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Wnt Signaling: From Mesenchymal Cell Fate to Lipogenesis and Other Mature Adipocyte Functions
Devika P. Bagchi and Ormond A. MacDougald
doi : 10.2337/dbi20-0015
Diabetes 2021 Jul; 70 (7): 1419-1430
Wnt signaling is an ancient and evolutionarily conserved pathway with fundamental roles in the development of adipose tissues. Roles of this pathway in mesenchymal stem cell fate determination and differentiation have been extensively studied. Indeed, canonical Wnt signaling is a significant endogenous inhibitor of adipogenesis and promoter of other cell fates, including osteogenesis, chondrogenesis, and myogenesis. However, emerging genetic evidence in both humans and mice suggests central roles for Wnt signaling in body fat distribution, obesity, and metabolic dysfunction. Herein, we highlight recent studies that have begun to unravel the contributions of various Wnt pathway members to critical adipocyte functions, including carbohydrate and lipid metabolism. We further explore compelling evidence of complex and coordinated interactions between adipocytes and other cell types within adipose tissues, including stromal, immune, and endothelial cells. Given the evolutionary conservation and ubiquitous cellular distribution of this pathway, uncovering the contributions of Wnt signaling to cell metabolism has exciting implications for therapeutic intervention in widespread pathologic states, including obesity, diabetes, and cancers.
Etiology of Autoimmune Islet Disease: Timing Is Everything
Åke Lernmark
doi : 10.2337/dbi18-0034
Diabetes 2021 Jul; 70 (7): 1431-1439
Life is about timing. —Carl Lewis.The understanding of autoimmune type 1 diabetes is increasing, and examining etiology separate from pathogenesis has become crucial. The components to explain type 1 diabetes development have been known for some time. The strong association with HLA has been researched for nearly 50 years. Genome-wide association studies added another 60+ non-HLA genetic factors with minor contribution to risk. Insulitis has long been known to be present close to clinical diagnosis. T and B cells recognizing ?-cell autoantigens are detectable prior to diagnosis and in newly diagnosed patients. Islet autoantibody tests against four major autoantigens have been standardized and used as biomarkers of islet autoimmunity. However, to clarify the etiology would require attention to time. Etiology may be defined as the cause of a disease (i.e., type 1 diabetes) or abnormal condition (i.e., islet autoimmunity). Timing is everything, as neither the prodrome of islet autoimmunity nor the clinical onset of type 1 diabetes tells us much about the etiology. Rather, the islet autoantibody that appears first and persists would mark the diagnosis of an autoimmune islet disease (AID). Events after the diagnosis of AID would represent the pathogenesis. Several islet autoantibodies without (stage 1) or with impaired glucose tolerance (stage 2) or with symptoms (stage 3) would define the pathogenesis culminating in clinical type 1 diabetes. Etiology would be about the timing of events that take place before the first-appearing islet autoantibody.
A Novel Mechanism of Regulation for Exosome Secretion in the Diabetic Kidney
Ye Feng, Bicheng Liu, Kyung Lee and John Cijiang He
doi : 10.2337/dbi21-0015
Diabetes 2021 Jul; 70 (7): 1440-1442
Fgf15 Neurons of the Dorsomedial Hypothalamus Control Glucagon Secretion and Hepatic Gluconeogenesis
Alexandre Picard, Salima Metref, David Tarussio, Wanda Dolci, Xavier Berney, Sophie Croizier, Gwenaël Labouebe and Bernard Thorens
doi : 10.2337/db20-1121
Diabetes 2021 Jul; 70 (7): 1443-1457
The counterregulatory response to hypoglycemia is an essential survival function. It is controlled by an integrated network of glucose-responsive neurons, which trigger endogenous glucose production to restore normoglycemia. The complexity of this glucoregulatory network is, however, only partly characterized. In a genetic screen of a panel of recombinant inbred mice we previously identified Fgf15, expressed in neurons of the dorsomedial hypothalamus (DMH), as a negative regulator of glucagon secretion. Here, we report on the generation of Fgf15CretdTomato mice and their use to further characterize these neurons. We show that they were glutamatergic and comprised glucose-inhibited and glucose-excited neurons. When activated by chemogenetics, Fgf15 neurons prevented the increase in vagal nerve firing and the secretion of glucagon normally triggered by insulin-induced hypoglycemia. On the other hand, they increased the activity of the sympathetic nerve in the basal state and prevented its silencing by glucose overload. Higher sympathetic tone increased hepatic Creb1 phosphorylation, Pck1 mRNA expression, and hepatic glucose production leading to glucose intolerance. Thus, Fgf15 neurons of the DMH participate in the counterregulatory response to hypoglycemia by a direct adrenergic stimulation of hepatic glucose production while suppressing vagally induced glucagon secretion. This study provides new insights into the complex neuronal network that prevents the development of hypoglycemia.
l-Theanine Activates the Browning of White Adipose Tissue Through the AMPK/?-Ketoglutarate/Prdm16 Axis and Ameliorates Diet-Induced Obesity in Mice
Wan-Qiu Peng, Gang Xiao, Bai-Yu Li, Ying-Ying Guo, Liang Guo and Qi-Qun Tang
doi : 10.2337/db20-1210
Diabetes 2021 Jul; 70 (7): 1458-1472
l-Theanine is a nonprotein amino acid with much beneficial efficacy. We found that intraperitoneal treatment of the mice with l-theanine (100 mg/kg/day) enhanced adaptive thermogenesis and induced the browning of inguinal white adipose tissue (iWAT) with elevated expression of Prdm16, Ucp1, and other thermogenic genes. Meanwhile, administration of the mice with l-theanine increased energy expenditure. In vitro studies indicated that l-theanine induced the development of brown-like features in adipocytes. The shRNA-mediated depletion of Prdm16 blunted the role of l-theanine in promoting the brown-like phenotypes in adipocytes and in the iWAT of mice. l-theanine treatment enhanced AMPK? phosphorylation both in adipocytes and iWAT. Knockdown of AMPK? abolished l-theanine–induced upregulation of Prdm16 and adipocyte browning. l-Theanine increased the ?-ketoglutarate (?-KG) level in adipocytes, which may increase the transcription of Prdm16 by inducing active DNA demethylation on its promoter. AMPK activation was required for l-theanine–induced increase of ?-KG and DNA demethylation on the Prdm16 promoter. Moreover, intraperitoneal administration with l-theanine ameliorated obesity, improved glucose tolerance and insulin sensitivity, and reduced plasma triglyceride, total cholesterol, and free fatty acids in the high-fat diet–fed mice. Our results suggest a potential role of l-theanine in combating diet-induced obesity in mice, which may involve l-theanine–induced browning of WAT.
Brown Adipose Tissue Volume and Fat Content Are Positively Associated With Whole-Body Adiposity in Young Men—Not in Women
Guillermo Sanchez-Delgado, Borja Martinez-Tellez, Francisco M. Acosta, Samuel Virtue, Antonio Vidal-Puig, Angel Gil, Jose M. Llamas-Elvira and Jonatan R. Ruiz
doi : 10.2337/db21-0011
Diabetes 2021 Jul; 70 (7): 1473-1485
Human brown adipose tissue (BAT) volume has consistently been claimed to be inversely associated with whole-body adiposity. However, recent advances in the assessment of human BAT suggest that previously reported associations may have been biased. The present cross-sectional study investigates the association of BAT volume, mean radiodensity, and 18F-fluorodeoxyglucose (18F-FDG) uptake (assessed via a static positron emission tomography [PET]–computed tomography [CT] scan after a 2-h personalized cold exposure) with whole-body adiposity (measured by DXA) in 126 young adults (42 men and 84 women; mean ± SD BMI 24.9 ± 4.7 kg/m2). BAT volume, but not 18F-FDG uptake, was positively associated with BMI, fat mass, and visceral adipose tissue (VAT) mass in men but not in women. These associations were independent of the date when the PET-CT was performed, insulin sensitivity, and body surface area. BAT mean radiodensity, an inverse proxy of BAT fat content, was negatively associated with BMI, fat mass, and VAT mass in men and in women. These results refute the widely held belief that human BAT volume is reduced in obese persons, at least in young adults, and suggest that it might even be the opposite in young men.
Human White Adipose Tissue Displays Selective Insulin Resistance in the Obese State
Enrichetta Mileti, Kelvin H.M. Kwok, Daniel P. Andersson, Anthony Mathelier, Amitha Raman, Jesper Bäckdahl, Jutta Jalkanen, Lucas Massier, Anders Thorell, Hui Gao, Peter Arner, Niklas Mejhert, Carsten O. Daub and Mikael Rydén
doi : 10.2337/db21-0001
Diabetes 2021 Jul; 70 (7): 1486-1497
Selective hepatic insulin resistance is a feature of obesity and type 2 diabetes. Whether similar mechanisms operate in white adipose tissue (WAT) of those with obesity and to what extent these are normalized by weight loss are unknown. We determined insulin sensitivity by hyperinsulinemic euglycemic clamp and insulin response in subcutaneous WAT by RNA sequencing in 23 women with obesity before and 2 years after bariatric surgery. To control for effects of surgery, women postsurgery were matched to never-obese women. Multidimensional analyses of 138 samples allowed us to classify the effects of insulin into three distinct expression responses: a common set was present in all three groups and included genes encoding several lipid/cholesterol biosynthesis enzymes; a set of obesity-attenuated genes linked to tissue remodeling and protein translation was selectively regulated in the two nonobese states; and several postobesity-enriched genes encoding proteins involved in, for example, one-carbon metabolism were only responsive to insulin in the women who had lost weight. Altogether, human WAT displays a selective insulin response in the obese state, where most genes are normalized by weight loss. This comprehensive atlas provides insights into the transcriptional effects of insulin in WAT and may identify targets to improve insulin action.
STAT3 but Not ERK2 Is a Crucial Mediator Against Diet-Induced Obesity via VMH Neurons
Gabriel Henrique Marques Gonçalves, Sabrina Mara Tristão, Rafaella Eduarda Volpi, Gislaine Almeida-Pereira, Beatriz de Carvalho Borges, José Donato, Margaret de Castro, José Antunes-Rodrigues and Lucila Leico Kagohara Elias
doi : 10.2337/db20-0658
Diabetes 2021 Jul; 70 (7): 1498-1507
Leptin plays an important role in the protection against diet-induced obesity (DIO) by its actions in ventromedial hypothalamic (VMH) neurons. However, little is known about the intracellular mechanisms involved in these effects. To assess the role of the STAT3 and ERK2 signaling in neurons that express the steroidogenic factor 1 (SF1) in the VMH in energy homeostasis, we used cre-lox technology to generate male and female mice with specific disruption of STAT3 or ERK2 in SF1 neurons of the VMH. We demonstrated that the conditional knockout of STAT3 in SF1 neurons of the VMH did not affect body weight, food intake, energy expenditure, or glucose homeostasis in animals on regular chow. However, with high-fat diet (HFD) challenge, loss of STAT3 in SF1 neurons caused a significant increase in body weight, food intake, and energy efficiency that was more remarkable in females, which also showed a decrease in energy expenditure. In contrast, deletion of ERK2 in SF1 neurons of VMH did not have any impact on energy homeostasis in both regular diet and HFD conditions. In conclusion, STAT3 but not ERK2 signaling in SF1 neurons of VMH plays a crucial role in protection against DIO in a sex-specific pattern.
Conversion of ?-Cells to ?-Cells in the Postpartum Mouse Pancreas Involves Lgr5 Progeny
Uylissa A. Rodriguez, Mairobys Socorro, Angela Criscimanna, Christina P. Martins, Nada Mohamed, Jing Hu, Krishna Prasadan, George K. Gittes and Farzad Esni
doi : 10.2337/db20-1059
Diabetes 2021 Jul; 70 (7): 1508-1518
In contrast to the skin and the gut, where somatic stem cells and their niche are well characterized, a definitive pancreatic multipotent cell population in the adult pancreas has yet to be revealed. Of particular interest is whether such cells may be endogenous in patients with diabetes, and if so, can they be used for therapeutic purposes? In the current study, we used two separate reporter lines to target Cre-recombinase expression to the Lgr5- or glucagon-expressing cells in the pancreas. We provide evidence for the existence of a population of cells within and in the proximity of the ducts that transiently express the stem-cell marker Lgr5 during late gestational stages. Careful timing of tamoxifen treatment in Lgr5EGFP-IRES-CreERT2;R26Tomato mice allowed us to show that these Lgr5-expressing progenitor cells can differentiate into ?-cells during pregnancy. Furthermore, we report on a spontaneous lineage conversion of ?- to ?-cells specifically after parturition. The contribution of Lgr5 progeny to the ?-cell compartment through an ?-cell intermediate phase early after pregnancy appears to be part of a novel mechanism that would counterbalance against excessive ?-cell mass reduction during ?-cell involution.
MEK/ERK Signaling in ?-Cells Bifunctionally Regulates ?-Cell Mass and Glucose-Stimulated Insulin Secretion Response to Maintain Glucose Homeostasis
Yoshiko Matsumoto Ikushima, Motoharu Awazawa, Naoki Kobayashi, Sho Osonoi, Seiichi Takemiya, Hiroshi Kobayashi, Hirotsugu Suwanai, Yuichi Morimoto, Kotaro Soeda, Jun Adachi, Masafumi Muratani, Jean Charron, Hiroki Mizukami, Noriko Takahashi and Kohjiro Ueki
doi : 10.2337/db20-1295
Diabetes 2021 Jul; 70 (7): 1519-1535
In diabetic pathology, insufficiency in ?-cell mass, unable to meet peripheral insulin demand, and functional defects of individual ?-cells in production of insulin are often concurrently observed, collectively causing hyperglycemia. Here we show that the phosphorylation of ERK1/2 is significantly decreased in the islets of db/db mice as well as in those of a cohort of subjects with type 2 diabetes. In mice with abrogation of ERK signaling in pancreatic ?-cells through deletion of Mek1 and Mek2, glucose intolerance aggravates under high-fat diet–feeding conditions due to insufficient insulin production with lower ?-cell proliferation and reduced ?-cell mass, while in individual ?-cells dampening of the number of insulin exocytosis events is observed, with the molecules involved in insulin exocytosis being less phosphorylated. These data reveal bifunctional roles for MEK/ERK signaling in ?-cells for glucose homeostasis, i.e., in regulating ?-cell mass as well as in controlling insulin exocytosis in individual ?-cells, thus providing not only a novel perspective for the understanding of diabetes pathophysiology but also a potential clue for new drug development for diabetes treatment.
FOXO1-Mediated Downregulation of RAB27B Leads to Decreased Exosome Secretion in Diabetic Kidneys
Mengru Zeng, Jin Wen, Zhengwei Ma, Li Xiao, Yutao Liu, Sangho Kwon, Yu Liu and Zheng Dong
doi : 10.2337/db20-1108
Diabetes 2021 Jul; 70 (7): 1536-1548
Exosomes have been implicated in diabetic kidney disease (DKD), but the regulation of exosomes in DKD is largely unknown. Here, we have verified the decrease of exosome secretion in DKD and unveiled the underlying mechanism. In Boston University mouse proximal tubule (BUMPT) cells, high-glucose (HG) treatment led to a significant decrease in exosome secretion, which was associated with specific downregulation of RAB27B, a key guanosine-5?-triphosphatase in exosome secretion. Overexpression of RAB27B restored exosome secretion in HG-treated cells, suggesting a role of RAB27B downregulation in the decrease of exosome secretion in DKD. To understand the mechanism of RAB27B downregulation, we conducted bioinformatics analysis that identified FOXO1 binding sites in the Rab27b gene promoter. Consistently, HG induced phosphorylation of FOXO1 in BUMPT cells, preventing FOXO1 accumulation and activation in the nucleus. Overexpression of nonphosphorylatable, constitutively active FOXO1 led to the upregulation of RAB27B and an increase in exosome secretion in HG-treated cells. In vivo, compared with normal mice, diabetic mice showed increased FOXO1 phosphorylation, decreased RAB27B expression, and reduced exosome secretion. Collectively, these results unveil the mechanism of exosome dysfunction in DKD where FOXO1 is phosphorylated and inactivated in DKD, resulting in RAB27B downregulation and the decrease of exosome secretion.
Vascular Expression of Permeability-Resistant Occludin Mutant Preserves Visual Function in Diabetes
Andreia Goncalves, Alyssa Dreffs, Cheng-mao Lin, Sarah Sheskey, Natalie Hudson, Jason Keil, Matthew Campbell and David A. Antonetti
doi : 10.2337/db20-1220
Diabetes 2021 Jul; 70 (7): 1549-1560
Diabetic retinopathy is one of the leading causes of vision loss and blindness. Extensive preclinical and clinical evidence exists for both vascular and neuronal pathology. However, the relationship of these changes in the neurovascular unit and impact on vision remains to be determined. Here, we investigate the role of tight junction protein occludin phosphorylation at S490 in modulating barrier properties and its impact on visual function. Conditional vascular expression of the phosphorylation-resistant Ser490 to Ala (S490A) form of occludin preserved tight junction organization and reduced vascular endothelial growth factor (VEGF)-induced permeability and edema formation after intraocular injection. In the retinas of streptozotocin-induced diabetic mice, endothelial-specific expression of the S490A form of occludin completely prevented diabetes-induced permeability to labeled dextran and inhibited leukostasis. Importantly, vascular-specific expression of the occludin mutant completely blocked the diabetes-induced decrease in visual acuity and contrast sensitivity. Together, these results reveal that occludin acts to regulate barrier properties downstream of VEGF in a phosphorylation-dependent manner and that loss of inner blood-retinal barrier integrity induced by diabetes contributes to vision loss.
Diabetic Kidney Disease Alters the Transcriptome and Function of Human Adipose-Derived Mesenchymal Stromal Cells but Maintains Immunomodulatory and Paracrine Activities Important for Renal Repair
LaTonya J. Hickson, Alfonso Eirin, Sabena M. Conley, Timucin Taner, Xiaohui Bian, Ahmed Saad, Sandra M. Herrmann, Ramila A. Mehta, Travis J. McKenzie, Todd A. Kellogg, James L. Kirkland, Tamar Tchkonia, Ishran M. Saadiq, Hui Tang, Kyra L. Jordan, Xiangyang Zhu, Mathew D. Griffin, Andrew D. Rule, Andre J. van Wijnen, Stephen C. Textor and Lilach O. Lerman
doi : 10.2337/db19-1268
Diabetes 2021 Jul; 70 (7): 1561-1574
Mesenchymal stem/stromal cells (MSCs) facilitate repair in experimental diabetic kidney disease (DKD). However, the hyperglycemic and uremic milieu may diminish regenerative capacity of patient-derived therapy. We hypothesized that DKD reduces human MSC paracrine function. Adipose-derived MSC from 38 participants with DKD and 16 control subjects were assessed for cell surface markers, trilineage differentiation, RNA sequencing (RNA-seq), in vitro function (coculture or conditioned medium experiments with T cells and human kidney cells [HK-2]), secretome profile, and cellular senescence abundance. The direction of association between MSC function and patient characteristics were also tested. RNA-seq analysis identified 353 differentially expressed genes and downregulation of several immunomodulatory genes/pathways in DKD-MSC versus Control-MSC. DKD-MSC phenotype, differentiation, and tube formation capacity were preserved, but migration was reduced. DKD-MSC with and without interferon-? priming inhibited T-cell proliferation greater than Control-MSC. DKD-MSC medium contained higher levels of anti-inflammatory cytokines (indoleamine 2,3-deoxygenase 1 and prostaglandin-E2) and prorepair factors (hepatocyte growth factor and stromal cell–derived factor 1) but lower IL-6 versus control-MSC medium. DKD-MSC medium protected high glucose plus transforming growth factor-?–exposed HK-2 cells by reducing apoptotic, fibrotic, and inflammatory marker expression. Few DKD-MSC functions were affected by patient characteristics, including age, sex, BMI, hemoglobin A1c, kidney function, and urine albumin excretion. However, senescence-associated ?-galactosidase activity was lower in DKD-MSC from participants on metformin therapy. Therefore, while DKD altered the transcriptome and migratory function of culture-expanded MSCs, DKD-MSC functionality, trophic factor secretion, and immunomodulatory activities contributing to repair remained intact. These observations support testing of patient-derived MSC therapy and may inform preconditioning regimens in DKD clinical trials.
Metformin’s Therapeutic Efficacy in the Treatment of Diabetes Does Not Involve Inhibition of Mitochondrial Glycerol Phosphate Dehydrogenase
Michael J. MacDonald, Israr-ul H. Ansari, Melissa J. Longacre and Scott W. Stoker
doi : 10.2337/db20-1143
Diabetes 2021 Jul; 70 (7): 1575-1580
Mitochondrial glycerol phosphate dehydrogenase (mGPD) is the rate-limiting enzyme of the glycerol phosphate redox shuttle. It was recently claimed that metformin, a first-line drug used for the treatment of type 2 diabetes, inhibits liver mGPD 30–50%, suppressing gluconeogenesis through a redox mechanism. Various factors cast doubt on this idea. Total-body knockout of mGPD in mice has adverse effects in several tissues where the mGPD level is high but has little or no effect in liver, where the mGPD level is the lowest of 10 tissues. Metformin has beneficial effects in humans in tissues with high levels of mGPD, such as pancreatic ?-cells, where the mGPD level is much higher than that in liver. Insulin secretion in mGPD knockout mouse ?-cells is normal because, like liver, ?-cells possess the malate aspartate redox shuttle whose redox action is redundant to the glycerol phosphate shuttle. For these and other reasons, we used four different enzyme assays to reassess whether metformin inhibited mGPD. Metformin did not inhibit mGPD in homogenates or mitochondria from insulin cells or liver cells. If metformin actually inhibited mGPD, adverse effects in tissues where the level of mGPD is much higher than that in the liver could prevent the use of metformin as a diabetes medicine.
A Transcription Start Site Map in Human Pancreatic Islets Reveals Functional Regulatory Signatures
Arushi Varshney, Yasuhiro Kyono, Venkateswaran Ramamoorthi Elangovan, Collin Wang, Michael R. Erdos, Narisu Narisu, Ricardo D’Oliveira Albanus, Peter Orchard, Michael L. Stitzel, Francis S. Collins, Jacob O. Kitzman and Stephen C.J. Parker
doi : 10.2337/db20-1087
Diabetes 2021 Jul; 70 (7): 1581-1591
Identifying the tissue-specific molecular signatures of active regulatory elements is critical to understand gene regulatory mechanisms. Here, we identify transcription start sites (TSS) using cap analysis of gene expression (CAGE) across 57 human pancreatic islet samples. We identify 9,954 reproducible CAGE tag clusters (TCs), ?20% of which are islet specific and occur mostly distal to known gene TSS. We integrated islet CAGE data with histone modification and chromatin accessibility profiles to identify epigenomic signatures of transcription initiation. Using a massively parallel reporter assay, we validated the transcriptional enhancer activity for 2,279 of 3,378 (?68%) tested islet CAGE elements (5% false discovery rate). TCs within accessible enhancers show higher enrichment to overlap type 2 diabetes genome-wide association study (GWAS) signals than existing islet annotations, which emphasizes the utility of mapping CAGE profiles in disease-relevant tissue. This work provides a high-resolution map of transcriptional initiation in human pancreatic islets with utility for dissecting active enhancers at GWAS loci.
Phospholipid Levels at Seroconversion Are Associated With Resolution of Persistent Islet Autoimmunity: The Diabetes Autoimmunity Study in the Young
Patrick M. Carry, Lauren A. Vanderlinden, Randi K. Johnson, Teresa Buckner, Oliver Fiehn, Andrea K. Steck, Katerina Kechris, Ivana Yang, Tasha E. Fingerlin, Marian Rewers and Jill M. Norris
doi : 10.2337/db20-1251
Diabetes 2021 Jul; 70 (7): 1592-1601
Reversion of islet autoimmunity (IA) may point to mechanisms that prevent IA progression. We followed 199 individuals who developed IA during the Diabetes Autoimmunity Study in the Young. Untargeted metabolomics was performed in serum samples following IA. Cox proportional hazards models were used to test whether the metabolites (2,487) predicted IA reversion: two or more consecutive visits negative for all autoantibodies. We conducted a principal components analysis (PCA) of the top metabolites; |hazard ratio (HR) >1.25| and nominal P < 0.01. Phosphatidylcholine (16:0_18:1(9Z)) was the strongest individual metabolite (HR per 1 SD 2.16, false discovery rate (FDR)-adjusted P = 0.0037). Enrichment analysis identified four clusters (FDR P < 0.10) characterized by an overabundance of sphingomyelin (d40:0), phosphatidylcholine (16:0_18:1(9Z)), phosphatidylcholine (30:0), and l-decanoylcarnitine. Overall, 63 metabolites met the criteria for inclusion in the PCA. PC1 (HR 1.4, P < 0.0001), PC2 (HR 0.85, P = 0.0185), and PC4 (HR 1.28, P = 0.0103) were associated with IA reversion. Given the potential influence of diet on the metabolome, we investigated whether nutrients were correlated with PCs. We identified 20 nutrients that were correlated with the PCs (P < 0.05). Total sugar intake was the top nutrient. Overall, we identified an association between phosphatidylcholine, sphingomyelin, and carnitine levels and reversion of IA.
