Breaking Barriers: The Life and Legacy of Gerty Cori in Biochemical Research.

Gerty Theresa Cori, a remarkable and pioneering biochemist, became the first woman to receive the Nobel Prize in Physiology or Medicine in 1947 for her groundbreaking research in carbohydrate metabolism. Her work, in collaboration with her husband Carl Ferdinand Cori, revolutionized the scientific understanding of carbohydrate metabolism and had a profound impact on medicine and human health. This paper offers a historical vignette of Gerty Cori's life, tracing her journey from her early years in Prague to her pivotal role in transforming biochemistry. It highlights her immense dedication to scientific research, overcoming significant gender-based challenges, and establishing a legacy that continues to inspire. Gerty Cori's contributions to science not only advanced our knowledge of metabolic processes but also paved the way for future generations of researchers, particularly women in science, technology, engineering, and mathematics.

Distinct lactate metabolism between hepatocytes and myotubes revealed by live cell imaging with genetically encoded indicators.

The process of glycolysis breaks down glycogen stored in muscles, producing lactate through pyruvate to generate energy. Excess lactate is then released into the bloodstream. When lactate reaches the liver, it is converted to glucose, which muscles utilize as a substrate to generate ATP. Although the biochemical study of lactate metabolism in hepatocytes and skeletal muscle cells has been extensive, the spatial and temporal dynamics of this metabolism in live cells are still unknown. We observed the dynamics of metabolism-related molecules in primary cultured hepatocytes and a skeletal muscle cell line upon lactate overload. Our observations revealed an increase in cytoplasmic pyruvate concentration in hepatocytes, which led to glucose release. Skeletal muscle cells exhibited elevated levels of lactate and pyruvate levels in both the cytoplasm and mitochondrial matrix. However, mitochondrial ATP levels remained unaffected, indicating that the increased lactate can be converted to pyruvate but is unlikely to be utilized for ATP production. The findings suggest that excess lactate in skeletal muscle cells is taken up into mitochondria with little contribution to ATP production. Meanwhile, lactate released into the bloodstream can be converted to glucose in hepatocytes for subsequent utilization in skeletal muscle cells.

Fibroblast growth factor 21 protects the liver from apoptosis in a type 1 diabetes mouse model via regulating L-lactate homeostasis.

AIMS/HYPOTHESIS: Fibroblast growth factor 21 (FGF21) is a hepatokine with pleiotropic effects on glucose and lipid metabolic homeostasis. Here, we aimed to elucidate the mechanisms underlying the protective effects of FGF21 on L-lactate homeostasis and liver lesions in a type 1 diabetes mellitus (T1DM) mice model. METHODS: Six-week-old male C57BL/6 mice were divided into control, T1DM, and FGF21 groups. We also examined hepatic apoptotic signaling and functional indices in wild-type and hydroxycarboxylic acid receptor 1 (HCA1) knockout mice with T1DM or long-term L-lactate exposure. After preincubation of high glucose- or L-lactate treated hepatic AML12 cells, L-lactate uptake, apoptosis, and monocarboxylic acid transporter 2 (MCT2) expression were investigated. RESULTS: In a mouse model of T1DM, hepatic FGF21 expression was downregulated by approximately 1.5-fold at 13 weeks after the hyperglycemic insult. In vivo administration of exogenous FGF21 (2 mg/kg) to diabetic or L-lactate-infused mice significantly prevented hepatic oxidative stress and apoptosis by activating extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways. HCA1-KO mice were less susceptible to diabetes- and L-lactate-induced hepatic apoptosis and dysfunction. In addition, inhibition of PI3K-mTOR activity revealed that FGF21 prevented L-lactate-induced Cori cycle alterations and hepatic apoptosis by upregulating MCT2 protein translation. CONCLUSIONS/INTERPRETATION: These results demonstrate that L-lactate homeostasis may be a therapeutic target for T1DM-related hepatic dysfunction. The protective effects of FGF21 on hepatic damage were associated with its ability to ameliorate MCT2-dependent Cori cycle alterations and prevent HCA1-mediated inhibition of ERK1/2, p38 MAPK, and AMPK signaling.

Lactate promotes survival and hepatocyte differentiation of human induced pluripotent stem cells in a medium without glucose and supplemented with galactose.

Human induced pluripotent stem (iPS) cells initiate hepatocyte differentiation in a medium without glucose and supplemented with galactose, oncostatin M and small molecules [hepatocyte differentiation inducer (HDI)]. To clarify the metabolic differences between iPS cells in HDI and ReproFF (undifferentiated state), a metabolome analysis was performed. iPS cells were cultured in a medium without glucose and supplemented with galactose, as well as 1 mM of calcium lactate, sodium lactate or lactic acid. After 7 days of culture, the cells were subjected to reverse transcription-quantitative PCR analysis. The galactose-1-phosphate concentration was significantly higher in cells cultured in HDI than in those cultured with ReproFF. The lactate concentration in the HDI group was significantly lower than that in the ReproFF group. The expression levels of α-feto protein and albumin were significantly higher in the groups cultured with calcium lactate, sodium lactate and lactic acid as compared with ReproFF. It was suggested that lactate promoted the survival of iPS cells cultured in a medium without glucose and supplemented with galactose. Under these conditions, iPS cells begin to differentiate into a hepatocyte lineage. Lactate may be applied to produce hepatocytes from iPS cells more efficiently.

Differential Metabolism of Glycerol Based on Oral versus Intravenous Administration in Humans.

Glycerol can be metabolized to glucose via gluconeogenesis or lactate via glycolysis. It is unknown if glycerol is metabolized similarly in the portal and systemic circulations in humans. Eight metabolically healthy overnight-fasted individuals received equimolar amounts of 13C3-glycerol orally and intravenously on two separate occasions with serial blood draws over four hours. Serum samples underwent liquid chromatography-mass spectrometry analysis. Oral 13C3-glycerol administration led to higher average serum glucose enrichment than intravenous administration (5.02 ± 1.43 versus 4.07 ± 0.79%, p = 0.009). In contrast, intravenous 13C3-glycerol administration yielded higher average serum lactate enrichment than oral administration (5.67 ± 0.80 versus 4.85 ± 1.30%, p = 0.032). Peak serum glucose enrichment was also higher with oral administration (9.37 ± 2.93 versus 7.12 ± 1.28%, p = 0.010). Glycerol metabolism across the portal and systemic circulations is not congruent. Orally administered labeled glycerol led to greater labeled glucose production, while intravenously administration yielded greater lactate production. These data support direct glycerol to lactate conversion in humans.

2-Deoxy-D-glucose Alleviates Cancer Cachexia-Induced Muscle Wasting by Enhancing Ketone Metabolism and Inhibiting the Cori Cycle.

Cachexia is characterized by progressive weight loss accompanied by the loss of specific skeletal muscle and adipose tissue. Increased lactate production, either due to the Warburg effect from tumors or accelerated glycolysis effects from cachectic muscle, is the most dangerous factor for cancer cachexia. This study aimed to explore the efficiency of 2-deoxy-D-glucose (2-DG) in blocking Cori cycle activity and its therapeutic effect on cachexia-associated muscle wasting. A C26 adenocarcinoma xenograft model was used to study cancer cachectic metabolic derangements. Tumor-free lean mass, hindlimb muscle morphology, and fiber-type composition were measured after in vivo 2-DG administration. Activation of the ubiquitin-dependent proteasome pathway (UPS) and autophagic-lysosomal pathway (ALP) was further assessed. The cachectic skeletal muscles of tumor-bearing mice exhibited altered glucose and lipid metabolism, decreased carbohydrate utilization, and increased lipid ß-oxidation. Significantly increased gluconeogenesis and decreased ketogenesis were observed in cachectic mouse livers. 2-DG significantly ameliorated cancer cachexia-associated muscle wasting and decreased cachectic-associated lean mass levels and fiber cross-sectional areas. 2-DG inhibited protein degradation-associated UPS and ALP, increased ketogenesis in the liver, and promoted ketone metabolism in skeletal muscle, thus enhancing mitochondrial bioenergetic capacity. 2-DG effectively prevents muscle wasting by increasing ATP synthesis efficiency via the ketone metabolic pathway and blocking the abnormal Cori cycle.

The elevated D-2-hydroxyglutarate level found as a characteristic metabolic change of colon cancer in both in vitro and in vivo models.

The D-2-hydroxyglutarate (D-2-HG), whose normal cellular concentration is low, can be accumulated 10-100 times natural levels in some cancer types and participates in the carcinogenesis process. D-2-HG is produced by different pathways specific to cancer type. In this study, the level of significant metabolites produced in some metabolic pathways related to D-2-HG in the energy metabolism was determined in colon adenocarcinoma cell lines at different stages. Then, the differences in TCA and Cori cycle, glutaminolysis, and Glycolysis were investigated in the brain, colon, liver, and tumor tissues extracted from xenograft models. The levels of glucose, pyruvate, lactate, all TCA cycle intermediates, and D-2-HG were determined by the HPLC analysis, DNS method, and pyruvate assay. The intracellular D-2-HG level was found at 22.6 µmol/mg in primary (Caco-2) and 152.6 µmol/mg in metastatic (SW620) colon adenocarcinoma cells, whereas it could not be detected in colon epithelial cell line (CCD-18Co). In the xenograft models, D-2-HG could not be detected in CCD-18Co colon and brain tissues, whereas it was produced in Caco-2 and SW620 tissues. Most importantly, the level of D-2-HG was 7.4 and 19.9-fold increased in Caco-2 and SW620 tumor tissues compared to healthy tissue, respectively. In addition, the D-2-HG production pathways were investigated. The results revealed that the carbon source of D-2-HG is glucose, and the imbalance of wt-IDH1/2 enzymes plays a role in its production. Overall, the in vitro and in vivo results show that the enhanced production of endogenous D-2-HG is a characteristic change in the metabolism of colon cancer.

Plasma Metabolomics Profile of "Insulin Sensitive" Male Hypogonadism after Testosterone Replacement Therapy.

Male hypogonadism is a disorder characterized by low levels of testosterone, but patients can either show normal insulin (insulin-sensitive (IS)) or over time they can become insulin-resistant (IR). Since the two groups showed different altered metabolisms, testosterone replacement therapy (TRT) could achieve different results. In this paper, we analyzed plasma from 20 IS patients with low testosterone (<8 nmol/L) and HOMAi < 2.5. The samples, pre- and post-treatment with testosterone for 60 days, were analyzed by UHPLC and mass spectrometry. Glycolysis was significantly upregulated, suggesting an improved glucose utilization. Conversely, the pentose phosphate pathway was reduced, while the Krebs cycle was not used. Branched amino acids and carnosine metabolism were positively influenced, while ß-oxidation of fatty acids (FFA) was not activated. Cholesterol, HDL, and lipid metabolism did not show any improvements at 60 days but did so later in the experimental period. Finally, both malate and glycerol shuttle were reduced. As a result, both NADH and ATP were significantly lower. Interestingly, a significant production of lactate was observed, which induced the activation of the Cori cycle between the liver and muscles, which became the main source of energy for these patients without involving alanine. Thus, the treatment must be integrated with chemicals which are not restored in order to reactivate energy production.

Murburn precepts for lactic-acidosis, Cori cycle, and Warburg effect: Interactive dynamics of dehydrogenases, protons, and oxygen.

It is unresolved why lactate is transported to the liver for further utilization within the physiological purview of Cori cycle, when muscles have more lactate dehydrogenase (LDH) than liver. We point out that the answer lies in thermodynamics/equilibriums. While the utilization of NADH for the reduction of pyruvate to lactate can be mediated via the classical mechanism, the oxidation of lactate (with/without the uphill reduction of NAD+ ) necessitates alternative physiological approaches. The latter pathway occurs via interactive equilibriums involving the enzyme, protons and oxygen or diffusible reactive oxygen species (DROS). Since liver has high DROS, the murburn activity at LDH would enable the cellular system to tide over the unfavorable energy barriers of the forward reaction (~476 kJ/mol; earlier miscalculated as ~26 kJ/mole). Further, the new mechanism does not necessitate any "smart decision-making" or sophisticated control by/of proteins. The DROS-based murburn theory explains the invariant active-site structure of LDH isozymes and their multimeric nature. The theoretical insights, in silico evidence and analyses of literature herein also enrich our understanding of the underpinnings of "lactic acidosis" (lowering of physiological pH accompanied by lactate production), Warburg effect (increased lactate production at high pO2 by cancer cells) and approach for cancer therapy.

Distinct glycolytic pathway regulation in liver, tumour and skeletal muscle of mice with cancer cachexia.

Energetically inefficient inter-organ substrate shuttles are proposed contributors to cachexia-related weight loss. Here, we examined glycolytic pathway metabolites, enzyme activity and transport proteins in skeletal muscle, liver and tumours of mice with cachexia-related weight loss induced by colon-26 cancer cells. Skeletal muscle of cachexic mice had increased [L-lactate]/[pyruvate], LDH activity and lactate transporter MCT1. Cachexic livers also showed increased MCT1. This is consistent with the proposal that the rate of muscle-derived lactate shuttling to liver for use in gluconeogenesis is increased, that is, an increased Cori cycle flux in weight-losing cachexic mice. A second shuttle between liver and tumour may also contribute to disrupted energy balance and weight loss. We found increased high-affinity glucose transporter GLUT1 in tumours, suggesting active glucose uptake, tumour MCT1 detection and decreased intratumour [L-lactate]/[pyruvate], implying increased lactate efflux and/or intratumour lactate oxidation. Last, high [L-lactate]/[pyruvate] and MCT1 in cachexic muscle provides a potential muscle-derived lactate supply for the tumour (a 'reverse Warburg effect'), supporting tumour growth and consequent cachexia. Our findings suggest several substrate shuttles among liver, skeletal muscle and tumour contribute to metabolic disruption and weight loss. Therapies that aim to normalize dysregulated substrate shuttling among energy-regulating tissues may alleviate unintended weight loss in cancer cachexia. SIGNIFICANCE OF THE STUDY: Cachexia is a serious complication of cancer characterized by severe weight loss, muscle atrophy and frailty. Cachexia occurs in roughly half of all cancer patients, and in up to 80% of patients with advanced disease. Cachexia independently worsens patient prognosis, lowers treatment efficacy, increases hospitalization cost and length of stay, and accounts for 20-30% of cancer-related deaths. There are no effective treatments. Our findings suggest several substrate shuttles among liver, skeletal muscle and tumour contribute to metabolic disruption and weight loss in cancer cachexia. Identifying therapies that normalize dysregulated substrate shuttling among energy-regulating tissues may protect against cachexia-related weight loss.

Early lactate and glucose kinetics following return to spontaneous circulation after out-of-hospital cardiac arrest.

OBJECTIVE: Lactate has been shown to be preferentially metabolized in comparison to glucose after physiological stress, such as strenuous exercise. Derangements of lactate and glucose are common after out-of-hospital cardiac arrest (OHCA). Therefore, we hypothesized that lactate decreases faster than glucose after return-to-spontaneous-circulation (ROSC) after OHCA. RESULTS: We included 155 OHCA patients in our analysis. Within the first 8 h of presentation to the emergency department, 843 lactates and 1019 glucoses were available, respectively. Lactate decreased to 50% of its initial value within 1.5 h (95% CI [0.2-3.6 h]), while glucose halved within 5.6 h (95% CI [5.4-5.7 h]). Also, in the first 8 h after presentation lactate decreases more than glucose in relation to their initial values (lactate 72.6% vs glucose 52.1%). In patients with marked hyperlactatemia after OHCA, lactate decreased expediently while glucose recovered more slowly, whereas arterial pH recovered at a similar rapid rate as lactate. Hospital non-survivors (N = 82) had a slower recovery of lactate (P = 0.002) than survivors (N = 82). The preferential clearance of lactate underscores its role as a prime energy substrate, when available, during recovery from extreme stress.

The anabolic role of the Warburg, Cori-cycle and Crabtree effects in health and disease.

In evolution, genes survived that could code for metabolic pathways, promoting long term survival during famines or fasting when suffering from trauma, disease or during physiological growth. This requires utilization of substrates, already present in some form in the body. Carbohydrate stores are limited and to survive long, their utilization is restricted to survival pathways, by inhibiting glucose oxidation and glycogen synthesis. This leads to insulin resistance and spares muscle protein, because being the main supplier of carbon for new glucose production. In these survival pathways, part of the glucose is degraded in glycolysis in peripheral (muscle) tissues to pyruvate and lactate (Warburg effect), which are partly reutilized for glucose formation in liver and kidney, completing the Cori-cycle. Another part of the glucose taken up by muscle contributes, together with muscle derived amino acids, to the production of substrates consisting of a complete amino acid mix but extra non-essential amino acids like glutamine, alanine, glycine and proline. These support cell proliferation, matrix deposition and redox regulation in tissues, specifically active in host response and during growth. In these tissues, also glucose is taken up delivering glycolytic intermediates, that branch off and act as building blocks and produce reducing equivalents. Lactate is also produced and released in the circulation, adding to the lactate released by muscle in the Cori-cycle and completing secondary glucose cycles. Increased fluxes through these cycles lead to modest hyperglycemia and hyperlactatemia in states of healthy growth and disease and are often misinterpreted as induced by hypoxia.

Carl and Gerty Cori: A collaboration that changed the face of biochemistry.

Carl Cori and Gerty Cori elucidated basic biochemical mechanisms involved in the utilization of energy by muscle and liver, first at Roswell Park Cancer Institute and then at Washington University. In 1929, they formulated the Cori cycle, the process by which glycogen is converted to glucose in liver and is then reconverted to glycogen in muscle. They later found that glycogen breakdown yielded glucose-1-phosphate (Cori ester) and lactate, key intermediates in the cycle; they also established that lactic acid provided the energy employed in muscle contraction. They later discovered phosphorylase, the enzyme that catalyzed glycogen breakdown. After purifiying and crystallizing muscle phosphorylase, they identified two forms of the enzyme and defined their respective roles in metabolic regulation. These studies emboldened other scientists to advance our knowledge of fundamental regulatory processes such as the adenylate cyclase-cyclic AMP system and enzyme phosphorylation. The Coris also built a world-renowned Department of Biochemistry at Washington University, which included seven future Nobelists. In 1947, the Coris were awarded the Nobel Prize, with Gerty Cori being the first American woman to win this prestigious honor.

Decreased Blood Glucose and Lactate: Is a Useful Indicator of Recovery Ability in Athletes?

During low-intensity exercise stages of the lactate threshold test, blood lactate concentrations gradually diminish due to the predominant utilization of total fat oxidation. However, it is unclear why blood glucose is also reduced in well-trained athletes who also exhibit decreased lactate concentrations. This review focuses on decreased glucose and lactate concentrations at low-exercise intensity performed in well-trained athletes. During low-intensity exercise, the accrued resting lactate may predominantly be transported via blood from the muscle cell to the liver/kidney. Accordingly, there is increased hepatic blood flow with relatively more hepatic glucose output than skeletal muscle glucose output. Hepatic lactate uptake and lactate output of skeletal muscle during recovery time remained similar which may support a predominant Cori cycle (re-synthesis). However, this pathway may be insufficient to produce the necessary glucose level because of the low concentration of lactate and the large energy source from fat. Furthermore, fatty acid oxidation activates key enzymes and hormonal responses of gluconeogenesis while glycolysis-related enzymes such as pyruvate dehydrogenase are allosterically inhibited. Decreased blood lactate and glucose in low-intensity exercise stages may be an indicator of recovery ability in well-trained athletes. Athletes of intermittent sports may need this recovery ability to successfully perform during competition.

Involvement of Lactate and Pyruvate in the Anti-Inflammatory Effects Exerted by Voluntary Activation of the Sympathetic Nervous System.

We recently demonstrated that the sympathetic nervous system can be voluntarily activated following a training program consisting of cold exposure, breathing exercises, and meditation. This resulted in profound attenuation of the systemic inflammatory response elicited by lipopolysaccharide (LPS) administration. Herein, we assessed whether this training program affects the plasma metabolome and if these changes are linked to the immunomodulatory effects observed. A total of 224 metabolites were identified in plasma obtained from 24 healthy male volunteers at six timepoints, of which 98 were significantly altered following LPS administration. Effects of the training program were most prominent shortly after initiation of the acquired breathing exercises but prior to LPS administration, and point towards increased activation of the Cori cycle. Elevated concentrations of lactate and pyruvate in trained individuals correlated with enhanced levels of anti-inflammatory interleukin (IL)-10. In vitro validation experiments revealed that co-incubation with lactate and pyruvate enhances IL-10 production and attenuates the release of pro-inflammatory IL-1ß and IL-6 by LPS-stimulated leukocytes. Our results demonstrate that practicing the breathing exercises acquired during the training program results in increased activity of the Cori cycle. Furthermore, this work uncovers an important role of lactate and pyruvate in the anti-inflammatory phenotype observed in trained subjects.

Impaired skeletal muscle mitochondrial pyruvate uptake rewires glucose metabolism to drive whole-body leanness.

Metabolic cycles are a fundamental element of cellular and organismal function. Among the most critical in higher organisms is the Cori Cycle, the systemic cycling between lactate and glucose. Here, skeletal muscle-specific Mitochondrial Pyruvate Carrier (MPC) deletion in mice diverted pyruvate into circulating lactate. This switch disinhibited muscle fatty acid oxidation and drove Cori Cycling that contributed to increased energy expenditure. Loss of muscle MPC activity led to strikingly decreased adiposity with complete muscle mass and strength retention. Notably, despite decreasing muscle glucose oxidation, muscle MPC disruption increased muscle glucose uptake and whole-body insulin sensitivity. Furthermore, chronic and acute muscle MPC deletion accelerated fat mass loss on a normal diet after high fat diet-induced obesity. Our results illuminate the role of the skeletal muscle MPC as a whole-body carbon flux control point. They highlight the potential utility of modulating muscle pyruvate utilization to ameliorate obesity and type 2 diabetes.

The association of early combined lactate and glucose levels with subsequent renal and liver dysfunction and hospital mortality in critically ill patients.

BACKGROUND: The development of renal and liver dysfunction may be accompanied by initially subtle derangements in the gluconeogenetic function. Discrepantly low glucose levels combined with high lactate levels might indicate an impaired Cori cycle. Our objective was to examine the relation between early lactate and glucose levels with subsequent renal and liver dysfunction and hospital mortality in critically ill patients. METHODS: Over a 4-year period (2011 to 2014), all adult patients admitted to our adult 48-bed teaching hospital intensive care unit (ICU) for at least 12 h were retrospectively analyzed. Lactate and glucose were regularly measured with point-of-care analyzers in all ICU patients. Lactate and glucose measurements were collected from 6 h before to 24 h after ICU admission. Patients with fewer than four lactate/glucose measurements were excluded. Patients received insulin according to a computer-guided control algorithm that aimed at a glucose level <8.0 mmol/L. Renal dysfunction was defined as the development of acute kidney injury (AKI) within 7 days, and liver function was based on the maximal bilirubin in the 7-day period following ICU admission. Mean lactate and mean glucose were classified into quintiles and univariate and multivariate analyses were related with renal and liver dysfunction and hospital mortality. Since glucose has a known U-shaped relation with outcome, we also accounted for this. RESULTS: We analyzed 92,000 blood samples from 9074 patients (63% males) with a median age of 64 years and a hospital mortality of 11%. Both lactate quintiles (≤1.0; 1.0-1.3; 1.3-1.7; 1.7-2.3; >2.3 mmol/L) and glucose quintiles (≤7.0; 7.0-7.6; 7.6-8.2; 8.2-9.0; >9.0 mmol/L) were related with outcome in univariate analysis (p < 0.001). Acute Physiology and Chronic Health Evaluation (APACHE) IV, lactate, and glucose were associated with renal and liver dysfunction in multivariate analysis (p < 0.001), with a U-shaped relationship for glucose. The combination of the highest lactate quintile with the lowest glucose quintile was associated with the highest rates of renal dysfunction, liver dysfunction, and mortality (p < 0.001) with a significant interaction between lactate and glucose (p ≤ 0.001). CONCLUSIONS: Abnormal combined lactate and glucose measurements may provide an early indication of organ dysfunction. In critically ill patients a 'normal' glucose with an elevated lactate should not be considered desirable, as this combination is related with increased mortality.

Targeting Oxygen-Sensing Prolyl Hydroxylase for Metformin-Associated Lactic Acidosis Treatment.

Metformin is one of the most widely used therapeutics for type 2 diabetes mellitus and also has anticancer and antiaging properties. However, it is known to induce metformin-associated lactic acidosis (MALA), a severe medical condition with poor prognosis, especially in individuals with renal dysfunction. Inhibition of prolyl hydroxylase (PHD) is known to activate the transcription factor hypoxia-inducible factor (HIF) that increases lactate efflux as a result of enhanced glycolysis, but it also enhances gluconeogenesis from lactate in the liver that contributes to reducing circulating lactate levels. Here, we investigated the outcome of pharmaceutical inhibition of PHD in mice with MALA induced through the administration of metformin per os and an intraperitoneal injection of lactic acid. We found that the PHD inhibitors significantly increased the expression levels of genes involved in gluconeogenesis in the liver and the kidney and significantly improved the survival of mice with MALA. Furthermore, the PHD inhibitor also improved the rate of survival of MALA induced in mice with chronic kidney disease (CKD). Thus, PHD represents a new therapeutic target for MALA, which is a critical complication of metformin therapy.