Systemic alterations in the metabolome of diabetic NOD mice delineate increased oxidative stress accompanied by reduced inflammation and hypertriglyceremia

Nonobese diabetic (NOD) mice are a commonly used model of type 1 diabetes (T1D). However, not all animals will develop overt diabetes despite undergoing similar autoimmune insult. In this study, a comprehensive metabolomic approach, consisting of gas chromatography time-of-flight (GC-TOF) mass spectrometry (MS), ultra-high-performance liquid chromatography-accurate mass quadruple time-of-flight (UHPLC-qTOF) MS and targeted UHPLC-tandem mass spectrometry-based methodologies, was used to capture metabolic alterations in the metabolome and lipidome of plasma from NOD mice progressing or not progressing to T1D. Using this multi-platform approach, we identified >1,000 circulating lipids and metabolites in male and female progressor and nonprogressor animals ( n = 71). Statistical and multivariate analyses were used to identify age- and sex-independent metabolic markers, which best differentiated metabolic profiles of progressors and nonprogressors. Key T1D-associated perturbations were related with 1) increases in oxidation products glucono-δ-lactone and galactonic acid and reductions in cysteine, methionine and threonic acid, suggesting increased oxidative stress; 2) reductions in circulating polyunsaturated fatty acids and lipid signaling mediators, most notably arachidonic acid (AA) and AA-derived eicosanoids, implying impaired states of systemic inflammation; 3) elevations in circulating triacylglyercides reflective of hypertriglyceridemia; and 4) reductions in major structural lipids, most notably lysophosphatidylcholines and phosphatidylcholines. Taken together, our results highlight the systemic perturbations that accompany a loss of glycemic control and development of overt T1D.

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N-Acetyl-l-Cysteine Supplement in Early Life or Adulthood Reduces Progression of Diabetes in Nonobese Diabetic Mice

Current Developments in Nutrition ◽

10.1093/cdn/nzy097 ◽

2018 ◽

Vol 3 (4) ◽

Author(s):

Lital Argaev Frenkel ◽

Hava Rozenfeld ◽

Konstantin Rozenberg ◽

Sanford R Sampson ◽

Tovit Rosenzweig

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Type 1 Diabetes ◽

Antioxidant Enzymes ◽

Early Life ◽

Nod Mice ◽

Morbidity Rate ◽

Nonobese Diabetic ◽

Total Antioxidant

ABSTRACT Background Oxidative stress contributes to the pathologic process leading to the development, progression, and complications of type 1 diabetes (T1D). Objective The aim of this study was to investigate the effect of the antioxidant N-acetyl-l-cysteine (NAC), supplemented during early life or adulthood on the development of T1D. Methods NAC was administered to nonobese diabetic (NOD) female mice during pregnancy and lactation, and the development of diabetes was followed in offspring. In an additional set of experiments, offspring of untreated mice were given NAC during adulthood, and the development of T1D was followed. Morbidity rate, insulitis and serum cytokines were measured in the 2 sets of experiments. In addition, markers of oxidative stress, glutathione, lipid peroxidation, total antioxidant capacity and activity of antioxidant enzymes, were followed. Results Morbidity rate was reduced in both treatment protocols. A decrease in interferon γ, tumor necrosis factor α, interleukin 1α, and other type 1 diabetes-associated proinflammatory cytokines was found in mice supplemented with NAC in adulthood or during early life compared with control NOD mice. The severity of insulitis was higher in control NOD mice than in treated groups. NAC administration significantly reduced oxidative stress, as determined by reduced lipid peroxidation and increased total antioxidant capacity in serum and pancreas of mice treated in early life or in adulthood and increased pancreatic glutathione when administrated in adulthood. The activity of antioxidant enzymes was not affected in mice given NAC in adulthood, whereas an increase in the activity of superoxide dismutase and catalase was demonstrated in the pancreas of their offspring. Conclusion NAC decreased morbidity of NOD mice by attenuating the immune response, presumably by eliminating oxidative stress, and might be beneficial in reducing morbidity rates of T1D in high-risk individuals.

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Circulating metabolites and lipids are associated to diabetic retinopathy in individuals with type 1 diabetes

10.2337/figshare.12733202 ◽

2020 ◽

Author(s):

Ada Admin ◽

Viktor Rotbain Curovic ◽

Tommi Suvitaival ◽

Ismo Mattila ◽

Linda Ahonen ◽

...

Keyword(s):

Mass Spectrometry ◽

Type 1 Diabetes ◽

Diabetic Retinopathy ◽

High Performance ◽

Time Of Flight ◽

Risk Marker ◽

Cox Models ◽

Flight Mass Spectrometry

<a>Omics based methods may provide new markers associated to diabetic retinopathy (DR). We investigated a wide omics panel of metabolites and lipids related to DR in type 1 diabetes. Metabolomic analyses were performed using two-dimensional gas chromatography with time-of-flight mass spectrometry and lipidomic analyses utilizing an ultra-high-performance liquid chromatography quadruple time-of-flight mass spectrometry method in 648 individuals with type 1 diabetes. Subjects were sub-divided into: no DR, mild non-proliferative DR (NPDR), moderate NPDR, severe NPDR and proliferative DR. Endpoints were any progression of DR, onset of DR and progression from mild to severe DR tracked from standard ambulatory care and investigated using Cox models. The cohort consisted of 648 participants aged mean 54.4±12.8 years, 55.5% were male, and follow-up was 5.1-5.5 years. Cross-sectionally, 2,4-dihydroxybutyric acid (DHBA), 3,4-DHBA, ribonic acid, ribitol, and the triglycerides 50:1 and 50:2 significantly correlated (p<0.042) to DR stage. Longitudinally, higher 3,4-DHBA was a risk marker for progression of DR (n=133) after adjustment (p=0.033). We demonstrated multiple metabolites being positively correlated to higher grade of DR in type 1 diabetes, and several triglycerides being negatively correlated. Furthermore, higher 3,4-DHBA was an independent risk marker for progression of DR, however, confirmation is required.</a>

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