Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications

Sas, Kelli M.; Kayampilly, Pradeep P.; Byun, Jaeman; Nair, Viji; Hinder, Lucy M.; Hur, Junguk; Zhang, Hongyu; Lin, Cheng‐mao; Qi, Nathan; Michailidis, George; Groop, Per‐Henrik; Nelson, Robert G.; Darshi, Manjula; Sharma, Kumar; Schelling, Jeffrey R.; Sedor, John R.; Pop‐Busui, Rodica; Weinberg, Joel M.; Soleimanpour, Scott A.; Abcouwer, Steven F; Gardner, Thomas W.; Burant, Charles F.; Feldman, Eva L.; Kretzler, Matthias; Brosius, Frank C.; Pennathur, Subramaniam

doi:10.1172/jci.insight.86976

Cited by 213 publications

(252 citation statements)

References 65 publications

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“…16,20,21 Several groups now have found that reduced mitochondrial function plays a key role in DKD both in mouse models and in patients with DKD. 20,22,23 By using transcriptomic, metabolomics, and flux approaches, Sas et al 16 reported significantly increased glycolytic intermediates and enzymes in kidney cortex, along with a significant reduction in mitochondrial function in a type 2 diabetic mouse model. Interestingly, in a very recent study, Qi et al 21 reported that enhanced pyruvate kinase II (PKM2) activity may preserve mitochondrial function by increasing glucose flux through glycolysis in podocytes and alleviate the progression of DKD in patients with diabetes.…”

Section: Warburg Effect/aerobic Glycolysis and Its Potential Role Inmentioning

confidence: 99%

“…16,20,21 By using targeted metabolomics and systems biology tools we reported that human DKD is associated with mitochondrial dysfunction. Gas chromatography-mass spectrometry–based targeted metabolomics were performed and 94 urinary metabolites were quantified in patients with established DKD and compared with healthy controls.…”

Section: Metabolomics Identify Mitochondrial Dysfunction and Warburgmentioning

confidence: 99%

“…15 New evidence indicates that alternative pathways such as enhanced fatty acid oxidation in mitochondria are involved in diabetic complications. 15,16 However, it still is unclear whether mitochondrial dysfunction in DKD results in altered glycolysis flux, or if glycolysis flux/accumulation of glycolytic intermediates in DKD drives the metabolic flux into the five pathways discussed earlier, leading to impaired mitochondrial function, or if a bidirectional causality exists. The current review high-lights the diabetes-induced metabolic switch from oxidative phosphorylation to glycolysis and the potential link to downstream effects on kidney function and disease progression.…”

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confidence: 99%

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The Warburg Effect in Diabetic Kidney Disease

Zhang

Darshi

Sharma

2018

Seminars in Nephrology

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Summary Diabetic kidney disease (DKD) is the leading cause of morbidity and mortality in diabetic patients. Defining risk factors for DKD using a reductionist approach has proven challenging. Integrative omics-based systems biology tools have shed new insights in our understanding of DKD and have provided several key breakthroughs for identifying novel predictive and diagnostic biomarkers. In this review, we highlight the role of the Warburg effect in DKD and potential regulating factors such as sphingomyelin, fumarate, and pyruvate kinase muscle isozyme M2 in shifting glucose flux from complete oxidation in mitochondria to the glycolytic pathway and its principal branches. With the development of highly sensitive instruments and more advanced automatic bioinformatics tools, we believe that omics analyses and imaging techniques will focus more on singular-cell-level studies, which will allow in-depth understanding of DKD and pave the path for personalized kidney precision medicine.

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Section: Warburg Effect/aerobic Glycolysis and Its Potential Role Inmentioning

confidence: 99%

Section: Metabolomics Identify Mitochondrial Dysfunction and Warburgmentioning

confidence: 99%

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confidence: 99%

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The Warburg Effect in Diabetic Kidney Disease

Zhang

Darshi

Sharma

2018

Seminars in Nephrology

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“…Renal studies show increased cellular flux of nutrients early in disease, which later declines, suggesting temporal changes with disease progression [24,32]. This may explain why glucose-lowering agents are more effective when given earlier in disease.…”

Section: Next Generation Glucose-lowering Therapiesmentioning

confidence: 99%

“…It is not known, however, whether this occurs in all organs affected by complications. Recent metabolomic flux studies in mice given a single oral gavage of isotopic substrate, such as glucose or fatty acids (palmitate-BSA), have supported the postulate that nutrient flux into energy generation pathways occurs at sites of diabetes complications [32]. Unfortunately, these flux studies, as performed so far, may not provide much information beyond that reported in previous work using static measurements, given that they are single-oral-administration studies in which tissue and blood measurements are performed in fasted mice without steady-state infusions of metabolites and lacking control for differences in organ blood flow.…”

Section: Next Generation Glucose-lowering Therapiesmentioning

confidence: 99%

Vascular complications in diabetes: old messages, new thoughts

Forbes

Fotheringham

2017

Diabetologia

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In parallel with the growing diabetes pandemic, there is an increasing burden of micro-and macrovascular complications, occurring in the majority of patients. The identification of a number of synergistic accelerators of disease, providing therapeutic pathways, has stabilised the incidence of complications in most western nations. However, the primary instigators of diabetic complications and, thus, prevention strategies, remain elusive. This has necessitated a refocus on natural history studies, where tissue and plasma samples are sequentially taken to determine when and how disease initiates. In addition, recent Phase III trials, wherein the pleiotropic effects of compounds were arguably as beneficial as their glucose-lowering capacity in slowing the progression of complications, have identified knowledge gaps. Recently the influence of other widely recognised pathological pathways, such as mitochondrial production of reactive oxygen species, has been challenged, highlighting the need for a diverse and robust global research effort to ascertain viable therapeutic targets. Technological advances, such as -omics, high-resolution imaging and computational modelling, are providing opportunities for strengthening and re-evaluating research findings. Newer areas such as epigenetics, energetics and the increasing scrutiny of our synergistic inhabitants, the microbiota, also offer novel targets as biomarkers. Ultimately, however, this field requires concerted lobbying to support all facets of diabetes research.

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Plasma lipid metabolites associate with diabetic polyneuropathy in a cohort with type 2 diabetes

Rumora

Guo

Alakwaa

et al. 2021

Ann Clin Transl Neurol

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Objective: The global rise in type 2 diabetes is associated with a concomitant increase in diabetic complications. Diabetic polyneuropathy is the most frequent type 2 diabetes complication and is associated with poor outcomes. The metabolic syndrome has emerged as a major risk factor for diabetic polyneuropathy; however, the metabolites associated with the metabolic syndrome that correlate with diabetic polyneuropathy are unknown. Methods: We conducted a global metabolomics analysis on plasma samples from a subcohort of participants from the Danish arm of Anglo-Danish-Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION-Denmark) with and without diabetic polyneuropathy versus lean control participants. Results: Compared to lean controls, type 2 diabetes participants had significantly higher HbA1c (p = 0.0028), BMI (p = 0.0004), and waist circumference (p = 0.0001), but lower total cholesterol (p = 0.0001). Out of 991 total metabolites, we identified 15 plasma metabolites that differed in type 2 diabetes participants by diabetic polyneuropathy status, including metabolites belonging to energy, lipid, and xenobiotic pathways, among others. Additionally, these metabolites correlated with alterations in plasma lipid metabolites in type 2 diabetes participants based on neuropathy status. Further evaluating all plasma lipid metabolites identified a shift in abundance, chain length, and saturation of free fatty acids in type 2 diabetes participants. Importantly, the presence of diabetic polyneuropathy impacted the abundance of plasma complex lipids, including acylcarnitines and sphingolipids. Interpretation: Our explorative study suggests that diabetic polyneuropathy in type 2 diabetes is associated with novel alterations in plasma metabolites related to lipid metabolism.

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Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications

Cited by 213 publications

References 65 publications

The Warburg Effect in Diabetic Kidney Disease

The Warburg Effect in Diabetic Kidney Disease

Vascular complications in diabetes: old messages, new thoughts

Plasma lipid metabolites associate with diabetic polyneuropathy in a cohort with type 2 diabetes

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