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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Hepatic glucose sensing is required to preserve beta-cell glucose competence

ABSTRACT: We assessed the impact of glucose transporter Glut2 gene inactivation in adult mouse liver (LG2KO mice). This suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditure, and insulin sensitivity were identical in LG2KO and control mice. Glucose tolerance was normal early after Glut2 inactivation but intolerance developed at later time. This was caused by progressive impairment of glucose-stimulated insulin secretion even though beta-cell mass and insulin content remained normal. Liver transcript profiling revealed a coordinate down-regulation of cholesterol biosynthesis genes in LG2KO mice. This was associated with reduced hepatic cholesterol in fasted mice and a 30 percent reduction in bile acid production. We showed that chronic bile acids or FXR agonist treatment of primary islets increases glucose-stimulated insulin secretion, an effect not seen in islets from fxr-/- mice. Collectively, our data show that glucose sensing by the liver controls beta-cell glucose competence, through a mechanism that likely depends on bile acid production and action on beta-cells. three replicates each of ps_ctrl_refed, ps_tamox_refed, ps_ctrl_fasted, ps_tamox_fasted

ORGANISM(S): Mus musculus

SUBMITTER: FrÃ©dÃ©ric SchÃ¼tz

PROVIDER: E-GEOD-43581 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Hepatic glucose sensing is required to preserve beta-cell glucose competence

Project description:We assessed the impact of glucose transporter Glut2 gene inactivation in adult mouse liver (LG2KO mice). This suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditure, and insulin sensitivity were identical in LG2KO and control mice. Glucose tolerance was normal early after Glut2 inactivation but intolerance developed at later time. This was caused by progressive impairment of glucose-stimulated insulin secretion even though beta-cell mass and insulin content remained normal. Liver transcript profiling revealed a coordinate down-regulation of cholesterol biosynthesis genes in LG2KO mice. This was associated with reduced hepatic cholesterol in fasted mice and a 30 percent reduction in bile acid production. We showed that chronic bile acids or FXR agonist treatment of primary islets increases glucose-stimulated insulin secretion, an effect not seen in islets from fxr-/- mice. Collectively, our data show that glucose sensing by the liver controls beta-cell glucose competence, through a mechanism that likely depends on bile acid production and action on beta-cells.

2013-01-18 | GSE43581 | GEO

MicroRNA-21 Promotes Pancreatic β cell Function through Modulating Glucose Uptake

Project description:Pancreatic β cell dysfunction greatly contributes to the pathogenesis of type 2 diabetes. MiR-21 has been shown to be induced in the islets of glucose intolerant patients and type 2 diabetic mice. However, the role of miR-21 in the regulation of pancreatic β cell function remains largely elusive. In the current study, we studied the pathway by which miR-21 regulates glucose-stimulated insulin secretion utilizing mice lacking miR-21 in their β cells (miR-21βKO). We found that miR-21βKO mice developed glucose intolerance due to impaired glucose-stimulated insulin secretion. Mechanistic studies revealed that miR-21 enhances glucose uptake and subsequently promotes insulin secretion by up-regulating Glut2 expression in a miR-21-Pdcd4-AP-1 dependent pathway. Over-expression of Glut2 in knockout islets resulted in rescue of the impaired glucose-stimulated insulin secretion. Furthermore, we demonstrated that delivery of miR-21 into the pancreas of type 2 diabetic db/db mice is able to promote Glut2 expression and significantly reduce blood glucose level. Taking together, our results reveal that miR-21 in islet β cell promotes insulin secretion and support a role for miR-21 in the adaptation of pancreatic β cell function in type 2 diabetes.

2022-05-16 | GSE191194 | GEO

Hepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism

Project description:A greater understanding of the glucose homeostasis mediated by glucagon-like peptide-1 (GLP-1) will facilitate the development of novel glucose-lowering treatments. Here we show that improved glucose metabolism in hypothyroid mice after treatment of T3, the active form of thyroid hormone (TH), is accompanied with increased GLP-1 production and insulin secretion. Treatment of a GLP-1 receptor antagonist is able to attenuate the observed T3 effect on insulin and glucose levels, suggesting that GLP-1 is critically involved in the regulation of glucose homeostasis by T3. By using a mouse model lacking hepatic TH receptor β (TRβ) and a liver-specific TRβ-selective agonist, we demonstrate that TRβ-mediated hepatic TH signalling is not only required for the regulation of GLP-1 production by T3 but also the insulinotropic and glucose-lowering effects of T3. Accordingly, administration of the liver-targeted TRβ-selective agonist is capable of increasing GLP-1 and insulin levels and alleviating hyperglycemia in diet-induced obesity. Mechanistically, through suppressing CYP8B1 expression, T3 shapes the bile acid (BA) composition and increases the levels of Farnesoid X receptor (FXR)-antagonistic BAs, thereby potentiating the GLP-1 production and insulin secretion by repressing intestinal FXR signalling. Consistently, correlations between the T3 levels and either GLP-1 or FXR-antagonistic BA levels can be observed in euthyroid human subjects. Thus, our study reveals a previously undescribed role of hepatic TH signalling in glucose homeostasis through the regulation of GLP-1 production via BA-mediated FXR antagonism, which will underpin the development of novel therapeutics.

2022-09-23 | GSE184055 | GEO

Hepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism [RNA-seq]

2022-09-23 | GSE184261 | GEO

Deletion of Histone Deacetylase 3 in Adult Beta Cells Improves Glucose Tolerance via Increased Insulin Secretion

Project description:Objective: Histone deacetylases are epigenetic regulators known to control gene transcription in various tissues. A member of this family, histone deacetylase 3 (HDAC3), has been shown to regulate metabolic genes. Cell culture studies with HDAC-specific inhibitors and siRNA suggest that HDAC3 plays a role in pancreatic β-cell function, but a recent genetic study in mice has been contradictory. Here we address the functional role of HDAC3 in β-cells of adult mice. Methods: An HDAC3 β-cell specific knockout was generated in adult MIP-CreERT transgenic mice using the Cre-loxP system. Induction of HDAC3 deletion was initiated at 8 weeks of age with administration of tamoxifen in corn oil (2 mg/day for 5 days). Mice were assayed for glucose tolerance, glucose-stimulated insulin secretion, and islet function 2 weeks after induction of the knockout. Transcriptional functions of HDAC3 were assessed by ChIP-seq as well as RNA-seq comparing control and -cell knockout islets. Results: HDAC3 β-cell specific knockout (HDAC3βKO) did not increase total pancreatic insulin content or β-cell mass. However, HDAC3βKO mice demonstrated markedly improved glucose tolerance. This improved glucose metabolism coincided with increased basal and glucose-stimulated insulin secretion in vivo as well as in isolated islets. Cistromic and transcriptomic analyses of pancreatic islets revealed that HDAC3 regulates multiple genes that contribute to glucose-stimulated insulin secretion. Conclusions: HDAC3 plays an important role in regulating insulin secretion in vivo and therapeutic intervention may improve glucose homeostasis.

2016-11-26 | GSE90531 | GEO

Checkpoint Kinase 2 Controls Insulin Secretion and Glucose Homeostasis

Project description:After the discovery of insulin a century ago, extensive work has been done to unravel the molecular network regulating insulin secretion. Here, we performed a chemical screen and identified AZD7762, a compound that potentiates glucose-stimulated insulin secretion (GSIS) of human β cell line, healthy and type 2 diabetic (T2D) human islets, and primary cynomolgus macaque islets. In vivo studies in diabetic mouse models and cynomolgus macaques demonstrated that AZD7762 enhances GSIS and improves glucose tolerance. Furthermore, genetic manipulation confirmed that ablation of CHEK2 in human β cells results in increased insulin secretion. Consistently, high-fat-diet fed Chk2-/- mice show elevated insulin secretion and improved glucose clearance. Finally, an untargeted metabolic profiling demonstrated the key role of the CHEK2-PP2A-PLK1-G6PD-PPP pathway in insulin secretion. This study successfully identifies a previously unknown insulin secretion regulating pathway that is conserved across rodents, cynomolgus macaques and human β cells in both healthy and T2D conditions.

2023-10-25 | GSE239335 | GEO

Expression data from fresh and cultured islets at different glucose concentrations

Project description:β-cell identity is determined by tightly regulated transcriptional networks that are modulated by extracellular cues, thereby ensuring β-cell adaptation to the organism’s insulin demands. We have observed in pancreatic islets that stimulatory glucose concentrations induced a gene profile that was similar to that of freshly isolated islets, indicating that glucose-elicited cues are involved in maintaining β-cell identity. Low glucose induces the expression of ubiquitous genes involved in stress responses, nutrient sensing, and organelle biogenesis. By contrast, stimulatory glucose concentrations activate genes with a more restricted expression pattern (β- and neuronal- cell identity). Consistently, glucose-induced genes are globally reduced in islets deficient with Hnf1a (MODY3), characterized by a deficient glucose metabolism. Of interest, a cell cycle gene module was the most enriched among the variable genes between intermediate and stimulatory glucose concentrations. Glucose regulation of the islet transcriptome was unexpectedly broadly maintained in islets from aged mice. However, the cell cycle gene module is selectively lost in old islets and the glucose activation of this module is not recovered even in the absence of the cell cycle inhibitor p16. We used microarrays to detail the global programme of gene expression regulated by glucose in young and aged pancreatic islets as well as freshly-isolated islets.

2013-07-01 | GSE42591 | GEO

O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function

Project description:In Type 2 diabetes, insulin resistance elicits compensatory insulin hypersecretion, provoking β-cell stress and eventually compensatory failure. In insulin deficient STZ treated diabetic mice the dual AMPK activator and mitochondrial uncoupler O304 stimulates insulin independent glucose uptake and utilization in skeletal muscle and heart in vivo, thus improving glucose homeostasis. In obese In type 2 diabetic db/db mice, O304 additionally preserves β-cell function by preventing decline in insulin secretion, β-cell mass, and pancreatic insulin content. It remains however unclear whether these effects of O304 is mediated by a direct protective effect on β-cells, or indirectly by improving glucose homeostasis thereby inducing β-cell rest. To investigate the ability of O304 to directly mitigate the detrimental effect of hyperglycemia on β-cell function, we exposed isolated islets ex vivo to normoglycemic and hyperglycemic comdition in the abscence or prescene of O304.

2023-08-17 | GSE240298 | GEO

pancreas glucose model

Project description:The pancreas plays a critical role in maintaining glucose homeostasis through the secretion of hormones from the islets of Langerhans. Glucose-stimulated insulin secretion (GSIS) by the pancreatic beta-cell is the main mechanism for reducing elevated plasma glucose. Here we present a systematic modeling workflow for the development of kinetic pathway models using the Systems Biology Markup Language (SBML). An important factor was the reproducibility and exchangeability of the model, which allowed the use of various existing tools. The workflow was applied to construct a novel data-driven kinetic model of GSIS in the pancreatic beta-cell based on experimental and clinical data from 39 studies spanning 50 years of pancreatic, islet, and beta-cell research in humans, rats, mice, and cell lines. The model consists of detailed glycolysis and phenomenological equations for insulin secretion coupled to cellular energy state, ATP dynamics and (ATP/ADP ratio). Key findings of our work are that in GSIS there is a glucose-dependent increase in almost all intermediates of glycolysis. This increase in glycolytic metabolites is accompanied by an increase in energy metabolites, especially ATP and NADH. One of the few decreasing metabolites is ADP, which, in combination with the increase in ATP, results in a large increase in ATP/ADP ratios in the beta-cell with increasing glucose. Insulin secretion is dependent on ATP/ADP, resulting in glucose-stimulated insulin secretion.

2024-01-18 | MODEL2401110001 | BioModels

Aldh1b1 controlled timing of pancreas specification is important for β cell functionality and glucose homeostasis in the adult.

Project description:Maintenance of normal glucose homeostasis is disturbed in diabetes. In the β cell, this involves a glucose sensor converting increased glucose levels to insulin secretion. Understanding the developmental regulatory networks that define a fully functional β cell is important for elucidating the genetic origins of the disease and deriving mature β cells for therapy. Here we show that Aldh1b1 regulates the timing of differentiation in the developing pancreas and the patterning of β cells. In its absence, expression of key β cell transcription factors is deregulated at birth. Null animals become glucose intolerant and hyperglycemic with age. Beta cell dysfunction is associated with extensive transcripteome changes, increased oxidative stress, energy depletion and defects in both glucose sensing and stimulus coupling secretion. These findings identify Aldh1b1 as a central regulator of the transition from the pancreas endocrine progenitor to the committed β cell and demonstrate that changes in the timing of this transition manifest much later in adult life with β cell dysfunction. Islets were isolated from postnatal day one and 8 week old Aldh1b1 null and wt mice. For each P1 samples islets from three mice were combined. Each week 8 sample came from a single mouse. Three samples were analysed per genotype and time point

2015-07-31 | E-GEOD-58025 | biostudies-arrayexpress

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