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2206.Full.Pdf 2206 Diabetes Volume 69, October 2020 Association of the 1q25 Diabetes-Specific Coronary Heart Disease Locus With Alterations of the g-Glutamyl Cycle and Increased Methylglyoxal Levels in Endothelial Cells Caterina Pipino,1,2,3 Hetal Shah,1,2 Sabrina Prudente,4 Natalia Di Pietro,3 Lixia Zeng,5 Kyoungmin Park,1,2 Vincenzo Trischitta,6,7 Subramanian Pennathur,5 Assunta Pandolfi,3 and Alessandro Doria1,2 Diabetes 2020;69:2206–2216 | https://doi.org/10.2337/db20-0475 A chromosome 1q25 variant (rs10911021) has been suggesting that such treatment may prevent CHD in 1q25 associated with coronary heart disease (CHD) in type risk allele carriers. 2 diabetes. In human umbilical vein endothelial cells (HUVECs), the risk allele “C” is associated with lower expression of the adjacent gene GLUL encoding gluta- Despite improvements in glycemic control and other pre- mine synthase, converting glutamic acid to glutamine. To ventive therapies, individuals with type 2 diabetes con- further investigate the mechanisms through which this tinue to experience an increased burden of cardiovascular locus affects CHD risk, we measured 35 intracellular complications such as coronary heart disease (CHD) (1). In metabolites involved in glutamic acid metabolism and order to change the status quo, new interventions are the g-glutamyl cycle in 62 HUVEC strains carrying dif- needed that specifically target the mechanisms linking the ferent rs10911021 genotypes. Eight metabolites were diabetic milieu to vascular damage. Our strategy to gain positively associated with the risk allele (17–58% in- insights into these mechanisms and identify novel targets crease/allele copy, P 5 0.046–0.002), including five for preventive therapies has been to study the genetic g-glutamyl amino acids, b-citryl-glutamate, N-acetyl- factors that modulate cardiovascular risk among people aspartyl-glutamate, and ophthalmate—a marker of with type 2 diabetes (2). g-glutamyl cycle malfunction. Consistent with these find- Following this approach, we have discovered a locus ings, the risk allele was also associated with decreased on chromosome 1q25 that is associated with CHD, with glutathione-to-glutamate ratio (29%, P 5 0.012), de- genome-wide significance, in multiple sets of patients creased S-lactoylglutathione (241%, P 5 0.019), and with type 2 diabetes (3). Subsequent studies have con- reduced detoxification of the atherogenic compound firmed this finding in other populations with type 2 di- GENETICS/GENOMES/PROTEOMICS/METABOLOMICS methylglyoxal (154%, P 5 0.008). GLUL downregulation abetes (4,5). This CHD locus is placed in the region of the by shRNA caused a 40% increase in the methylglyoxal GLUL gene, which codes for glutamate-ammonia ligase level, which was completely prevented by glutamine (also known as glutamine synthase) catalyzing the con- supplementation. In summary, we have identified in- version of glutamic acid to glutamine (6). In the original tracellular metabolic traits associated with the 1q25 report, the risk allele of the lead variant (rs10911021) risk allele in HUVECs, including impairments of the was associated with decreased GLUL expression in endo- g-glutamyl cycle and methylglyoxal detoxification. Glu- thelial cells and with a lower pyroglutamic-to-glutamic tamine supplementation abolishes the latter abnormality, acid ratio in plasma, suggesting an impairment of glutamic 1Research Division, Joslin Diabetes Center, Boston, MA Corresponding author: Alessandro Doria, [email protected] 2 Department of Medicine, Harvard Medical School, Boston, MA Received 5 May 2020 and accepted 3 July 2020 3Department of Medical, Oral and Biotechnological Sciences, Center for Advanced This article contains supplementary material online at https://doi.org/10.2337/ Studies and Technology - CAST (ex CeSI-MeT), University G. d’Annunzio of Chieti- figshare.12616442. Pescara, Chieti, Italy 4Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa © 2020 by the American Diabetes Association. Readers may use this article as Sollievo della Sofferenza, San Giovanni Rotondo, Italy long as the work is properly cited, the use is educational and not for profit, and the 5Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, MI work is not altered. More information is available at https://www.diabetesjournals 6Research Unit of Diabetes and Endocrine Diseases, Fondazione IRCCS Casa Sollievo .org/content/license. della Sofferenza, San Giovanni Rotondo, Italy 7Department of Experimental Medicine, Sapienza University, Rome, Italy diabetes.diabetesjournals.org Pipino and Associates 2207 acid metabolism and the g-glutamyl cycle, of which Genotyping pyroglutamic acid is an intermediate, as a possible mech- DNA was extracted from HUVECs by standard methods. anism underlying the association with CHD (3). The Genotyping of the rs10911021 variant was performed g-glutamyl cycle is responsible for the generation of by means of a custom TaqMan assay (Life Technologies, glutathione—a natural antioxidant playing a critical Foster City, CA) on a 7900HT platform (Applied Biosys- role in the protection from free radicals and other tems, Foster City, CA). Genotyping quality was tested by reactive compounds (7)—whose deficit may predispose including six blinded duplicate samples in each 96-well to increased oxidative stress and accelerated athero- assay. The average agreement rate of the duplicate samples . sclerosis (7,8). was 99%. The goal of the current study was to seek further Metabolomic Profiling support for this hypothesis by analyzing the association at the cellular level between the 1q25 lead variant Cell Culture – fl (rs10911021) and metabolites involved in glutamic acid HUVECs at 60 70% con uence were incubated with media metabolism and the g-glutamyl cycle in a unique collection containing 10% FBS and 5.5 mmol/L D-glucose (basal of human umbilical vein endothelial cells (HUVECs) iso- condition, low glucose) or 25 mmol/L D-glucose (high lated from a large group of newborns and therefore glucose). After 48 h of treatment, cells were trypsinized, allowing the study of the impact of natural genetic transferred to a 50-mL polypropylene Falcon tube, and centrifuged at 1,200 rpm for 10 min. Supernatants were variation on cellular functions. Our results support the discarded and cell pellets gently resuspended in PBS and hypothesis of an association between the 1q25 locus and transferred to prelabeled 2.0-mL polypropylene tubes. Cell alternations in the g-glutamyl cycle and point to a reduced suspensions were centrifuged (1,200 rpm for 10 min) and glutathione-mediated detoxification of methylglyoxal—a all supernatants carefully removed. Cell pellets were im- precursor of advanced glycation end products (AGEs)—as mediately stored at 280°C until all biological replicates a possible mechanism linking these metabolic changes were collected and shipped to Metabolon (Durham, NC) to the increased CHD risk experienced by 1q25 risk allele for metabolomic profiling. carriers with type 2 diabetes. Metabolite Measurements RESEARCH DESIGN AND METHODS The current study considered 35 metabolites involved in HUVEC Preparation and Culture glutamic acid metabolism, the g-glutamyl cycle, and glu- The study was performed on HUVECs isolated from the tathione metabolism that were extracted from a larger umbilical cords of 62 newborns delivered by randomly Metabolon panel of 597 metabolites according to the fi selected, healthy Caucasian mothers between the 36th and prespeci ed hypothesis of an impact of the 1q25 locus on these metabolic pathways. These 35 metabolites included the 40th gestational week at the Hospital of Chieti and all those whose “Sub-pathway” field in the Metabolon Pescara (Italy). HUVECs were isolated from the umbilical report was labeled as “glutathione metabolism” (n 5 9), cords by extraction with 1 mg/mL collagenase 1A at 37°C, “glutamate metabolism” (n 5 13), or “g-glutamyl amino as previously described (9). All procedures were in agree- acid” (n 5 10), plus cysteine and glycine (the two amino ment with the ethical standards of the local Institutional acids that are used together with glutamic acid to synthe- Committee on Human Experimentation (reference size glutathione) and a-ketoglutarate, a Krebs cycle in- number: 1879/09COET) (University G. d’Annunzio of termediate that is in direct equilibrium with glutamic acid Chieti-Pescara, Chieti, Italy) and with the Declaration through amination/deamination by glutamate dehydroge- of Helsinki ethical principles. After approval of the nase. Samples were prepared by Metabolon using the protocol by the Institutional Review Board, signed in- automated MicroLab STAR system from Hamilton formed consent was obtained from each participating Company. Several recovery standards were added before subject. the first step in the extraction process for quality control For this study, HUVECs were grown on 1.5% gelatin- purposes. coated tissue culture plates (Sigma-Aldrich) in complete To remove proteins, dissociate small molecules bound low-glucose (1 g/L) culture medium composed of DMEM to proteins or trapped in the precipitated protein matrix, (provided by Joslin Media Core) supplemented with 20% and to recover chemically diverse metabolites, proteins FBS (Gibco by Life Technologies), 200 units/mL penicillin, were precipitated with methanol under vigorous shaking 200 mg/mL streptomycin (Sigma-Aldrich), 10 mg/mL hep- for 2 min (GenoGrinder 2000; Glen Mills), followed by arin (Stem Cell Technologies), and 50 mg/mL endothelial
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