Intracellular lipid metabolism impairs β cell compensation during diet-induced obesity

Ye, Risheng; Gordillo, Ruth; Shao, Mengle; Onodera, Toshiharu; Chen, Zhe; Chen, Shiuhwei; Lin, Xiaojun; SoRelle, Jeffrey A.; Li, Xiaohong; Tang, Miao; Keller, Mark P.; Kuliawat, Regina; Attie, Alan D.; Gupta, Rana K.; Holland, William L.; Beutler, Bruce; Herz, Joachim; Scherer, Philipp E.

doi:10.1172/jci97702

Cited by 34 publications

(28 citation statements)

References 65 publications

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“…decreased GSIS in Min6 cells and murine islets) after inhibiting specific components of sphingolipid metabolism. Recently Ye et al [53] showed that during dietinduced obesity, mice with knockout of pancreatic beta cellspecific LDL receptor-related protein 1 (a pleiotropic mediator of cholesterol, insulin, energy metabolism and other cellular processes) were unable to compensate beta cell function partly due to downregulation of sphingolipid metabolism. Therefore, downregulated sphingolipid metabolism may play a causal role in pancreatic beta cell dysfunction.…”

Section: Discussionmentioning

confidence: 99%

The discovery of novel predictive biomarkers and early-stage pathophysiology for the transition from gestational diabetes to type 2 diabetes

et al. 2019

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Aims/hypothesis Gestational diabetes mellitus (GDM) affects up to 20% of pregnancies, and almost half of the women affected progress to type 2 diabetes later in life, making GDM the most significant risk factor for the development of future type 2 diabetes. An accurate prediction of future type 2 diabetes risk in the early postpartum period after GDM would allow for timely interventions to prevent or delay type 2 diabetes. In addition, new targets for interventions may be revealed by understanding the underlying pathophysiology of the transition from GDM to type 2 diabetes. The aim of this study is to identify both a predictive signature and early-stage pathophysiology of the transition from GDM to type 2 diabetes. Methods We used a well-characterised prospective cohort of women with a history of GDM pregnancy, all of whom were enrolled at 6-9 weeks postpartum (baseline), were confirmed not to have diabetes via 2 h 75 g OGTT and tested anually for type 2 diabetes on an ongoing basis (2 years of follow-up). A large-scale targeted lipidomic study was implemented to analyse~1100 lipid metabolites in baseline plasma samples using a nested pair-matched case-control design, with 55 incident cases matched to 85 non-case control participants. The relationships between the concentrations of baseline plasma lipids and respective follow-up status (either type 2 diabetes or no type 2 diabetes) were employed to discover both a predictive signature and the underlying pathophysiology of the transition from GDM to type 2 diabetes. In addition, the underlying pathophysiology was examined in vivo and in vitro. Results Machine learning optimisation in a decision tree format revealed a seven-lipid metabolite type 2 diabetes predictive signature with a discriminating power (AUC) of 0.92 (87% sensitivity, 93% specificity and 91% accuracy). The signature was highly robust as it includes 45-fold cross-validation under a high confidence threshold (1.0) and binary output, which together minimise the chance of data overfitting and bias selection. Concurrent analysis of differentially expressed lipid metabolite pathways uncovered the upregulation of α-linolenic/linoleic acid metabolism (false discovery rate [FDR] 0.002) and fatty acid biosynthesis (FDR 0.005) and the downregulation of sphingolipid metabolism (FDR 0.009) as being strongly associated with the risk of developing future type 2 diabetes. Focusing specifically on sphingolipids, the downregulation of sphingolipid metabolism

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Section: Discussionmentioning

confidence: 99%

The discovery of novel predictive biomarkers and early-stage pathophysiology for the transition from gestational diabetes to type 2 diabetes

et al. 2019

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“…For example, in vitro high-glucose stimulation can induce IL-1β secretion from islets through activation of the NLRP3 inflammasome 42,43 . Circulating SFAs could also induce islet inflammation, particularly in the presence of hyperglycaemia 10,44,45 . Although circulating cytokine levels are often increased in obesity and diabetes mellitus, these cytokines serve primarily as biomarkers of systemic inflammation, as the concentration of circulating cytokines is much lower than the biologically active levels that occur within the local tissue microenvironment.…”

Section: The Initiating Factors For Islet Inflammation An Important mentioning

confidence: 99%

“…Several studies have indicated that SFAs and potentially lipoproteins are circulating factors that might contribute to islet inflammation, β-cell dysfunction and β-cell hyperplasia 10,44,45 . For example, experimental elevation of palmitate levels in mice induces islet inflammation 10 .…”

Section: Lipids As Mediators Of Crosstalkmentioning

confidence: 99%

“…Another interesting connection between circulating lipoproteins and β-cell function has been reported. LDL receptor-related protein 1 (LRP1) can interact with extracellular lipoproteins, and one research group generated β-cell-specific LRP1-deficient mice and showed that these animals were partially protected from the adverse effects of a HFD on β-cell insulin secretion, as well as HFD-induced β-cell hyperplasia 45 . The same study also found that this could be related to the effect of LRP1 deletion to upregulate β-cell peroxisome proliferatoractivated receptor-γ2 (PPARγ2) in HFD-fed mice, as transgenic overexpression of PPARγ2 in β-cells partially recapitulated the LRP1 phenotype.…”

Section: Lipids As Mediators Of Crosstalkmentioning

confidence: 99%

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The role of macrophages in obesity-associated islet inflammation and β-cell abnormalities

et al. 2019

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“…Yang et al [21] directly revealed that high glucose could induce autophagy via the mTORC1 pathway, which led to PF and ultrafiltration failure. Moreover, studies have also demonstrated that the activation of the mTORC1 pathway disrupts the intracellular cholesterol homeostasis, which results in excessive uptake of cholesterol, and ultimately exacerbation of organ injury [22,23]. To clarify the mechanisms of action by which high-glucose PDS and mTORC1 influence ECM in PMCs, we observed the intracellular lipid homeostasis.…”

Section: High-glucose Pds-mediated Activation Of Mtorc1 Contributed Tmentioning

confidence: 99%

Mammalian Target of Rapamycin Complex 1 Activation Disrupts the Low-Density Lipoprotein Receptor Pathway: A Novel Mechanism for Extracellular Matrix Accumulation in Human Peritoneal Mesothelial Cells

et al. 2018

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Peritoneal fibrosis (PF) is characterized by progressive extracellular matrix (ECM) accumulation. Increasing evidence has suggested that ECM synthesis was increased in human peritoneal mesothelial cells (HPMCs) under high-glucose conditions, but the effects of high-glucose peritoneal dialysis solution (PDS) on ECM synthesis have not been fully elucidated. The aim of this study was to explore the potential mechanisms of high-glucose PDS-induced production of ECM in HPMCs. HPMCs were stimulated by high-glucose PDS. The activity of mammalian target of rapamycin complex 1 (mTORC1) was inhibited by rapamycin or regulatory-associated protein of mTOR (raptor) siRNA. Morphological changes in the cells were observed under an inverted microscope. Oil red O, filipin staining and high-performance liquid chromatography were used to examine lipid accumulation. The expression of low-density lipoprotein receptor (LDLr) regulation, the mTORC1 pathway and ECM-associated markers were assessed by real-time polymerase chain reaction and western blot analysis. The results showed that after treatment with PDS, HPMCs showed notable elongation consistent with the morphology of myofibroblasts, and the expression of ECM proteins such as α-smooth muscle actin, fibroblast specific protein-1 and collagen I was increased. In addition, there was a parallel increase in the ECM and lipid accumulation. Moreover, the effect of intracellular lipid deposition was closely correlated with the dysregulation of LDLr, which was mediated through the upregulation of LDLr, sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), and SREBP-2 and through the enhanced coexpression of the SCAP with the Golgin. Further analysis showed that PDS enhanced the protein phosphorylation of mTOR, eukaryotic initiation factor 4E-binding protein 1, and p70 S6 kinase. Interestingly, blocking mTORC1 activity reversed the dysregulation of LDLr, even in the presence of PDS. These effects were also accompanied by a decrease in the expression of ECM components. Our findings demonstrated that increased mTORC1 activity exacerbated ECM formation in HPMCs by disrupting LDLr regulation, which contributed to lipid disorder-mediated PF.

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Intracellular lipid metabolism impairs β cell compensation during diet-induced obesity

Cited by 34 publications

References 65 publications

The discovery of novel predictive biomarkers and early-stage pathophysiology for the transition from gestational diabetes to type 2 diabetes

The discovery of novel predictive biomarkers and early-stage pathophysiology for the transition from gestational diabetes to type 2 diabetes

The role of macrophages in obesity-associated islet inflammation and β-cell abnormalities

Mammalian Target of Rapamycin Complex 1 Activation Disrupts the Low-Density Lipoprotein Receptor Pathway: A Novel Mechanism for Extracellular Matrix Accumulation in Human Peritoneal Mesothelial Cells

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