Glycerate from intestinal fructose metabolism induces islet cell damage and glucose intolerance

Wu, Yanru; Wong, Chi W.; Chiles, Eric; Mellinger, Allyson L.; Bae, Hosung; Jung, Sunhee; Peterson, Ted; Wang, Jamie; Negrete, Marcos; Huang, Qiang; Wang, Lihua; Jang, Cholsoon; Muddiman, David C.; Su, Xiaoyang; Williamson, Ian; Shen, Xiling

doi:10.1016/j.cmet.2022.05.007

Cited by 11 publications

(5 citation statements)

References 65 publications

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“…Thus, increased pyruvate and lactate levels may form characteristic markers of obesity and IR in children 28 . Existing evidence has shown that high‐fat diet promoted fructose metabolism and increased the levels of glyceric acid, damaging the secretion and function of islet β ‐cells and accelerating the occurrence of type 2 diabetes 30 …”

Section: Discussionmentioning

confidence: 99%

“…28 Existing evidence has shown that high-fat diet promoted fructose metabolism and increased the levels of glyceric acid, damaging the secretion and function of islet β-cells and accelerating the occurrence of type 2 diabetes. 30 Notably, adolescent development is one of the important physiological factors affecting IR. At this stage, the increase of growth hormone and sex hormone levels is accompanied by a transient decrease of insulin sensitivity and compensatory increase of insulin secretion.…”

Section: Discussionmentioning

confidence: 99%

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The link between obesity and insulin resistance among children: Effects of key metabolites

Yan,

Wu,

Liu

et al. 2023

Journal of Diabetes

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BackgroundChildhood obesity became a severe public health challenge, and insulin resistance (IR) was one of the common complications. Both obesity and IR were considered as the basis of metabolic disorders. However, it is unclear which common key metabolites are associated with childhood obesity and IR.MethodsThe children were divided into normal weight and overweight/obese groups. Fasting blood glucose and fasting insulin were measured, and homeostasis model assessment of insulin resistance was calculated. Liquid chromatography–tandem mass spectrometry was applied for metabonomic analysis. Multiple linear regression analysis and correlation analysis explored the relationships between obesity, IR, and metabolites. Random forests were used to rank the importance of differential metabolites, and relative operating characteristic curves were used for prediction.ResultsA total of 88 normal‐weight children and 171 obese/overweight children participated in the study. There was a significant difference between the two groups in 30 metabolites. Childhood obesity was significantly associated with 10 amino acid metabolites and 20 fatty acid metabolites. There were 12 metabolites significantly correlated with IR. The ranking of metabolites in random forest showed that glutamine, tyrosine, and alanine were important in amino acids, and pyruvic‐ox‐2, ethylmalonic‐2, and phenyllactic‐2 were important in fatty acids. The area under the curve of body mass index standard deviation score (BMI‐SDS) combined with key amino acid metabolites and fatty acid metabolites for predicting IR was 80.0% and 76.6%, respectively.ConclusionsThere are common key metabolites related to IR and obese children, and these key metabolites combined with BMI‐SDS could effectively predict the risk of IR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The link between obesity and insulin resistance among children: Effects of key metabolites

Yan,

Wu,

Liu

et al. 2023

Journal of Diabetes

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“…Glucagon was shown to stimulate mitochondrial anaplerotic flux from glutamine, identifying hepatic glutaminase as a new target to treat hyperglycemia [ 27 ]. In vivo studies in mice using (U- 13 C 6 ) fructose showed that high systemic glycerate levels cause glucose intolerance and damage pancreatic beta cells [ 28 ]. Maternal/fetal metabolic relationship probed in a recent study revealed that fetal nutrient sourcing was dependent on maternal glycemic state.…”

Section: Integrative Health and Systemic Disordersmentioning

confidence: 99%

Toward Systems-Level Metabolic Analysis in Endocrine Disorders and Cancer

Lakhani,

Kang,

Kang

et al. 2023

Endocrinol Metab

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Metabolism is a dynamic network of biochemical reactions that support systemic homeostasis amidst changing nutritional, environmental, and physical activity factors. The circulatory system facilitates metabolite exchange among organs, while the endocrine system finely tunes metabolism through hormone release. Endocrine disorders like obesity, diabetes, and Cushing’s syndrome disrupt this balance, contributing to systemic inflammation and global health burdens. They accompany metabolic changes on multiple levels from molecular interactions to individual organs to the whole body. Understanding how metabolic fluxes relate to endocrine disorders illuminates the underlying dysregulation. Cancer is increasingly considered a systemic disorder because it not only affects cells in localized tumors but also the whole body, especially in metastasis. In tumorigenesis, cancer-specific mutations and nutrient availability in the tumor microenvironment reprogram cellular metabolism to meet increased energy and biosynthesis needs. Cancer cachexia results in metabolic changes to other organs like muscle, adipose tissue, and liver. This review explores the interplay between the endocrine system and systems-level metabolism in health and disease. We highlight metabolic fluxes in conditions like obesity, diabetes, Cushing’s syndrome, and cancers. Recent advances in metabolomics, fluxomics, and systems biology promise new insights into dynamic metabolism, offering potential biomarkers, therapeutic targets, and personalized medicine.

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“…When consumed with high fructose intake, a HFD promotes fructose metabolism in the small intestine, releasing glyceric acid into circulation. Elevated levels of glyceric acid lead to pancreatic cell damage and impaired glucose tolerance, increasing the risk of diabetes ( 35 ). From an epigenetic perspective, a HFD can induce DNA methylation, histone modifications, and increased expression of non-coding RNAs, resulting in decreased transcriptional activity of key β-cell genes, leading to insulin resistance and the development of diabetes-related epigenetic mechanisms and metabolic regulation ( 36 ).…”

Section: Hfd Promotes the Development Of Metabolic Diseasesmentioning

confidence: 99%

Exploring a novel therapeutic strategy: the interplay between gut microbiota and high-fat diet in the pathogenesis of metabolic disorders

Jia,

Chen,

et al. 2023

Front. Nutr.

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In the past two decades, the rapid increase in the incidence of metabolic diseases, including obesity, diabetes, dyslipidemia, non-alcoholic fatty liver disease, hypertension, and hyperuricemia, has been attributed to high-fat diets (HFD) and decreased physical activity levels. Although the phenotypes and pathologies of these metabolic diseases vary, patients with these diseases exhibit disease-specific alterations in the composition and function of their gut microbiota. Studies in germ-free mice have shown that both HFD and gut microbiota can promote the development of metabolic diseases, and HFD can disrupt the balance of gut microbiota. Therefore, investigating the interaction between gut microbiota and HFD in the pathogenesis of metabolic diseases is crucial for identifying novel therapeutic strategies for these diseases. This review takes HFD as the starting point, providing a detailed analysis of the pivotal role of HFD in the development of metabolic disorders. It comprehensively elucidates the impact of HFD on the balance of intestinal microbiota, analyzes the mechanisms underlying gut microbiota dysbiosis leading to metabolic disruptions, and explores the associated genetic factors. Finally, the potential of targeting the gut microbiota as a means to address metabolic disturbances induced by HFD is discussed. In summary, this review offers theoretical support and proposes new research avenues for investigating the role of nutrition-related factors in the pathogenesis of metabolic disorders in the organism.

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Glycerate from intestinal fructose metabolism induces islet cell damage and glucose intolerance

Cited by 11 publications

References 65 publications

The link between obesity and insulin resistance among children: Effects of key metabolites

The link between obesity and insulin resistance among children: Effects of key metabolites

Toward Systems-Level Metabolic Analysis in Endocrine Disorders and Cancer

Exploring a novel therapeutic strategy: the interplay between gut microbiota and high-fat diet in the pathogenesis of metabolic disorders

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