectomized and nephrectomized. As
shown in Fig. 2, functional removal of the
kidneys in hepatectomized animals led to an
abrupt increase in the amount of glucose
required to maintain euglycemia, results that Figure 2—Effect of functional nephrectomy on glucose requirements to maintain euglycemia in hepa-
would be consistent with the hypothesis that tectomized rabbits. – – –, Functionally nephrectomized-hepatectomized animals; —, functionally
the kidneys are a source of plasma glucose. hepatectomized animals. Reproduced from Bergman and Drury (15) with permission.
than the liver, and because both organs view that the liver was the sole source of Because the kidney is both a consumer
had comparable blood flows (and hence glucose, except after prolonged fasting or and producer of glucose, net balance mea-
comparable provision of gluconeogenic under acidotic conditions. It is worth not- surements do not provide information on the
precursors), Krebs hypothesized that the ing, however, that Aber et al. (26) did find individual processes of renal glucose pro-
kidney might be as important a gluco- net renal glucose release in nonacidotic duction and utilization. For example, let us
neogenic organ in vivo as the liver (23,25). pulmonary patients and that Björkman et assume that the net balance of glucose across
Given these data, one may ask why the al. (28) found significant net renal glucose the kidney is zero (i.e., arterial and renal
kidney was not considered an important release in normal volunteers who fasted for venous glucose concentrations are equiva-
source of glucose in humans. Failure to only 60 h. Nevertheless, we must empha- lent), as has been commonly observed in
recognize the limitations of net balance size that net balance measurements under- postabsorptive humans. Let us further
experiments and analytical problems are estimate renal glucose release to the extent assume that the kidney uses glucose at a rate
probably the major reasons. that the kidney takes up glucose. of 100 µmol/min, as has been reported in
postabsorptive humans (33). For the law of
EARLY HUMAN PHYSIOLOGICAL conservation of matter to hold, the kidney
STUDIES — Studies of human renal glu- CONSIDERATIONS — The kidney must also release glucose at a rate of 100
cose metabolism began in the late 1950s and can be considered two separate organs µmol/min. Thus, under these circumstances,
focused on measurements of differences because glucose utilization occurs predom- the net balance approach will underestimate
between arterial and renal venous glucose inantly in the renal medulla, whereas glu- renal glucose release. To measure renal glu-
concentrations. Such experiments yielded cose release is confined to the renal cortex cose release in vivo, it is necessary to use a
information concerning the net glucose bal- (29–31). This functional partition is a result combined isotopic–net balance approach,
ance across the kidney, i.e., the difference of differences in the distribution of various which permits simultaneous determination
between the production and the utilization enzymes along the nephron. For example, of renal glucose utilization and renal glucose
of glucose by the kidney. As summarized in cells in the renal medulla have appreciable release (see below).
Table 1, most investigators found little or no glucose-phosphorylating and glycolytic One might argue that if the net renal
arteriovenous differences in glucose con- enzyme activity, and, like the brain, they are glucose release is negligible, the kidneys are
centrations in nondiabetic overnight-fasted obligate users of glucose (32). These cells, not important, because their removal or
humans, indicating little or no net glucose however, lack glucose-6-phosphatase and absence would lead to comparable decre-
release by the kidneys. By not taking into other gluconeogenic enzymes. Thus, ments in glucose release and uptake, caus-
consideration the fact that the kidney simul- although they can take up, phosphorylate, ing no net overall change in glucose
taneously produces and consumes glucose glycolyse, and accumulate glycogen, they homeostasis. This, of course, is a theoretical
(see below), it was erroneously concluded cannot release free glucose into the circula- construct that ignores the numerous meta-
that the kidney did not release glucose in tion (29–31). On the other hand, cells in the bolic changes that occur in the anephric
postabsorptive humans. renal cortex possess gluconeogenic enzymes state. It also ignores the fact that renal glu-
In 1966, Aber et al. (26) found that (including glucose-6-phosphatase), and thus cose release and renal glucose uptake are
there was net renal glucose release in they can make and release glucose into the differentially regulated. But more impor-
patients with pulmonary disease, which circulation. But these cells have little phos- tantly, it ignores the fact that the calculation
was negatively correlated with arterial pH phorylating capacity and, under normal of glucose release into the circulation by iso-
(i.e., the greater the acidosis, the greater the conditions, they cannot synthesize appre- topic techniques depends on the dilution of
net renal glucose release). Shortly there- ciable concentrations of glycogen (29–31). the infused isotope’s specific activity (or
after, Owen et al. (27) demonstrated that Therefore, the release of glucose by the nor- enrichment) by the release of unlabeled glu-
there was substantial net renal glucose mal kidney is mainly, if not exclusively, a cose from the liver and kidney, irrespective
release in morbidly obese patients who result of renal cortical gluconeogenesis, of these organs’ uptake of glucose. Finally, it
fasted for 5–6 weeks. From these observa- whereas glucose uptake and utilization ignores the consequences in situations other
tions, there evolved the current textbook occur in other parts of the kidney. than the overnight postabsorptive state.
During such situations (e.g., while fasting Because only the kidney and liver release glucose levels approximate arterial values.
and after meal ingestion), differential glucose into the circulation, use of this The latter is certainly not true after meal
changes in renal glucose release and combined isotopic–net balance approach ingestion and is probably not true in people
uptake might be important (see below). permits estimation of hepatic glucose with diabetes. Furthermore, the coefficient
For example, after a 60-h fast (34) or dur- release as the difference between overall of variation of measurements in different
ing hypoglycemia (35), renal glucose glucose release (determined with the hepatic veins is 15%, indicating that
uptake decreases while renal glucose same infused isotope used to measure results from the catheterization of one
release increases. Therefore, to say that the renal glucose fractional extraction) and hepatic vein may not be representative of
kidney is negligible because the net renal renal glucose release: hepatic glucose the whole liver (39); thus, there may be
glucose balance is negligible in the postab- release = overall glucose release – renal greater variability with this approach than
sorptive state is to clearly underestimate glucose release. with the renal vein approach.
the potential importance of the kidney. Hepatic glucose release can be esti- When faced with physiologically
mated from measurements of splanchnic impossible negative fractional extractions of
METHODOLOGICAL glucose fractional extraction and net bal- glucose across the kidney, some investiga-
CONSIDERATIONS — With the ance made during catheterization of a tors have chosen to consider them as zero;
combined isotopic–net balance approach, hepatic vein (37,38). This approach can other investigators have accepted these data
renal glucose release (RGR) is calculated as also be used to calculate renal glucose at face value, whereas some have repeated
the difference between the net renal glucose release; one would first determine the such measurements as well as those con-
balance (NRGB) and renal glucose uptake hepatic (splanchnic) glucose release and sidered to yield unrealistically high frac-
(RGU), because NRGB represents the alge- then subtract this from the total endoge- tional extractions. The first approach seems
braic sum of RGU and RGR: nous glucose release to obtain the renal glu- reasonable, but it would introduce some
cose release. This approach, as well as the bias favoring increased renal glucose
RGR = NRGB RGU net renal balance–isotopic approach, has uptake, which, by use of the equations
recently been used by Ekberg et al. (34). described earlier, would lead to the calcu-
Thus, from the example given above, 100 Because renal blood flow is 1,000– lation of increased renal glucose release.
µmol/min = 0 100 µmol/min. 1,500 ml/min, arterial-renal venous differ- The second approach is very conservative,
NRGB is calculated as the product of ences in glucose and tracer concentrations but it would have the greatest variance,
the difference between arterial glucose (AG) are relatively small. Consequently, analytical thus decreasing its power to detect a sig-
and renal vein glucose (VG) concentrations imprecision in measuring these parameters nificant difference in renal glucose release if
and renal blood flow (RBF), as measured by can lead to substantial error in calculating one were present.
the clearance of paraminohippuric acid renal glucose fluxes, including physiologi- In our studies, we chose the third
(36): cally impossible negative values for renal approach: to rerun specific activity or elim-
glucose fractional extraction, uptake, and inate an obvious statistical outlier among
NRGB = (AG – VG) RBF release (34,35). It should be noted that the triplicates of blood glucose concentra-
although hepatic blood flow is comparable tions if either a negative or an exceedingly
RGU is calculated as the product of the with that of the kidney, larger arterial-hepatic high fractional extraction was observed. We
fractional extraction of glucose by the kid- venous differences result in a greater signal- realize that our approach is not founded on
ney (FX), the AG, and RBF: to-noise ratio and generally, but not always any statistical precedent and could lead to
(34), obviate this problem. Nevertheless, biased or even erroneous results. However,
RGU = AG FX RBF because the same measurements and equa- we believe that our use of this approach has
tions are used to calculate splanchnic and not led to such results. For example, in one
The fractional extraction of glucose by the renal glucose fractional extraction, uptake, of our recent experiments (35), 18 of 200
kidney is calculated from isotopic glucose and release, comparable analytical impreci- samples initially yielded negative fractional
data as the difference between the amount sion would be expected for determinations extractions, and 13 yielded unrealistically
of tracer entering the kidney and the of hepatic and renal glucose release. Thus, high fractional extractions. With our
amount of tracer leaving the kidney divided the coefficients of variation for both hepatic approach (i.e., reassaying samples or delet-
by the amount of tracer entering the kidney. and renal glucose release have been esti- ing obvious statistical outliers), all high frac-
In practice, the amount of tracer entering mated to be 9% (38). tional extractions were lowered. We found
and leaving the kidney is usually calculated The major assumption with renal stud- that 15 of the negative fractional extrac-
as the product of the plasma glucose con- ies is that data obtained from one kidney tions became less negative, whereas 3
centrations and the respective specific represent half of the total renal glucose became more negative. There were still
activities or enrichments, depending on release. This seems reasonable, although seven negative fractional extractions (3.5%
whether stable or radioactive glucose iso- catheter displacement can result in both of all determinations). The initial average
topes are used. The following equation dilution of glucose concentrations and fractional extraction of all these samples
considers the case of using radioactive glu- increases in glucose specific activities or changed from 1.4 to 1.8%. However,
cose tracers, where GSA stands for glucose enrichments, resulting in underestimations because of the robustness of the equations
specific activity: of renal glucose release. On the other hand, used to calculate renal glucose release (i.e.,
(AGSA AG – VGSA VG)
with hepatic studies, one must assume that changes in glucose concentration produce
FX = data from one hepatic vein are representa- changes in net balance, which affect
AGSA AG tive of the whole liver and that portal vein changes in fractional extraction), renal glu-
Table 2—Proportion of total glucose release hepatic glucose release, as has been done in volunteers. The net amount of lactate, glu-
due to renal glucose release in normal the past (41,42). Isotopic determinations of tamine, glycerol, and alanine taken up by
postabsorptive humans using the combined endogenous glucose release should be the kidney could, if wholly converted to
isotopic net balance technique referred to as endogenous glucose release glucose, account for 20% of all glucose
and not hepatic glucose release. released into the circulation and nearly
Reference Proportion
90% of the glucose released by the kidney.
RENAL GLUCONEOGENESIS — Because these calculations do not include
Moller et al., 1999 (85) 21 If one assumes that the average mentioned the net uptake of amino acids other than
Ekberg et al., 1999 (34) 5 above (i.e., 20 ± 2%) approximates the glutamine and alanine, they may some-
Cersosimo et al., 1999 (64) 22 renal contribution to total glucose release, what underestimate the gluconeogenic
Cersosimo et al., 1999 (53) 25 one can draw inferences regarding the rel- potential of the kidney. Nevertheless, if glu-
Meyer et al., 1998 (77) 17 ative importance of the liver and kidney as coneogenesis represents 50% of overall glu-
Meyer et al., 1998 (56) 21 gluconeogenic organs. Current evidence cose release in the postabsorptive state,
Stumvoll et al., 1998 (52) 22 indicates that in overnight-fasted normal these data indicate that renal gluconeogen-
Stumvoll et al., 1998 (57) 22 humans, gluconeogenesis accounts for esis could account for 40% of overall
Meyer et al., 1997 (86) 13 about half of all glucose released into the gluconeogenesis under these conditions,
Stumvoll et al., 1995 (58) 28 circulation (2,5). Because all of the glucose and they are consistent with independent
Mean ± SEM 20 ± 2 released by the kidney can reasonably be determinations of the contribution of the
Data are % of total glucose release. ascribed to gluconeogenesis, it would kidney to overall gluconeogenesis based
appear that, if renal glucose release accounts on the combined isotopic–net glucose bal-
for 20% of overall endogenous glucose ance experiments of renal glucose release.
cose release did not change (1.74 vs. 1.71 release, it should be responsible for 40% Furthermore, these data are also con-
µmol kg1 min1). Nevertheless, in ret- of all gluconeogenesis. sistent with recent studies by Cersosimo et
rospect it would have been preferable to The studies of Felig et al. (9), Wahren et al. (38), who found that renal net uptake of
determine glucose specific activity and con- al. (10), and Ahlborg et al. (11) indicated lactate, alanine, and glycerol could account
centration measurements with sufficient that net splanchnic uptake of gluconeogenic for 85% of renal glucose release and 21% of
replicates, allowing us to apply a statistically precursors would maximally allow gluco- overall glucose release. Thus, given the
recognized approach, such as that proposed neogenesis by the liver to account for only imprecision of the measurements involved
by Winer (40), to minimize the effects of 20–25% of net splanchnic glucose release. in the determination of both gluconeogen-
analytical imprecision. Adding the kidney’s contribution to overall esis and the release of glucose by the liver
gluconeogenesis (based on the combined and kidney, for practical purposes, one
RENAL GLUCOSE RELEASE IN isotopic–net renal glucose balance approach could consider the kidney as important a
POSTABSORPTIVE HUMANS — [20%]) to that of the liver (based on the gluconeogenic organ as the liver in normal
Given the analytical difficulties in measur- net splanchnic uptake of gluconeogenic postabsorptive humans.
ing renal and hepatic glucose release in precursors [20–25%]) could, within exper-
humans, it is not surprising that widely imental error, account for total gluconeoge- RENAL GLUCONEOGENIC
varying results have been reported and that nesis, as assessed by methods yielding the SUBSTRATES — Lactate, glutamine,
the exact contribution of the kidney to highest values for gluconeogenesis (2–5). alanine, and glycerol are the main gluco-
overall glucose release is controversial. Table 3 shows the results of our stud- neogenic precursors in humans, together
Table 2 summarizes the results of all 10 ies regarding the net renal uptake of gluco- accounting for 90% of overall gluconeo-
studies, which to date have used the com- neogenic precursors and their potential genesis (1). Although considerable human
bined isotopic–net renal balance approach contribution to both renal and overall glu- data are available for renal net balances of
to determine renal glucose release in cose release in postabsorptive normal gluconeogenic precursors (27,28,43–50),
humans. Values between 5 and 28% were
found for the contribution of renal glucose
release to overall glucose release. The Table 3—Relation of net renal uptake of gluconeogenic precursors to overall glucose release
unweighted average (mean ± SEM) of all of and renal glucose release in postabsorptive normal volunteers
these studies is 20 ± 2%, with 95% CIs
from 8 to 32%.
Although renal glucose release may n Means ± SEM
have been overestimated in studies using Net renal gluconeogenic precursor uptake (µmol/min, glucose equivalents) 58
zero in place of negative renal glucose frac- Lactate 16 96 ± 11
tional extraction values, these data taken as Glutamine 37 22 ± 2
a whole clearly indicate that the human Glycerol 10 30 ± 5
kidney releases glucose into the circulation Alanine 9 7±5
of normal postabsorptive humans. Conse- Overall glucose release* (µmol/min) 58 825 ± 15
quently, regardless of the absolute contri- Renal glucose release† (µmol/min) 58 176 ± 9
bution of the kidney, it is no longer Data are from references 35, 51, 52, 56, and 58 and other unpublished studies. *Proportion accounted for by
appropriate to equate whole-body isotopi- renal precursor uptake is 19% (assuming all precursors taken up were converted to glucose). †Proportion
cally determined glucose release with accounted for by renal precursor uptake is 88% (assuming all precursors taken up were converted to glucose).
used a combined isotopic–net splanchnic effects of substrate availability, pharmaco- and amino acids. J Clin Invest 53:1080–
balance approach to measure hepatic glu- logical agents, and additional hormones on 1090, 1974
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in hepatic glucose release between control tions (e.g., renal insufficiency, hepatic failure, tate in basal state and after oral glucose
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increased in the diabetic subjects. At face Acknowledgments — The present work was production compensates for the liver dur-
value, one might conclude that the dis- supported in part by National Institutes of ing the anhepatic phase of liver transplan-
crepancy between increased overall glu- Health/Division of Research Resources/General tation. Diabetes 49:450–456, 2000
cose release and normal hepatic glucose Clinical Research Center Grants 5M01- 14. Battezzati A, Fattorini A, Caumo A, Coppa
release could have been caused wholly by RR00044 and National Institute of Diabetes and J, Romito R, Regalia E, Matthews DE, Maz-
increased renal glucose release. But the Digestive and Kidney Diseases 20411. We wish zaferro V, Luzi L: Non-hepatic glucose pro-
to thank the staff of the General Clinical duction in humans (Abstract). Diabetes 48
small number of subjects studied may have Research Center for their excellent technical (Suppl. 1):A49, 1999
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