Summary Cancer cells consume glucose and secrete lactate in culture. It is unknown whether lactate contributes to energy metabolism in living tumors. We previously reported that human non-small cell lung cancers (NSCLC) oxidize glucose in the tricarboxylic acid (TCA) cycle. Here we show that lactate is also a TCA cycle carbon source for NSCLC. In human NSCLC, evidence of lactate utilization was most apparent in tumors with high 18fluorodeoxyglucose uptake and aggressive oncological behavior. Infusing human NSCLC patients with 13C-lactate revealed extensive labeling of TCA cycle metabolites. In mice, deleting monocarboxylate transporter-1 (MCT1) from tumor cells eliminated lactate-dependent metabolite labeling, confirming tumor-cell autonomous lactate uptake. Strikingly, directly comparing lactate and glucose metabolism in vivo indicated that lactate's contribution to the TCA cycle predominates. The data indicate that tumors, including bona fide human NSCLC, can use lactate as a fuel in vivo.

SUMMARY Non-small cell lung cancer (NSCLC) is heterogeneous in the genetic and environmental parameters that influence cell metabolism in culture. Here, we assessed the impact of these factors on human NSCLC metabolism in vivo using intra-operative 13C-glucose infusions in nine NSCLC patients to compare metabolism between tumors and benign lung. While enhanced glycolysis and glucose oxidation were common among these tumors, we observed evidence for oxidation of multiple nutrients in each of them, including lactate as a potential carbon source. Moreover, metabolically heterogeneous regions were identified within and between tumors, and surprisingly, our data suggested potential contributions of non-glucose nutrients in well-perfused tumor areas. Our findings not only demonstrate the heterogeneity in tumor metabolism in vivo but also highlight the strong influence of the microenvironment on this feature.

ARDS is primarily a clinicoradiologic diagnosis; however, lung biopsy plays an important diagnostic role in certain cases. A significant amount of progress has been made in the elucidation of ARDS pathophysiology and in predicting patient response, however, currently there is no viable predictive molecular biomarkers for predicting the severity of ARDS, or molecular-based ARDS therapies. The proinflammatory cytokines TNF-α (tumor necrosis factor α), interleukin (IL)-1β, IL-6, IL-8, and IL-18 are among the most promising as biomarkers for predicting morbidity and mortality.

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The mechanism of insulin dysregulation in children with hyperinsulinism associated with inactivating mutations of short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) was examined in mice with a knock-out of the hadh gene (hadh ؊/؊ ). Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in infants and children (1). Six genetic loci have been associated with the disorder. The most common of these disorders are due to inactivating mutations of the sulfonylurea receptor 1 (SUR1) 2 and Kir6.2 subunits of the ␤-cell ATP-dependent potassium (K ATP ) channel or to activating mutations of glutamate dehydrogenase (GDH) and glucokinase. Recently, several children have been described with a recessively inherited form of hyperinsulinism that is associated with deficiency of a mitochondrial fatty acid ␤-oxidation enzyme, short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) encoded by the HADH gene on 4q (2-4). SCHAD catalyzes the third step in the ␤-oxidation cycle for medium and short-chain 3-hydroxy fatty acyl-CoAs. Children afflicted with SCHAD deficiency have recurrent episodes of hypoglycemia that can be prevented by treatment with diazoxide (2, 3) and also have characteristic accumulations of fatty acid metabolites, including plasma 3-hydroxybutyrylcarnitine and urinary 3-hydroxyglutaric acid (2, 3). This form of abnormal insulin regulation is unique, because other genetic disorders of mitochondrial fatty acid oxidation do not cause hyperinsulinism (5). In addition, the genetic defect in SCHAD deficiency is expected to impair, rather than increase, the production of ATP, which normally serves as the triggering signal for insulin release. An important clue to the mechanism of insulin dysregulation in SCHAD deficiency has been recently provided by the report * This work was supported, in whole or in part, by National Institutes of Health Grants DK53012 (to C. A. S.), DK22122 (to F. M. M.), DK 53761 (to I. N.), HL075421 (to A. W. S.). This work was also supported by a fellowship award from Society for Inherited Metabolic Disorders (to A. P.