ABSTRACT

Glucose levels are tightly regulated at all times. Gluconeogenesis is the metabolic pathway dedicated to glucose synthesis from non-hexose precursors. Gluconeogenesis is critical for glucose homoeostasis, particularly during fasting or stress conditions. The renal contribution to systemic gluconeogenesis is increasingly recognized. During the post-absorptive phase, the kidney accounts for ∼40% of endogenous gluconeogenesis, occurring mainly in the kidney proximal tubule. The main substrate for renal gluconeogenesis is lactate and the process is regulated by insulin and cellular glucose levels, but also by acidosis and stress hormones. The kidney thus plays an important role in the maintenance of glucose and lactate homoeostasis during stress conditions. The impact of acute and chronic kidney disease and proximal tubular injury on gluconeogenesis is not well studied. Recent evidence shows that in both experimental and clinical acute kidney injury, impaired renal gluconeogenesis could significantly participate in systemic metabolic disturbance and thus alter the prognosis. This review summarizes the biochemistry of gluconeogenesis, the current knowledge of kidney gluconeogenesis, its modifications in kidney disease and the clinical relevance of this fundamental biological process in human biology.

INTRODUCTION

Glucose is one of the main body fuels and its blood levels are tightly regulated. Plasma glucose values are maintained within a narrow range throughout the day despite wide fluctuations in the delivery and removal of glucose from the circulation in order to fuel the body organs and notably the brain. Gluconeogenesis is the pathway by which glucose is synthesized from non-hexose precursors such as glycerol, lactate, pyruvate and glucogenic amino acids and is crucial in maintaining normoglycaemia during fasting and stress conditions. After an overnight fast, glucose production relies on endogenous production by both glycogenolysis and gluconeogenesis.

Glycogenolysis is the breakdown of glycogen to glucose-6-phosphate (G6P) and further hydrolysis to glucose. As fasting progresses, glycogen, stored mainly in the liver and the muscles, is depleted. After around 60 h of starvation in humans, gluconeogenesis becomes the only source of glucose production [1]. Gluconeogenesis is classically attributed to the liver. However, in 1937, the ability of the mammalian kidney to produce glucose from non-carbohydrate precursors was discovered [2] and further investigated in animal models, healthy persons and—more recently—in patients with kidney disease [3]. This review summarizes the biochemistry of gluconeogenesis, the current knowledge of renal gluconeogenesis and its potential clinical relevance.

Metabolic pathway

Gluconeogenesis is an anabolic pathway consisting of 11 reactions catalysed by enzymes (summarized in Figure 1), resulting in the production of glucose from non-hexose precursors. Most of these reactions are the reverse steps of glycolysis, except for four reactions, which are irreversible and specific to gluconeogenesis. These specific reactions are catalysed by four enzymes: pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PEPCK, PCK1), fructose-1,6-bisphosphatase (FBP) and G6P. Of them, PC is the only one localized in the mitochondria and converts pyruvate to oxaloacetate [4]. Pyruvate can originate from glucose through the final steps of glycolysis, from lactate oxidation via lactate dehydrogenase or from the transformation of amino acids such as alanine. Oxaloacetate cannot cross the mitochondrial membrane and is first transformed to aspartate or malate through malate dehydrogenase or aspartate aminotransferase in order to be transported to the cytosol, where it is reconverted back to oxaloacetate. In the cytosol, oxaloacetate is both decarboxylated and phosphorylated by PEPCK/PCK1. This reaction is widely accepted as a rate-limiting step for gluconeogenesis [5]. PEPCK/PCK1 activity appears well related to the amount of PCK1 messenger RNA (mRNA), although post-transcriptional regulations are described [6]. FBP catalyses the hydrolysis of FBP to frutcose-6-phosphate. The activity of FBP is regulated either at the pre- or the post-translational level [7]. Finally, G6P dephosphorylates to glucose. G6P is also regulated at the transcriptional level [8]. In addition to the classical pathway, two shunts exist in the gluconeogenesis pathway: some ketogenic and glucogenic amino acids (in particular glutamine) can join the TCA cycle and be transformed directly to oxaloacetate, whereas glycerol, released by the hydrolysis of triglycerides, can also join gluconeogenesis via its conversion to dihydroxyacetone phosphate [9]. Gluconeogenesis is an energy-requiring process. For each molecule of glucose generated, six high-energy phosphate bonds are needed.

Gluconeogenesis pathway.
FIGURE 1

Gluconeogenesis pathway.

Gluconeogenic organs and regulation of renal gluconeogenesis.
FIGURE 2

Gluconeogenic organs and regulation of renal gluconeogenesis.

Renal gluconeogenesis in the proximal tubule cells.
FIGURE 3

Renal gluconeogenesis in the proximal tubule cells.

Renal gluconeogenesis in the healthy kidney

The liver was generally considered as the site of gluconeogenesis. In 1937, the ability of kidney slices to produce glucose in response to pyruvate and lactate exposure suggested the gluconeogenic role of the kidney [2]. One year later, another group showed that, compared with hepatectomized rabbits, those who additionally underwent renal artery ligatures needed more glucose to maintain euglycaemia [10]. Four decades later, with the isotopic method, the kidney was finally well recognized as a major organ for gluconeogenesis [3]. In the kidney, gluconeogenesis takes place in the proximal tubule, where the key specific enzymes are exclusively expressed in segments S1–S3 [11–13], with much lower activities in the latter portion of the nephron [14, 15]. Even under maximal stimulation, distal nephron segments are unable to perform gluconeogenesis. We confirmed using transcriptomic data from single-nucleus RNA sequencing of mice kidneys that the expression of rate-limiting enzymes PEPCK/PCK1 and FBP are restricted to segments S1, S2 and S3 of the proximal tubule in mice [16]. In contrast, the distal nephron consumes glucose and expresses the key enzymes of the glycolytic pathway (hexokinases, 6-phosphofructokinases and pyruvate kinases), which are not present in the proximal tubule in normal conditions [15, 17, 18].

Due to this functional partition resulting in both consumption and production of glucose, renal gluconeogenesis has been underestimated by net organ balance measurements [19–22]. In 1995, the first isotopic method able to measure separately renal glucose uptake and release was described [23]. In the post-absorptive phase, after 14–16 h of fasting, serum glucose levels were stable, implying that systemic glucose release was equivalent to systemic glucose uptake, at a rate of ~10 µmol/kg/min. In this study, the kidney accounted for ∼30% of the systemic glucose rate of appearance in 10 healthy human volunteers after an overnight fast. Interestingly, because of the considerable renal glucose uptake observed in these patients (20% of systemic glucose disposal), the renal net balance was small (˂1 µmol/kg/min) compared with that of the liver (8 µmol/kg/min). Subsequent human studies obtained similar results, with a renal contribution to systemic gluconeogenesis equivalent to 20 ± 2% of the total body glucose production [3] after an overnight fast. Considering that gluconeogenesis accounts for ∼50% of glucose production after an overnight fast [24–29] and that all renal glucose release is produced by gluconeogenesis, as normal kidney contains only limited glycogen stocks in the medulla [30] with only low levels of G6P enzymes expression [31], one can conclude that renal gluconeogenesis is responsible for ∼40% of the systemic gluconeogenesis after an overnight fast [3]. As fasting progresses, glycogen stores are depleted and the role of gluconeogenesis increases to maintain stable glucose levels, reaching 90% of the whole-body glucose production in healthy humans after fasting >40 h [1, 25, 26]. After prolonged starvation, the kidney contributed up to 50% of the total systemic glucose production [32]. Altogether, kidney gluconeogenesis plays a critical role in glucose homoeostasis, particularly in fasting conditions (Figure 2).

Substrates of renal gluconeogenesis

Gluconeogenesis can produce glucose from various precursors such as glycerol, lactate and amino acids, mostly alanine and glutamine. In post-absorptive healthy volunteers, renal gluconeogenesis was shown to rely mainly on lactate, glutamine and glycerol that accounted for ∼50, 20 and 10% of renal glucose release, respectively, in two different studies [29, 33]. The kidney is also able to metabolize fructose, since the infusion of 2 mmol/min fructose in healthy humans after a 60-h fast induced an increase in net renal glucose and lactate production, suggesting an enhancement of both glycolytic and gluconeogenic pathways [34]. In freshly microdissected human nephron segments, proximal tubules exhibited heterogeneity in the gluconeogenic rate from lactate but not glutamine, with the S2 and S3 segments synthesizing more glucose from lactate than the S1 segment [35]. These findings thus highlighted the role of the kidney in lactate metabolism.

Lactate is fully filtered by the glomerulus and reabsorbed in the proximal tubule [36] until a threshold of 10 mmol/L is reached, where urinary excretion occurs [37]. Lactate uptake from the tubular lumen occurs through a carrier-mediated process involving sodium-coupled monocarboxylate transporters (MCTs) 1 and 2 and proton-linked MCTs (MCT8), all using the sodium gradient as a driving force [38, 39]. Tubular proximal cells also expressed proton-linked MCTs (MCT1 and MCT2) at the basolateral side and may act as an efflux pathway of the reabsorbed lactate towards the blood or in taking up lactate or pyruvate from the circulation for gluconeogenesis [40].

The kidney is both a lactate producer and consumer, with marked differences between the cortex and the medulla. Due to the low oxygen tension [41], the distal nephron segments rely mainly on glycolysis to generate adenosine triphosphate (ATP) [42], resulting in net lactate generation [43]. Thus the distal nephron, including the thick ascending limb, the distal convoluted tubules and the collecting duct, all display the highest activity of glycolytic enzymes [43]. This produced lactate acts as a substrate for cortical gluconeogenesis, leading to a corticomedullary glucose lactate recycling loop [44]. In contrast, the cortex relies mainly on oxidative phosphorylation to generate ATP [45–47]. Renal lactate uptake is a non-saturable process over a wide range of lactate levels, as shown after lactate infusion in healthy sheep [48]. As a consequence, at an arterial concentration of 9 mmol/L, the liver is not the dominant organ for lactate clearance [48]. Renal lactate uptake is not directly related to oxygen consumption, suggesting that most lactate reabsorbed in the kidney is used for gluconeogenesis [49]. Finally, in rats submitted to an intravenous lactic acid load, the kidney was responsible for 30% of lactate removal, highlighting the major role of the kidney in systemic lactate clearance [50] (Figure 3).

Regulation of renal gluconeogenesis

Renal gluconeogenesis is hormonally regulated. A 3-fold increase in renal gluconeogenesis was observed after the infusion of stress hormones (combining hydrocortisone, epinephrine, norepinephrine and glucagon) in dogs, accounting at the end for 22% of the overall glucose production. In this experiment, the kidney seemed to be more sensitive to the stimulation than the liver [51]. Further studies focused on each hormone separately. Methylprednisolone infusion was shown to increase glucose net balance of isolated perfused rat kidney 2-fold [52]. This effect could be mediated by an increase in PEPCK and PC activities [53–55] related to upregulation in gene expression [56, 57] and translation [58]. In post-absorptive healthy volunteers, a continuous infusion of epinephrine at a rate of 50 ng/kg/min increased renal glucose release by 2-fold, accounting for 40% of total systemic glucose [23]. This response was sustained in the kidney, whereas it was only transient in the liver. Epinephrine may also increase gluconeogenic substrate availability and increase the efficiency of renal gluconeogenesis [29]. Renal denervation may also directly regulate renal glucose production, as unilateral renal denervation leads to a decrease in renal glucose release [59].

The effects of insulin on gluconeogenesis have been extensively studied. In healthy post-absorptive humans, two independent groups reported a decrease in renal glucose release and an increase in renal glucose uptake during a hyperinsulinaemic–euglycaemic clamp experiment. Several mechanisms link insulin to gluconeogenesis. At the transcriptional level, insulin decreases PCK1 and G6P mRNA expression both in vivo and in vitro [60] via tyrosine phosphorylation of insulin receptor substrates (IRSs) 1 and 2 and further phosphorylation of forkhead box protein O1 (FOXO1) via the canonical pathway IRS/Pi3k/Akt/FOXO1 [61], leading to its nuclear exclusion. Insulin also reduces the availability of gluconeogenic substrates, mainly glycerol and glutamine [62, 63]. The suppression of plasma-free fatty acids could itself decrease renal gluconeogenesis [64]. Finally, insulin could induce a redirection of the gluconeogenic substrates to the oxidative pathways to compensate for the decrease in free fatty acid and sustain energy production [3, 62].

Glucose levels play a direct role in renal gluconeogenesis regulation. Proximal tubules reabsorb glucose via sodium-dependent glucose transporters (SGLTs) 1 and 2. In a glucose-rich medium, glucose reabsorption increases, increasing the ratio between the oxidized and reduced form of nicotinamide adenine dinucleotide (NAD+/NADH), inhibiting deacetylation of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) in sirtuin-1SIRT1–dependent manner, leading to a downregulation of PCK1 gene expression [60]. Interestingly, the novel SGLT2 inhibitors stimulate renal gluconeogenesis in the proximal tubule [60].

Acidosis induces PEPCK mRNA expression [14] and activity [58] in the proximal tubule. This transcriptional regulation is independent of nuclear factors but requires an intact hepatocyte nuclear factor (HNF)-1 binding site in the gene promoter [65]. It results in an increase in renal glucose production [66]. Whereas extrarenal lactate clearance decreases with acidosis, renal ability to remove lactate increases with a low pH [50]. Coordinated with ammoniogenesis, renal gluconeogenesis results in glucose production and acid excretion, contributing to maintenance of systemic acid–base homoeostasis [67, 68].

Both in vitro and in vivo studies have reported the relation between gluconeogenic substrate concentrations and the rate of gluconeogenesis. For example, isotopic lactate or alanine infusion in patients with non-insulin-dependent diabetes mellitus increased the systemic gluconeogenesis rate >2-fold, accounting for ∼50% of glucose [69]. Similar results were reported for glycerol [70, 71] or alanine [72] infusion in dogs. In addition, fatty acids [73], ketone bodies [74] and glycerol [71] could inhibit the oxidation of lactate and pyruvate and simultaneously increase their conversion to glucose through a sparing effect on other precursors and action on enzymatic activity. Altogether, renal gluconeogenesis appears to be particularly enhanced by stress hormones, insulin and acidosis, suggesting a critical role in critical illness.

Gluconeogenesis and kidney disease

Renal function and hypoglycaemia risk

Hypoglycaemia has classically been related to liver failure. Considering the high rate of renal gluconeogenesis and its importance in glucose homoeostasis, impairment of renal function could also lead to hypoglycaemia. In 1986, a retrospective study reported in 94 hospitalized patients that chronic kidney disease [CKD; defined as a serum creatinine level >265 µmol/L, estimated glomerular filtration rate (eGFR)˂40 mL/min or the need for renal replacement therapy] was the factor most associated with the incidence of hypoglycaemia (defined as glucose levels ˂49 mg/dL) [75]. A possible link with renal gluconeogenesis impairment was then suggested [76]. In a woman with diabetes mellitus and chronic renal failure, endogenous glucose production was measured because of repetitive episodes of fasting hypoglycaemia. Using glucose isotope infusion, the authors described a severe impairment of systemic gluconeogenesis [77]. A report from 1978 mentioned four non-diabetic patients on dialysis developing spontaneous hypoglycaemia associated with metabolic acidosis related to hyperlactataemia [78]. Reduced insulin clearance has been speculated to explain part of this observation [79], but a recent study showed that insulin secretion, sensitivity and clearance were not associated with eGFR when adjusted for confounding factors in non-diabetic CKD patients with an eGFR ˂60 mL/min/1.73 m2 compared with healthy volunteers [80]. In 2009, a large retrospective cohort analysis including 243 222 patients reported a higher incidence of hypoglycaemia in patients with CKD. This was also true in non-diabetic patients (2.23 versus 3.46/100 patient-months, P < 0.0001), excluding the participation of anti-diabetic therapies [81]. Altogether these data demonstrate an association between renal function and the risk of hypoglycaemia.

Renal function and lactate clearance

Because the kidney mostly depends on lactate as a gluconeogenic substrate, it also plays a major role in the systemic clearance of this metabolite. Renal disease could thus be associated with decreased lactate clearance and hyperlactataemia. The clinical relevance of this metabolic function could be major since lactate clearance during acute disease is associated with mortality [82]. However, only one observational cohort study was performed in end-stage renal disease patients and reported a high prevalence of hyperlactataemia, but without the presence of a control group [83].

Renal gluconeogenesis in acute kidney injury (AKI)

Renal disease is associated with large modifications of renal metabolism [84–86]. In vitro, the medullary thick ascending limb and the cortical and outer medullar collecting duct dramatically increase their glycolysis rate in response to anoxia, leading to an increase in lactate release [42]. Several models of renal injury have confirmed this pattern, including mercuric acid-induced acute tubular necrosis [87] and septic [88] and ischaemia–reperfusion injury (IRI)-related AKI [89–91]. These changes were shown to be persistent in atrophic tubules [92]. Taken together, these results suggest a switch from oxidative phosphorylation to glycolysis during renal injury.

In contrast, little is known about gluconeogenesis regulation during AKI. Considering the facts that a competition exists between renal sodium transport and glucose production [52, 93–96] and lactate consumption [44] when ATP disposal is limited and that glycolysis and gluconeogenesis are reciprocally regulated [97], a decrease in renal gluconeogenesis during AKI seemed plausible. We recently demonstrated using human renal arteriovenous catheterization that cardiac surgery–related AKI was associated with decreased renal glucose release and lactate uptake [16]. This was in line with a recent study where renal arteriovenous catheterization was performed in kidney allograft recipients, showing that patients who experienced delayed graft function exhibited a positive net renal lactate balance and a lower glucose renal tissue content [98]. Consistent with this hypothesis, we could show that the expression of gluconeogenic enzymes dramatically decreased during the reperfusion phase of a kidney allograft compared with a more stable phase. To confirm the defect in gluconeogenesis, we further performed several in vivo experiments to demonstrate that systemic lactate clearance was altered in AKI and that renal glucose release was reduced after ischaemic AKI in rats, in agreement with the expression, translation and activities of key gluconeogenic enzymes such as PCK1 and FBP1. The cause of these changes has yet to be determined. In particular, further investigations are required to elucidate whether changes in renal gluconeogenesis represent a passive effect of impaired cell energy metabolism or a coordinated regulated biologic process. In fact, several elements suggest that the fundamental changes in metabolism occurring in the kidney responding to injury may represent a coordinated process. Notably, several recent studies have highlighted that the oxidative phosphorylation defect occurring during AKI and driving the transition to CKD [84–86, 99, 100] was related to PGC1α downregulation [85, 99, 101, 102]. PGC1α is a transcriptional coactivator acting as a global metabolism enhancer, including for stimulation of oxidative metabolism and mitochondria biogenesis [103] and gluconeogenesis through the HNF4α [104] and FOXO1 (Forkhead Box Protein O1) [105]. Overexpression of PGC1α in hepatic cells enhances PCK1, G6P and FBP1 transcription and increases glucose production [106]. NAD is required for gluconeogenesis, both directly for reduction of diphosphoglycerate to glyceraldehyde phosphate [107, 108] and indirectly for sirtuin-1 enhancement. Sirtuin-1 is a histone deacetylase shown to be protective in IRI AKI [109, 110] Sirtuin-1 deacetylates PCK1, restoring its gluconeogenic capacity [111]. Kidney NAD content decreases in different experimental models of AKI [100]. Using single nucleus RNA sequencing, we confirmed that expression of gluconeogenic rate-limiting enzymes was strongly reduced after IRI-induced AKI as well as classical transcriptional regulators such as peroxisome proliferator-activated receptor α and HNF4. Thus alteration of gluconeogenesis is likely to be an important component of a global metabolic switch occurring in the kidney tubular cells in response to injury.

Renal gluconeogenesis and metabolic syndrome

In patients with morbid obesity, renal and hepatic gluconeogenesis are almost similar after a prolonged fast [32]. In proteinuric obese patients, mammalian target of rapamycin complex 1  is upregulated in the proximal tubule cells [112] and the uptake of fatty acid is increased [113], leading to lipid droplet accumulation as triacylglycerol in the cortex [114] and, finally, to enhancement of renal gluconeogenesis via an increase in acetyl coenzyme A concentrations [115]. Intracellular fat accumulation has also been shown to drive insulin resistance [116]. Considering the renal effect of insulin on gluconeogenesis, one could hypothesize an increase in renal glucose production in obesity through insulin resistance. Mice with proximal tubule deletion of the insulin receptor displayed higher fasting glucose levels associated with elevated activity of G6P in renal cortex homogenates, which could be related to enhanced gluconeogenesis [117]. In insulin-resistant diabetic Zucker rats, a disinhibition of renal gluconeogenesis due to increased mRNA expression and activity of gluconeogenic enzymes was observed [118]. Nevertheless, a recent study conducted by Sasaki et al. [60] reported that, in streptozotocin-treated animals, gluconeogenesis was downregulated, likely via a different pathway than insulin resistance . Thus the net effect of metabolic syndrome on renal gluconeogenesis is still to be determined.

Clinical relevance of renal gluconeogenesis alterations

Is renal gluconeogenesis important and is the regulation observed during AKI of clinical interest? To answer these questions we retrospectively analysed glucose and lactate levels in intensive care unit (ICU) patients and observed, as already suggested by Freire Jorge et al. [119], that AKI correlates with a specific systemic metabolic pattern associating high lactate and low glucose levels. Interestingly, the impact of liver failure was less important than renal failure. Very importantly, and in agreement with the fact that both hypoglycaemia and decreased lactate clearance [82, 119] are associated with an adverse outcome, AKI-associated mortality was restricted to patients displaying higher lactate and lower glucose levels. This suggests that the metabolic function of tubule cells could have a systemic relevance beyond the kidney and may influence the systemic aspect of metabolism and finally mortality, at least in the specific context of critical illness. The enhanced glycolysis observed during renal disease may also play an important role in the phenotype [92, 120].

Whether gluconeogenesis modulation during AKI only reflects the injury severity or plays a role in disease progression should be investigated. For instance, whereas FBP1 has been shown to be depleted in clear cell renal cell carcinoma, in vitro overexpression inhibited glycolysis and restrained cell proliferation by inhibiting nuclear hypoxia-inducible factor function [121]. In hepatocarcinoma, dexamethasone, an active form of synthesized glucocorticoids, is able to restore gluconeogenesis, leading to therapeutic efficacy against hepatocarcinoma [122]. As previously described, renal gluconeogenesis may be modulated by several stimuli. Among these, SGLT2 inhibitors appear to be associated with the enhancement of renal gluconeogenesis [123] and improvement of the renal prognosis [124]. Steroids are known enhancers of renal and liver gluconeogenesis (see above). Recent meta-analyses including all major randomized controlled trials reported that steroids confer no or minimal mortality benefit in septic patients, but the very different complex of this class precludes any conclusion on a specific effect on renal gluconeogenesis [125–127]. Thiamine is a critical cofactor for several reactions occurring in the mitochondria [128]. In a retrospective study using propensity score for thiamine supplementation matching, we observed an improvement in the systemic metabolic pattern and a decrease in ICU mortality in patients receiving thiamine. This was in line with previous studies showing improvement in both lactate clearance and 28-day mortality in patients receiving thiamine [129]. If confirmed in prospective interventional trials, these data would promote renal gluconeogenesis as one of the most important functions of the kidney in ICU patients and as a new pharmacological target to improve overall prognosis in AKI.

CONCLUSION

Gluconeogenesis is a neglected metabolic function of the kidney. Alterations of renal gluconeogenesis may be an important part of the global metabolic changes observed during AKI and its systemic repercussions may be of major importance in critically ill patients. Whether modulation of this pathway can rescue the poor prognosis of AKI deserves further studies.

FUNDING

D.L. is the recipient of a STARTER grant (RS03-25) from the the foundation of the Geneva University Hospitals and the University of Geneva’s Faculty of Medicine. S.d.S. is supported by the Swiss National Science Foundation (grant PP00P3 157454).

REFERENCES

1

Rothman
DL
Magnusson
I
Katz
LD
et al.
Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR
.
Science
1991
;
254
:
573
576

2

Elliott
KAC
Greig
ME
Benoy
MP.
The metabolism of lactic and pyruvic acids in normal and tumour tissues
.
Biochem J
1937
;
31
:
1003
1020

3

Gerich
JE
Meyer
C
Woerle
HJ
et al.
Renal gluconeogenesis: its importance in human glucose homeostasis
.
Diabetes Care
2001
;
24
:
382
391

4

Gray
LR
Tompkins
SC
Taylor
EB.
Regulation of pyruvate metabolism and human disease
.
Cell Mol Life Sci
2014
;
71
:
2577
2604

5

Rognstad
R.
Rate-limiting steps in metabolic pathways
.
J Biol Chem
1979
;
254
:
1875
1878

6

Quinn
PG
Yeagley
D.
Insulin regulation of PEPCK gene expression: a model for rapid and reversible modulation
.
Curr Drug Targets Immune Endocr Metabol Disord
2005
;
5
:
423
437

7

Bertinat
R
Pontigo
JP
Pérez
M
et al.
Nuclear accumulation of fructose 1,6-bisphosphatase is impaired in diabetic rat liver
.
J Cell Biochem
2012
;
113
:
848
856

8

Mithieux
G
Vidal
H
Zitoun
C
et al.
Glucose-6-phosphatase mRNA and activity are increased to the same extent in kidney and liver of diabetic rats
.
Diabetes
1996
;
45
:
891
896

9

Stumvoll
M
Perriello
G
Meyer
C
et al.
Role of glutamine in human carbohydrate metabolism in kidney and other tissues
.
Kidney Int
1999
;
55
:
778
792

10

Bergman
H
Drury
DR.
The relationship of kidney function to the glucose utilization of the extra abdominal tissues
.
Am J Physiol
1938
;
124
:
279
284

11

Schmid
H
Scholz
M
Mall
A
et al.
Carbohydrate metabolism in rat kidney: heterogeneous distribution of glycolytic and gluconeogenic key enzymes
.
Curr Probl Clin Biochem
1977
;
8
:
282
289

12

Guder
WG
Schmidt
U.
The localization of gluconeogenesis in rat nephron. Determination of phosphoenolpyruvate carboxykinase in microdissected tubules.
Hoppe-Seylers Z Physiol Chem
1974
;
355
:
273
278

13

Vandewalle
A
Wirthensohn
G
Heidrich
HG
et al.
Distribution of hexokinase and phosphoenolpyruvate carboxykinase along the rabbit nephron
.
Am J Physiol
1981
;
240
:
F492
F
500

14

Burch
HB
Narins
RG
Chu
C
et al.
Distribution along the rat nephron of three enzymes of gluconeogenesis in acidosis and starvation
.
Am J Physiol
1978
;
235
:
F246
F
253

15

Guder
WG
Ross
BD.
Enzyme distribution along the nephron
.
Kidney Int
1984
;
26
:
101
111

16

Legouis
D
Ricksten
SE
Faivre
A
et al.
Altered proximal tubular cell glucose metabolism during acute kidney injury is associated with mortality
.
Nat Metab
2020
;
2
:
732–743

17

Ross
BD
Espinal
J
Silva
P.
Glucose metabolism in renal tubular function
.
Kidney Int
1986
;
29
:
54
67

18

Lee
JW
Chou
C-L
Knepper
MA.
Deep sequencing in microdissected renal tubules identifies nephron segment-specific transcriptomes
.
J Am Soc Nephrol
2015
;
26
:
2669
2677

19

Meriel
P
Galinier
F
Suc
J
et al.
Le metabolisme du rein humain
.
Rev Franc Etudes Clin et Biol
1958
;
3
:
332
344

20

Björkman
O
Gunnarsson
R
Hagström
E
et al.
Splanchnic and renal exchange of infused fructose in insulin-deficient type 1 diabetic patients and healthy controls
.
J Clin Invest
1989
;
83
:
52
59

21

Ahlborg
G
Weitzberg
E
Sollevi
A
et al.
Splanchnic and renal vasoconstrictor and metabolic responses to neuropeptide Y in resting and exercising man
.
Acta Physiol Scand
1992
;
145
:
139
149

22

Brundin
T
Wahren
J.
Renal oxygen consumption, thermogenesis, and amino acid utilization during i.v. infusion of amino acids in man
.
Am J Physiol
1994
;
267
:
E648
E655

23

Stumvoll
M
Chintalapudi
U
Perriello
G
et al.
Uptake and release of glucose by the human kidney. Postabsorptive rates and responses to epinephrine
.
J Clin Invest
1995
;
96
:
2528
2533

24

Petersen
KF
Price
T
Cline
GW
et al.
Contribution of net hepatic glycogenolysis to glucose production during the early postprandial period
.
Am J Physiol Endocrinol Metab
1996
;
270
:
E186
E191

25

Landau
BR
Wahren
J
Chandramouli
V
et al.
Contributions of gluconeogenesis to glucose production in the fasted state
.
J Clin Invest
1996
;
98
:
378
385

26

Chandramouli
V
Ekberg
K
Schumann
WC
et al.
Quantifying gluconeogenesis during fasting
.
Am J Physiol Endocrinol Metab
1997
;
273
:
E1209
E1215

27

Gay
LJ
Schneiter
P
Schutz
Y
et al.
A non-invasive assessment of hepatic glycogen kinetics and post-absorptive gluconeogenesis in man
.
Diabetologia
1994
;
37
:
517
523

28

Tayek
JA
Katz
J.
Glucose production, recycling, and gluconeogenesis in normals and diabetics: a mass isotopomer [U-13C] glucose study
.
Am J Physiol Endocrinol Metab
1996
;
270
:
E709
E717

29

Meyer
C
Stumvoll
M
Dostou
J
et al.
Renal substrate exchange and gluconeogenesis in normal postabsorptive humans
.
Am J Physiol Endocrinol Metab
2002
;
282
:
E428
E434

30

Needleman
P
Passonneau
JV
Lowry
OH.
Distribution of glucose and related metabolites in rat kidney
.
Am J Physiol
1968
;
215
:
655
659

31

Wu
H
Uchimura
K
Donnelly
EL
et al.
Comparative analysis and refinement of human PSC-derived kidney organoid differentiation with single-cell transcriptomics
.
Cell Stem Cell
2018
;
23
:
869
881.e8

32

Owen
OE
Felig
P
Morgan
AP
et al.
Liver and kidney metabolism during prolonged starvation
.
J Clin Invest
1969
;
48
:
574
583

33

Stumvoll
M
Meyer
C
Kreider
M
et al.
Effects of glucagon on renal and hepatic glutamine gluconeogenesis in normal postabsorptive humans
.
Metabolism
1998
;
47
:
1227
1232

34

Björkman
O
Felig
P.
Role of the kidney in the metabolism of fructose in 60-hour fasted humans
.
Diabetes
1982
;
31
(6 Pt 1):
516
520

35

Conjard
A
Martin
M
Guitton
J
et al.
Gluconeogenesis from glutamine and lactate in the isolated human renal proximal tubule: longitudinal heterogeneity and lack of response to adrenaline
.
Biochem J
2001
;
360(Pt 2
):
371
377

36

Höhmann
B
Frohnert
PP
Kinne
R
et al.
Proximal tubular lactate transport in rat kidney: a micropuncture study
.
Kidney Int
1974
;
5
:
261
270

37

Leal-Pinto
E
Park
H
King
F
et al.
Metabolism of lactate by the intact functioning kidney of the dog
.
Am J Physiol Legacy Content
1973
;
224
:
1463
1467

38

Halestrap
AP.
Monocarboxylic acid transport
.
Comprehen Physiol
2013
;
3
:
33

39

Becker
HM
Mohebbi
N
Perna
A
et al.
Localization of members of MCT monocarboxylate transporter family Slc16 in the kidney and regulation during metabolic acidosis
.
Am J Physiol Renal Physiol
2010
;
299
:
F141
F154

40

Iwanaga
T
Kishimoto
A.
Cellular distributions of monocarboxylate transporters: a review
.
Biomed Res
2015
;
36
:
279
301

41

Baumgärtl
H
Leichtweiss
HP
Lübbers
DW
et al.
The oxygen supply of the dog kidney: measurements of intrarenal pO
2.
Microvasc Res
1972
;
4
:
247
257

42

Bagnasco
S
Good
D
Balaban
R
et al.
Lactate production in isolated segments of the rat nephron
.
Am J Physiol Renal Physiol
1985
;
248
:
F522
F526

43

Wirthensohn
G
Guder
WG.
Renal substrate metabolism
.
Physiol Rev
1986
;
66
:
469
497

44

Bartlett
S
Espinal
J
Janssens
P
et al.
The influence of renal function on lactate and glucose metabolism
.
Biochem J
1984
;
219
:
73
78

45

Klein
KL
Wang
MS
Torikai
S
et al.
Substrate oxidation by isolated single nephron segments of the rat
.
Kidney Int
1981
;
20
:
29
35

46

Weidemann
MJ
Krebs
HA.
The fuel of respiration of rat kidney cortex
.
Biochem J
1969
;
112
:
149
166

47

Baverel
G
Forissier
M
Pellet
M.
Lactate and pyruvate metabolism in dog renal outer medulla. Effects of oleate and ketone bodies
.
Int J Biochem
1980
;
12
:
163
168

48

Naylor
JM
Kronfeld
DS
Freeman
DE
et al.
Hepatic and extrahepatic lactate metabolism in sheep: effects of lactate loading and pH
.
Am J Physiol Endocrinol Metab
1984
;
247
:
E747
E755

49

Brand
P
Cohen
J
Bignall
M.
Independence of lactate oxidation from net Na+ reabsorption in dog kidney in vivo
.
Am J Physiol Legacy Content
1974
;
227
:
1255
1262

50

Yudkin
J
Cohen
RD.
The contribution of the kidney to the removal of a lactic acid load under normal and acidotic conditions in the conscious rat
.
Clin Sci Mol Med
1975
;
48
:
121
131

51

McGuinness
OP
Fugiwara
T
Murrell
S
et al.
Impact of chronic stress hormone infusion on hepatic carbohydrate metabolism in the conscious dog
.
Am J Physiol
1993
;
265
(2 Pt 1):
E314
E322

52

Silva
P
Ross
B
Spokes
K.
Competition between sodium reabsorption and gluconeogenesis in kidneys of steroid-treated rats
.
Am J Physiol
1980
;
238
:
F290
F295

53

Filsell
OH
Jarrett
IG
Taylor
PH
et al.
Effects of fasting, diabetes and glucocorticoids on gluconeogenic enzymes in the sheep
.
Biochim Biophys Acta
1969
;
184
:
54
63

54

Flores
H
Alleyne
GA.
Phosphoenolpyruvate carboxykinase of kidney. Subcellular distribution and response to acid-base changes
.
Biochem J
1971
;
123
:
35
39

55

Joseph
PK
Subrahmanyam
K.
Evaluation of the rate-limiting steps in the pathway of glucose metabolism in kidney cortex of normal, diabetic, cortisone-treated and growth hormone-treated rats
.
Biochem J
1972
;
128
:
1293
1301

56

Iynedjian
PB
Hanson
RW.
Messenger RNA for renal phosphoenolpyruvate carboxykinase (GTP). Its translation in a heterologous cell-free system and its regulation by glucocorticoids and by changes in acid-base balance
.
J Biol Chem
1977
;
252
:
8398
8403

57

Meisner
H
Loose
DS
Hanson
RW.
Effect of hormones on transcription of the gene for cytosolic phosphoenolpyruvate carboxykinase (GTP) in rat kidney
.
Biochemistry
1985
;
24
:
421
425

58

Longshaw
ID
Alleyne
GAO
Pogson
CI.
The effect of steroids and ammonium chloride acidosis on phosphoenolpyruvate carboxykinase in rat kidney cortex: II. the kinetics of enzyme induction
.
J Clin Invest
1972
;
51
:
2284
2291

59

Bischoff
SJ
Schmidt
M
Lehmann
T
et al.
Renal glucose release during hypoglycemia is partly controlled by sympathetic nerves – a study in pigs with unilateral surgically denervated kidneys
.
Physiol Rep
2015
;
3
:
e12603

60

Sasaki
M
Sasako
T
Kubota
N
et al.
Dual regulation of gluconeogenesis by insulin and glucose in the proximal tubules of the kidney
.
Diabetes
2017
;
66
:
2339
2350

61

Accili
D
Arden
KC.
FoxOs at the crossroads of cellular metabolism, differentiation, and transformation
.
Cell
2004
;
117
:
421
426

62

Meyer
C
Dostou
J
Nadkarni
V
et al.
Effects of physiological hyperinsulinemia on systemic, renal, and hepatic substrate metabolism
.
Am J Physiol
1998
;
275
:
F915
F
921

63

Cersosimo
E
Garlick
P
Ferretti
J.
Insulin regulation of renal glucose metabolism in humans
.
Am J Physiol Endocrinol Metab
1999
;
276
:
E78
E84

64

Staehr
P
Hother-Nielsen
O
Landau
BR
et al.
Effects of free fatty acids per se on glucose production, gluconeogenesis, and glycogenolysis
.
Diabetes
2003
;
52
:
260
267

65

Cassuto
H
Olswang
Y
Heinemann
S
et al.
The transcriptional regulation of phosphoenolpyruvate carboxykinase gene in the kidney requires the HNF-1 binding site of the gene
.
Gene
2003
;
318
:
177
184

66

Steiner
A
Goodman
A
Treble
D.
Effect of metabolic acidosis on renal gluconeogenesis in vivo
.
Am J Physiol
1968
;
215
:
211
217

67

Curthoys
NP
Gstraunthaler
G.
pH-responsive, gluconeogenic renal epithelial LLC-PK1-FBPase+ cells: a versatile in vitro model to study renal proximal tubule metabolism and function
.
Am J Physiol Renal Physiol
2014
;
307
:
F1
F11

68

Curthoys
NP
Moe
OW.
Proximal tubule function and response to acidosis
.
Clin J Am Soc Nephrol
2014
;
9
:
1627
1638

69

Jenssen
T
Nurjhan
N
Consoli
A
et al.
Failure of substrate-induced gluconeogenesis to increase overall glucose appearance in normal humans. Demonstration of hepatic autoregulation without a change in plasma glucose concentration
.
J Clin Invest
1990
;
86
:
489
497

70

Steele
R
Winkler
B
Altszuler
N.
Inhibition by infused glycerol of gluconeogenesis from other precursors
.
Am J Physiol
1971
;
221
:
883
888

71

Jahoor
F
Peters
EJ
Wolfe
RR.
The relationship between gluconeogenic substrate supply and glucose production in humans
.
Am J Physiol Endocrinol Metab
1990
;
258
:
E288
E296

72

Diamond
MP
Rollings
RC
Steiner
KE
et al.
Effect of alanine concentration independent of changes in insulin and glucagon on alanine and glucose homeostasis in the conscious dog
.
Metab Clin Exp
1988
;
37
:
28
33

73

Guder
WG
Wieland
OH
Stukowski
B.
Metabolism of isolated kidney tubules. Additive effects of parathyroid hormone and free-fatty acids on renal gluconeogenesis
.
Eur J Biochem
1972
;
31
:
69
79

74

Krebs
HA
Speake
RN
Hems
R.
Acceleration of renal gluconeogenesis by ketone bodies and fatty acids
.
Biochem J
1965
;
94
:
712
720

75

Fischer
KF
Lees
JA
Newman
JH.
Hypoglycemia in hospitalized patients. Causes and outcomes
.
N Engl J Med
1986
;
315
:
1245
1250

76

Peitzman
SJ
Agarwal
BN.
Spontaneous hypoglycemia in end-stage renal failure
.
Nephron
1977
;
19
:
131
139

77

Garber
AJ
Bier
DM
Cryer
PE
et al.
Hypoglycemia in compensated chronic renal insufficiency: substrate limitation of gluconeogenesis
.
Diabetes
1974
;
23
:
982
986

78

Rutsky
EA
McDaniel
HG
Tharpe
DL
et al.
Spontaneous hypoglycemia in chronic renal failure
.
Arch Intern Med
1978
;
138
:
1364
1368

79

Rabkin
R
Simon
NM
Steiner
S
et al.
Effect of renal disease on renal uptake and excretion of insulin in man
.
N Engl J Med
1970
;
282
:
182
187

80

de Boer
IH
Zelnick
L
Afkarian
M
et al.
Impaired glucose and insulin homeostasis in moderate-severe CKD
.
J Am Soc Nephrol
2016
;
27
:
2861
2871

81

Moen
MF
Zhan
M
Hsu
VD
et al.
Frequency of hypoglycemia and its significance in chronic kidney disease
.
Clin J Am Soc Nephrol
2009
;
4
:
1121
1127

82

Levraut
J
Ichai
C
Petit
I
et al.
Low exogenous lactate clearance as an early predictor of mortality in normolactatemic critically ill septic patients
.
Critic Care Med
2003
;
31
:
705
710

83

Hourmozdi
JJ
Gill
J
Miller
JB
et al.
Change in lactate levels after hemodialysis in patients with end-stage renal disease
.
Ann Emerg Med
2018
;
71
:
737
742

84

Kang
HM
Ahn
SH
Choi
P
et al.
Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development
.
Nat Med
2015
;
21
:
37
11

85

Tran
MT
Zsengeller
ZK
Berg
AH
et al.
PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection
.
Nature
2016
;
531
:
528
532

86

Poyan Mehr
A
Tran
MT
Ralto
KM
et al.
De novo NAD+ biosynthetic impairment in acute kidney injury in humans
.
Nat Med
2018
;
24
:
1351
1359

87

Ash
SR
Cuppage
FE.
Shift toward anaerobic glycolysis in the regenerating rat kidney
.
Am J Pathol
1970
;
60
:
385
402

88

Waltz
P
Carchman
E
Gomez
H
et al.
Sepsis results in an altered renal metabolic and osmolyte profile
.
J Surg Res
2016
;
202
:
8
12

89

Smith
JA
Stallons
LJ
Schnellmann
RG.
Renal cortical hexokinase and pentose phosphate pathway activation through the EGFR/Akt signaling pathway in endotoxin-induced acute kidney injury
.
Am J Physiol Renal Physiol
2014
;
307
:
F435
F4
44

90

Zager
RA
Johnson
ACM
Becker
K.
Renal cortical pyruvate depletion during AKI
.
J Am Soc Nephrol
2014
;
25
:
998
1012

91

Eklund
T
Wahlberg
J
Ungerstedt
U
et al.
Interstitial lactate, inosine and hypoxanthine in rat kidney during normothermic ischaemia and recirculation
.
Acta Physiol Scand
1991
;
143
:
279
286

92

Lan
R
Geng
H
Singha
PK
et al.
Mitochondrial pathology and glycolytic shift during proximal tubule atrophy after ischemic AKI
.
J Am Soc Nephrol
2016
;
27
:
3356
3367

93

Soltoff
SP.
ATP and the regulation of renal cell function
.
Annu Rev Physiol
1986
;
48
:
9
31

94

Gullans
SR
Brazy
PC
Dennis
VW
et al.
Interactions between gluconeogenesis and sodium transport in rabbit proximal tubule
.
Am J Physiol
1984
;
246
:
F859
F
869

95

Veiga
JA
Carpenter
CA
Saggerson
ED.
Effect of the Na+ ionophore monensin on basal and noradrenaline stimulated gluconeogenesis in rat renal tubule fragments
.
FEBS Lett
1981
;
134
:
183
184

96

Fulgraff
G
Nemann
H
Sudhoff
D.
Effects of the diuretics furosemide, ethacrynic acid, and chlorothiazide on gluconeogenesis from various substrates in rat kidney cortex slices
.
Naunyn Schmiedebergs Arch Pharmacol
1972
;
273
:
86
98

97

Berg
JM
Tymoczko
JL
Stryer
L.
Glycolysis and gluconeogenesis. In: Biochemistry. 5th edn. New York: W. H. Freeman,
2002
. https://www.ncbi.nlm.nih.gov/books/NBK21150/ (11 May 2020, date last accessed)

98

Wijermars
LGM
Schaapherder
AF
de Vries
DK
et al.
Defective postreperfusion metabolic recovery directly associates with incident delayed graft function
.
Kidney Int
2016
;
90
:
181
191

99

Tran
M
Tam
D
Bardia
A
et al.
PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice
.
J Clin Invest
2011
;
121
:
4003
4014

100

Katsyuba
E
Mottis
A
Zietak
M
et al.
De novo NAD+ synthesis enhances mitochondrial function and improves health
.
Nature
2018
;
563
:
354
359

101

Ruiz-Andres
O
Suarez-Alvarez
B
Sánchez-Ramos
C
et al.
The inflammatory cytokine TWEAK decreases PGC-1α expression and mitochondrial function in acute kidney injury
.
Kidney Int
2016
;
89
:
399
410

102

Collier
JB
Whitaker
RM
Eblen
ST
et al.
Rapid renal regulation of peroxisome proliferator-activated receptor gamma coactivator-1α by extracellular regulated kinase 1/2 in physiological and pathological conditions
.
J Biol Chem
2016
; 291
:
26850
26859

103

Wu
Z
Puigserver
P
Andersson
U
et al.
Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1
.
Cell
1999
;
98
:
115
124

104

Rhee
J
Inoue
Y
Yoon
JC
et al.
Regulation of hepatic fasting response by PPARΓ coactivator-1α (PGC-1): requirement for hepatocyte nuclear factor 4α in gluconeogenesis
.
Proc Natl Acad Sci USA
2003
;
100
:
4012
4017

105

Puigserver
P
Rhee
J
Donovan
J
et al.
Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1α interaction
.
Nature
2003
;
423
:
550
555

106

Yoon
JC
Puigserver
P
Chen
G
et al.
Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1
.
Nature
2001
;
413
:
131
138

107

Krebs
HA
Hems
R.
Reduced nicotinamide–adenine dinucleotide as a rate-limiting factor in gluconeogenesis
.
Biochem J
1964
;
93
:
623
627

108

Ou
SYL
Kempson
SA
Dousa
TP.
Relationship between rate of gluconeogenesis and content of nicotinamide adenine dinucleotide in renal cortex
.
Life Sci
1981
;
29
:
1195
1202

109

Wang
H
Guan
Y
Karamercan
MA
et al.
Resveratrol rescues kidney mitochondrial function following hemorrhagic shock
.
Shock
2015
;
44
:
173
180

110

Fan
H
Yang
HC
You
L
et al.
The histone deacetylase, SIRT1, contributes to the resistance of young mice to ischemia/reperfusion-induced acute kidney injury
.
Kidney Int
2013
;
83
:
404
413

111

Zhao
S
Xu
W
Jiang
W
et al.
Regulation of cellular metabolism by protein lysine acetylation
.
Science
2010
;
327
:
1000
1004

112

Yamahara
K
Kume
S
Koya
D
et al.
Obesity-mediated autophagy insufficiency exacerbates proteinuria-induced tubulointerstitial lesions
.
J Am Soc Nephrol
2013
;
24
:
1769
1781

113

Rebelos
E
Dadson
P
Oikonen
V
et al.
Renal hemodynamics and fatty acid uptake: effects of obesity and weight loss
.
Am J Physiol Endocrinol Metab
2019
;
317
:
E871
E878

114

Wirthensohn
G
Guder
WG.
Renal lipid metabolism
.
Miner Electrolyte Metab
1983
;
9
:
203
211

115

Mandel
LJ.
Metabolic substrates, cellular energy production, and the regulation of proximal tubular transport
.
Annu Rev Physiol
1985
;
47
:
85
101

116

Markova
I
Miklankova
D
Hüttl
M
et al.
The effect of lipotoxicity on renal dysfunction in a nonobese rat model of metabolic syndrome: a urinary proteomic approach
.
J Diabetes Res
2019
;
2019
:
8712979

117

Tiwari
S
Singh
RS
Li
L
et al.
Deletion of the insulin receptor in the proximal tubule promotes hyperglycemia
.
J Am Soc Nephrol
2013
;
24
:
1209
1214

118

Eid
A
Bodin
S
Ferrier
B
et al.
Intrinsic gluconeogenesis is enhanced in renal proximal tubules of Zucker diabetic fatty rats
.
J Am Soc Nephrol
2006
;
17
:
398
405

119

Freire Jorge
P
Wieringa
N
de Felice
E
et al.
The association of early combined lactate and glucose levels with subsequent renal and liver dysfunction and hospital mortality in critically ill patients
.
Crit Care
2017
;
21
:
218

120

Lemos
DR
McMurdo
M
Karaca
G
et al.
Interleukin-1β activates a MYC-dependent metabolic switch in kidney stromal cells necessary for progressive tubulointerstitial fibrosis
.
J Am Soc Nephrol
2018
;
29
:
1690
1705

121

Li
B
Qiu
B
Lee
DSM
et al.
Fructose-1,6-bisphosphatase opposes renal carcinoma progression
.
Nature
2014
;
513
:
251
255

122

Ma
R
Zhang
W
Tang
K
et al.
Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma
.
Nat Commun
2013
;
4
:
2508

123

Merovci
A
Solis-Herrera
C
Daniele
G
et al.
Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production
.
J Clin Invest
2014
;
124
:
509
514

124

Neuen
BL
Young
T
Heerspink
HJL
et al.
SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis
.
Lancet Diabet Endocrinol
2019
;
7
:
845
854

125

Rygård
SL
Butler
E
Granholm
A
et al.
Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis
.
Intensive Care Med
2018
;
44
:
1003
1016

126

Rochwerg
B
Oczkowski
SJ
Siemieniuk
RAC
et al.
Corticosteroids in sepsis: an updated systematic review and meta-analysis
.
Crit Care Med
2018
;
46
:
1411
1420

127

Annane
D
Bellissant
E
Bollaert
PE
et al.
Corticosteroids for treating sepsis in children and adults
.
Cochrane Database Syst Rev
2019
;
12
:
CD002243

128

Depeint
F
Bruce
WR
Shangari
N
et al.
Mitochondrial function and toxicity: role of B vitamins on the one-carbon transfer pathways
.
Chem Biol Interact
2006
;
163
:
113
132

129

Woolum
JA
Abner
EL
Kelly
A
et al.
Effect of thiamine administration on lactate clearance and mortality in patients with septic shock
.
Crit Care Med
2018
;
46
:
1747
1752

Author notes

None declared.

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