Metabolic Signature Shift in Type 2 Diabetes Mellitus Revealed by Mass Spectrometry-based Metabolomics

Xu, Fengguo; Tavintharan, Subramaniam; Sum, Chee Fang; Woon, Kaing; Lim, Su Chi; Ong, Choon Nam

doi:10.1210/jc.2012-4132

Cited by 214 publications

(210 citation statements)

References 20 publications

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“…Sphingomyelins are generated by virtue of both salvage and de novo ceramide pathways (37), which may be relevant to their debated role in health and disease. Epidemiologic data demonstrate a positive correlation between total serum sphingomyelin concentration and CVD (18,29), yet total serum sphingomyelin has been reported as lower in CVD-prone states such as obesity, type 1 diabetes, and type 2 diabetes (35,39). Metabolomic profiling has helped clarify this discrepancy by associating certain sphingomyelin species, rather than total concentration, with metabolic parameters.…”

Section: Discussionmentioning

confidence: 99%

Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans

Bergman

Brozinick

Strauss

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

126

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Ceramides and sphingolipids are a family of lipid molecules that circulate in serum and accumulate in skeletal muscle, promoting insulin resistance. Plasma ceramide and dihydroceramide are related to insulin resistance, yet less is known regarding other ceramide and sphingolipid species. Despite its association with insulin sensitivity, chronic endurance exercise training does not change plasma ceramide and sphingolipid content, with little known regarding a single bout of exercise. We measured basal relationships and the effect of acute exercise (1.5 h at 50% V O2 max) and recovery on serum ceramide and sphingolipid content in sedentary obese individuals, endurancetrained athletes, and individuals with type 2 diabetes (T2D). Basal serum C18:0, C20:0, and C24:1 ceramide and C18:0 and total dihydroceramide were significantly higher in T2D and, along with C16:0 ceramide and C18:0 sphingomyelin, correlated positively with insulin resistance. Acute exercise significantly increased serum ceramide, glucosylceramide, and GM3 gangliosides, which largely decreased to basal values in recovery. Sphingosine 1-phosphate and sphingomyelin did not change during exercise but decreased below basal values in recovery. Serum C16:0 and C18:0 ceramide and C18:0 sphingomyelin, but not the total concentrations of either of them, were positively correlated with markers of muscle NF-B activation, suggesting that specific species activate intracellular inflammation. Interestingly, a subset of sphingomyelin species, notably C14:0, C22:3, and C24:4 species, was positively associated with insulin secretion and glucose tolerance. Together, these data show that unique ceramide and sphingolipid species associate with either protective or deleterious features for diabetes and could provide novel therapeutic targets for the future. insulin sensitivity; athlete's paradox; lipid composition; plasma biomarkers THE GLOBAL BURDEN OF DIABETES continues to rise, fueled by the even greater epidemic of prediabetes (9). Nevertheless, not all of those with prediabetes will develop diabetes (27), highlighting the need to identify nonglycemic markers of disease progression that may also prove useful as new targets for the treatment of diabetes itself. Advances in lipidomics have provided new tools to investigate processes that govern the development of diabetes and its complications beyond that of glucose itself. Serum ceramides, a family of sphingolipids involved in diverse and relevant metabolic processes, have received considerable attention in relation to diabetes, making them prime candidates for further examination. Unlike other biomarkers, discrete serum ceramide profiles are rendered across the spectrum of diabetogenesis, creating speculation that ceramides not only mark but contribute to the disease process (8, 17).Much of this speculation is derived from data generated from in vitro and animal experimentation. Human data to date are limited largely to associations between serum ceramide concentration and risk for both diabetes (15) and related comp...

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Section: Discussionmentioning

confidence: 99%

Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans

Bergman

Brozinick

Strauss

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

126

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“…In the absence of dietary survey data, it is unclear if this identified trend in erythritol levels was due to increased consumption of sweeteners or DR-related metabolic dysregulation. Mannose, a metabolite in galactose metabolism, was previously identified as a marker for impaired fasting glucose (14,15) and diabetes (14,20). Increased plasma levels of mannose were identified in DR cases from discovery metabonomic profiling ( Fig.…”

Section: Metabonomic Profiling Identifies Dr-associated Pathwaysmentioning

confidence: 97%

“…2-Hydroxybutyric acid, a derivative of a-ketobutyrate, was previously identified as a marker (14,21) and predictor (44) for diabetes. The ketone body, 3-hydroxybutyric acid, was identified as a marker for impaired glucose tolerance (13) and type 2 diabetes (20,21) and was also identified as a marker for DR in the study by Li et al (26).…”

Section: Unique Signatures Of Hydroxy Fatty Acids In Drmentioning

confidence: 99%

“…The study of metabolic phenotypes (metabotypes) in association with disease states may reveal new knowledge in disease mechanism and pathophysiology (12). Recent metabonomic studies have uncovered plasma and sera metabolic signatures associated with, or predictive of, impaired glucose tolerance and diabetes (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Furthermore, DR is a complex disease where findings from genomewide association studies have not been conclusive (23).…”

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Plasma Metabonomic Profiling of Diabetic Retinopathy

et al. 2016

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Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of visual impairment in working-age adults. Patients with diabetes often develop DR despite appropriate control of systemic risk factors, suggesting the involvement of other pathogenic factors. We hypothesize that the plasma metabolic signature of DR is distinct and resolvable from that of diabetes alone. A nested populationbased case-control metabonomic study was first performed on 40 DR cases and 40 control subjects with diabetes using gas chromatography-mass spectrometry. Eleven metabolites were found to be correlated with DR, and the majority were robust when adjusted for metabolic risk factors and confounding kidney disease. The metabolite markers 2-deoxyribonic acid; 3,4-dihydroxybutyric acid; erythritol; gluconic acid; and ribose were validated in an independent sample set with 40 DR cases, 40 control subjects with diabetes, and 40 individuals without diabetes. DR cases and control subjects with diabetes were matched by HbA 1c in the validation set. Activation of the pentose phosphate pathway was identified from the list of DR metabolite markers. The identification of novel metabolite markers for DR provides insights into potential new pathogenic pathways for this microvascular complication and holds translational value in DR risk stratification and the development of new therapeutic measures.Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of visual impairment in working-age adults worldwide (1,2). The global prevalence of diabetes is rising and the number of people with diabetes is projected to increase by 54% in 2030, compared with 2010 (3). The public health burden of diabetes and DR would thus increase correspondingly. The major risk factors of DR are poor glycemic control and hypertension, as well as the duration of diabetes (4,5), but their relative importance varies between studies (2,6). Although the risks of DR progression and vision loss are reduced with intensive control of risk factors (7,8), many patients with diabetes continue to develop complications despite tight glycemic and blood pressure control. There is increasing evidence to suggest that "metabolic memory" is responsible for this observation. The term metabolic memory refers to the persistent epigenetic modifications caused by early exposure to hyperglycemia that, in turn, predispose individuals to the development of diabetes complications even after good glycemic control

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“…Recent metabolomics studies have suggested that certain metabolites and metabolite classes may be associated with the risk of obesity, insulin resistance and type 2 diabetes [2][3][4][5][6][7][8][9][10][11][12][13][14][15]. The Framingham Offspring Study, a 12-year prospective cohort study, has shown that increases in certain branched-chain amino acids (BCAAs) (such as leucine, isoleucine and valine) and aromatic amino acids (AAAs) (such as tyrosine and phenylalanine) could predict the incidence of type 2 diabetes [6].…”

Section: Introductionmentioning

confidence: 99%

Metabolic signatures and risk of type 2 diabetes in a Chinese population: an untargeted metabolomics study using both LC-MS and GC-MS

et al. 2016

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Aims/hypothesis Metabolomics has provided new insight into diabetes risk assessment. In this study we characterised the human serum metabolic profiles of participants in the Singapore Chinese Health Study cohort to identify metabolic signatures associated with an increased risk of type 2 diabetes. Methods In this nested case-control study, baseline serum metabolite profiles were measured using LC-MS and GC-MS during a 6-year follow-up of 197 individuals with type 2 diabetes but without a history of cardiovascular disease or cancer before diabetes diagnosis, and 197 healthy controls matched by age, sex and date of blood collection. Results A total of 51 differential metabolites were identified between cases and controls. Of these, 35 were significantly associated with diabetes risk in the multivariate analysis after false discovery rate adjustment, such as increased branchedchain amino acids (leucine, isoleucine and valine), nonesterified fatty acids (palmitic acid, stearic acid, oleic acid and linoleic acid) and lysophosphatidylinositol (LPI) species Conclusions/interpretation Our findings show that branched-chain amino acids and NEFA are potent predictors of diabetes development in Chinese adults. Our results also indicate the potential of lysophospholipids for predicting diabetes.Electronic supplementary material The online version of this article

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Metabolic Signature Shift in Type 2 Diabetes Mellitus Revealed by Mass Spectrometry-based Metabolomics

Cited by 214 publications

References 20 publications

Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans

Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans

Plasma Metabonomic Profiling of Diabetic Retinopathy

Metabolic signatures and risk of type 2 diabetes in a Chinese population: an untargeted metabolomics study using both LC-MS and GC-MS

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