A New Metabolomic Signature in Type-2 Diabetes Mellitus and Its Pathophysiology

Padberg, Inken; Peter, Erik; Gonzalez-Maldonado, S.; Witt, Henning; Müeller, Matthias; Weis, Tanja; Bethan, Bianca; Liebenberg, Volker; Wiemer, J.; Katus, Hugo A.; Rein, Dietrich; Schatz, Philipp

doi:10.1371/journal.pone.0085082

Cited by 89 publications

(72 citation statements)

References 25 publications

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“…Although those findings are in agreement with the role of arachidonic acid being a precursor of proinflammatory eicosanoids (38), no significant differences between linoleic acid and arachidonic acid levels were found between DR cases and control subjects with diabetes in the discovery set (Supplementary Table 8). The levels of arachidonic acid are likely correlated to the use of antihypertensive medications rather than to DR status (39). This is supported by the similar numbers of participants on antihypertensive medications among the DR cases and control subjects with diabetes (27 and 24, respectively).…”

Section: Nonreplicable Metabolite Markers Of Drmentioning

confidence: 87%

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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Section: Nonreplicable Metabolite Markers Of Drmentioning

confidence: 87%

Plasma Metabonomic Profiling of Diabetic Retinopathy

et al. 2016

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“…Decreased ADMA levels, related to altered endothelial functions, were reported for type 2 diabetes [23]; and low plasma levels of 1,5-anhydrosorbitol that result from competitive inhibition of reabsorption via glucose transporters in kidney by the high load of filtered glucose are also known in type 2 diabetes [24]. Furthermore, glyoxylate, recently described as a new marker for diabetes [12], was strongly increased in plasma of db/db mice. Decreased creatinine concentrations reflect a reduced muscle mass [25] here showing a stronger decrease in the db/db model.…”

Section: Discussionmentioning

confidence: 99%

“…Prediabetic participants were defined by the WHO's criteria and diabetic patients were defined according to self-reporting, and/or type-2 diabetes medication, and/or HbA 1c >6.5% (47.5 mmol/mol) and fasting plasma glucose levels >5.55 mmol/l. While parts of both studies were recently published [8,12], we focused on novel metabolite measurements from these studies and could identify similar changes in human plasma for various known but also several yet undescribed metabolites. Interestingly, while most changes in phospholipid concentrations of prediabetic individuals were concordant with the alterations in both ob/ob and db/db mice, metabolite profiles of diabetic individuals showed strongest similarities to db/db mice, substantiating the discriminant power of the specific alterations observed in plasma from mice in this study.…”

Section: Discussionmentioning

confidence: 99%

Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes

et al. 2015

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Aims/hypothesis Metabolomics approaches in humans have identified around 40 plasma metabolites associated with insulin resistance (IR) and type 2 diabetes, which often coincide with those for obesity. We aimed to separate diabetesassociated from obesity-associated metabolite alterations in plasma and study the impact of metabolically important tissues on plasma metabolite concentrations. Methods Two obese mouse models were studied; one exclusively with obesity (ob/ob) and another with type 2 diabetes (db/db). Both models have impaired leptin signalling as a cause for obesity, but the different genetic backgrounds determine the susceptibility to diabetes. In these mice, we profiled plasma, liver, skeletal muscle and adipose tissue via semiquantitative GC-MS and quantitative liquid chromatography (LC)-MS/MS for a wide range of metabolites. Results Metabolite profiling identified 24 metabolites specifically associated with diabetes but not with obesity. Among these are known markers such as 1,5-anhydro-D-sorbitol, 3-hydroxybutyrate and the recently reported marker glyoxylate. New metabolites in the diabetic model were lysine, Ophosphotyrosine and branched-chain fatty acids. We also identified 33 metabolites that were similarly altered in both models, represented by branched-chain amino acids (BCAA) as well as glycine, serine, trans-4-hydroxyproline, and various lipid species and derivatives. Correlation analyses showed stronger associations for plasma amino acids with adipose tissue metabolites in db/db mice compared with ob/ob mice, suggesting a prominent contribution of adipose tissue to changes in plasma in a diabetic state. Conclusions/interpretation By studying mice with metabolite signatures that resemble obesity and diabetes in humans, we have found new metabolite entities for validation in appropriate human cohorts and revealed their possible tissue of origin.

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“…This part of nutri-metabolomics has been investigated both with NMR and GC-MS. The knowledge acquired may lead to new advances towards a better understanding of the epidemic of diabesity that has recently characterized babies and adolescents [8,9].…”

mentioning

confidence: 99%