Longitudinal analysis of hepatic transcriptome and serum metabolome demonstrates altered lipid metabolism following the onset of hyperglycemia in spontaneously diabetic biobreeding rats

Regnell, Simon E.; Hessner, Martin J.; Song, Jia; Åkesson, Lina; Stenlund, Hans; Moritz, Thomas; Torre, Daria La; Lernmark, Åke

doi:10.1371/journal.pone.0171372

Cited by 5 publications

(8 citation statements)

References 41 publications

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“…The low ratio of Serpinb1:Plin2 genes in 8-and 30-day BBdp rats would likely favor β-cell death. A previous study demonstrated alterations in lipid metabolism in liver of prediabetic BBDR lyp/lyp rats with decreased insulin levels contributing to altered gene expression (Regnell et al 2017). We demonstrate here that hepatic genes are also altered in the prediabetic period.…”

Section: Journal Of Endocrinologysupporting

confidence: 70%

Changes in insulin, glucagon and ER stress precede immune activation in type 1 diabetes

Crookshank

Serrano

Wang

et al. 2018

Journal of Endocrinology

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It is unknown whether there is a gene signature in pancreas which is associated with type 1 diabetes (T1D). We performed partial pancreatectomies on 30 day preinsulitic, diabetes-prone BioBreeding (BBdp) rats to prospectively identify factors involved in early prediabetes. Microarrays of the biopsies revealed downregulation of ER stress, metabolism and apoptosis. Based on these results, additional investigations compared gene expression in control (BBc) and BBdp rats age ~8, 30 and 60 days using RT-qPCR. Neonates had increased ER stress gene expression in pancreas. This was associated with decreased insulin, cleaved caspase-3 and Ins1 whereas Gcg and Pcsk2 were increased. The increase in ER stress was not sustained at 30 days and decreased by 60 days. In parallel, the liver gene profile showed a similar signature in neonates but with an early decrease of the unfolded protein response (UPR) at 30 days. This suggested that changes in the liver precede those in the pancreas. Tnf and Il1b expression was increased in BBdp pancreas in association with increased caspase-1, cleaved caspase-3 and decreased proinsulin area. Glucagon area was increased in both 30 day and 60 day BBdp rats. Increased co-localization of BIP and proinsulin was observed at 60 days in the pancreas, suggesting insulin-related ER dysfunction. We propose that dysregulated metabolism leads to ER stress in neonatal rats long before insulitis, creating a microenvironment in both pancreas and liver that promotes autoimmunity.

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Section: Journal Of Endocrinologysupporting

confidence: 70%

Changes in insulin, glucagon and ER stress precede immune activation in type 1 diabetes

Crookshank

Serrano

Wang

et al. 2018

Journal of Endocrinology

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“…Although there are scarce data on changes in gene expression induced by excessive GV, there is a large pool of studies on gene profiling related to hyperglycemia. Using high-throughput technologies, differential gene expression was measured under hyperglycemic conditions in beta cells [140,141], pancreatic cells [142], hepatic cells [143,144], endothelial cells [145], myotubes [146], cardiomyocytes [147], vascular smooth muscle cells [148,149], adipose progenitor cells [150], kidney cells [151], renal tubular epithelial cells [152], retina [153,154], immune cells [155,156] and others. The genes that demonstrate an altered expression in hyperglycemia are mostly involved in glucose metabolism, inflammation and immune processes, endothelial dysfunction, angiogenesis, oxidative stress, mitochondrial dysfunction, hypoxia and cell death.…”

Section: Gene Expressionmentioning

confidence: 99%

Glucose Variability: How Does It Work?

Климонтов

Saik

Korbut

2021

IJMS

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A growing body of evidence points to the role of glucose variability (GV) in the development of the microvascular and macrovascular complications of diabetes. In this review, we summarize data on GV-induced biochemical, cellular and molecular events involved in the pathogenesis of diabetic complications. Current data indicate that the deteriorating effect of GV on target organs can be realized through oxidative stress, glycation, chronic low-grade inflammation, endothelial dysfunction, platelet activation, impaired angiogenesis and renal fibrosis. The effects of GV on oxidative stress, inflammation, endothelial dysfunction and hypercoagulability could be aggravated by hypoglycemia, associated with high GV. Oscillating hyperglycemia contributes to beta cell dysfunction, which leads to a further increase in GV and completes the vicious circle. In cells, the GV-induced cytotoxic effect includes mitochondrial dysfunction, endoplasmic reticulum stress and disturbances in autophagic flux, which are accompanied by reduced viability, activation of apoptosis and abnormalities in cell proliferation. These effects are realized through the up- and down-regulation of a large number of genes and the activity of signaling pathways such as PI3K/Akt, NF-κB, MAPK (ERK), JNK and TGF-β/Smad. Epigenetic modifications mediate the postponed effects of glucose fluctuations. The multiple deteriorative effects of GV provide further support for considering it as a therapeutic target in diabetes.

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“…It is just beginning to be recognized that inter-organ communication could play a role in diabetes pathogenesis 9,22 . It has been recognized in the pathogenesis of T2D 9 and changes in the liver are known to occur in overt T1D 56 , but the role of inter-organ communication in the early developmental stages of T1D remains an open question. Crosstalk between the liver and the immune system has the potential for integrating the sensing of nutrients and pathogens 57 , and could begin to explain the effects of diet and gut microbiota on T1D development.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated liver lipid metabolism and innate immunity associated with hepatic steatosis in neonatal BBdp rats and NOD mice

Serrano

Crookshank

Morgan

et al. 2019

Sci Rep

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In a previous study we reported that prediabetic rats have a unique gene signature that was apparent even in neonates. Several of the changes we observed, including enhanced expression of pro-inflammatory genes and dysregulated UPR and metabolism genes were first observed in the liver followed by the pancreas. In the present study we investigated further early changes in hepatic innate immunity and metabolism in two models of type 1 diabetes (T1D), the BBdp rat and NOD mouse. There was a striking increase in lipid deposits in liver, particularly in neonatal BBdp rats, with a less striking but significant increase in neonatal NOD mice in association with dysregulated expression of lipid metabolism genes. This was associated with a decreased number of extramedullary hematopoietic clusters as well as CD68+ macrophages in the liver of both models. In addition, PPARɣ and phosphorylated AMPKα protein were decreased in neonatal BBdp rats. BBdp rats displayed decreased expression of antimicrobial genes in neonates and decreased M2 genes at 30 days. This suggests hepatic steatosis could be a common early feature in development of T1D that impacts metabolic homeostasis and tolerogenic phenotype in the prediabetic liver.

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Longitudinal analysis of hepatic transcriptome and serum metabolome demonstrates altered lipid metabolism following the onset of hyperglycemia in spontaneously diabetic biobreeding rats

Cited by 5 publications

References 41 publications

Changes in insulin, glucagon and ER stress precede immune activation in type 1 diabetes

Changes in insulin, glucagon and ER stress precede immune activation in type 1 diabetes

Glucose Variability: How Does It Work?

Dysregulated liver lipid metabolism and innate immunity associated with hepatic steatosis in neonatal BBdp rats and NOD mice

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