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Integrated in vivo quantitative proteomics and nutrient tracing reveals age-related metabolic rewiring of pancreatic B-cell function

ABSTRACT: Aging is associated with fundamental changes in pancreatic B-cell physiology; yet, the mechanisms that drive these age-related changes are poorly understood. We performed comprehensive proteomic profiling of pancreatic islets from adolescent and old mice. The analysis revealed striking differences in abundance of enzymes controlling glucose metabolism not reflected at the transcript level. We show that these changes in protein abundance are associated with increased activity of the amplifying pathway of insulin secretion. The amplifying pathway stimulates insulin secretion through coupling factors produced during glucose metabolism. Nutrient tracing and targeted metabolomics demonstrate accelerated accumulation of glucose-derived metabolites and coupling factors in aged islets, indicating that age-related changes in glucose metabolism contribute to the improved response of B-cells to glucose with age. Together, our study provides the first in-depth characterization of changes in the islet proteome during aging and establishes metabolic rewiring as an important mechanism for age-associated changes in B-cell function.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Maike Sander

PROVIDER: MSV000081577 | MassIVE | Tue Oct 03 11:18:00 BST 2017

SECONDARY ACCESSION(S): PXD007899

REPOSITORIES: MassIVE

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Integrated in vivo quantitative proteomics and nutrient tracing reveals age-related metabolic rewiring of pancreatic beta-cell function

Project description:Aging is associated with fundamental changes in pancreatic β-cell physiology; yet, the mechanisms that drive these age-related changes are poorly understood. We performed comprehensive proteomic profiling of pancreatic islets from adolescent and old mice. The analysis revealed striking differences in abundance of enzymes controlling glucose metabolism not reflected at the transcript level. We show that these changes in protein abundance are associated with increased activity of the amplifying pathway of insulin secretion. The amplifying pathway stimulates insulin secretion through coupling factors produced during glucose metabolism. Nutrient tracing and targeted metabolomics demonstrate accelerated accumulation of glucose-derived metabolites and coupling factors in aged islets, indicating that age-related changes in glucose metabolism contribute to the improved response of β-cells to glucose with age. Together, our study provides the first in-depth characterization of changes in the islet proteome during aging and establishes metabolic rewiring as an important mechanism for age-associated changes in β-cell function.

2018-12-03 | GSE104591 | GEO

Acceleration of beta cell aging plays a key role in diabetes and senolysis improves metabolic, functional and cellular outcomes

Project description:The risk of type 2 diabetes increases with age. Although changes in function and proliferation of aged beta cells resemble those preceding the development of diabetes, the contribution of beta cell aging and senescence remains unclear. The proportion of aged beta cells increases with animal age but even in young mice, senescent beta cells can be found. We showed that different models of insulin resistance accelerated aging and senescence marker expression in beta cells, BGal, led to loss of function and impaired glucose tolerance. Clearance of p16Ink4a+ cells, using the INK-ATTAC mouse model, ameliorated glucose metabolism, insulin secretion and decreased expression of aging, senescence and SASP genes in pancreatic islets. Senolytic drug ABT263 also improved glucose metabolism and beta cell identity when administered during insulin resistance. Human beta cells from diabetic and non-diabetic donors shared some of the same biology laying the foundation for translation into humans. These novel findings lay the framework to pursue senolysis of beta cells as a preventive and alleviating strategy for T2D.

2019-05-10 | GSE121539 | GEO

Sustained hyperglycemia specifically targets translation of mRNAs for insulin secretion

Project description:Pancreatic beta-cells are specialized for coupling glucose metabolism to insulin peptide production and secretion. Acute glucose exposure robustly and coordinately increases translation of proinsulin and proteins required for secretion of mature insulin peptide. By contrast, chronically elevated glucose levels that occur during diabetes impair beta-cell insulin secretion and have been shown experimentally to suppress insulin translation. Whether translation of other genes critical for insulin secretion are similarly downregulated by chronic high glucose is unknown. Here, we used high-throughput ribosome profiling and nascent proteomics in MIN6 insulinoma cells to elucidate the genome-wide impact of sustained high glucose on beta-cell mRNA translation. Prior to induction of ER stress or suppression of global translation, sustained high glucose suppressed glucose-stimulated insulin secretion and downregulated translation of not only insulin, but also of mRNAs related to insulin secretory granule formation, exocytosis, and metabolism-coupled insulin secretion. Translation of these mRNAs was also downregulated in primary rat and human islets following ex-vivo incubation with sustained high glucose and in an in vivo model of chronic mild hyperglycemia. Furthermore, translational downregulation decreased cellular abundance of these proteins. Our study uncovered a translational regulatory circuit during beta-cell glucose toxicity that impairs expression of proteins with critical roles in beta-cell function.

2023-12-01 | GSE248349 | GEO

The G Protein-coupled Receptor P2Y14 Influences Insulin Release and Smooth Muscle Function in Mice

Project description:UDP-sugars were identified as extracellular signaling molecules, assigning a new function to these compounds in addition to their well defined role in intracellular substrate metabolism and storage. Previously regarded as an orphan receptor, the G protein-coupled receptor (GPCR) P2Y14 (GPR105) was found to bind extracellular UDP and UDP-sugars. Little is known about the physiological functions of this GPCR. To study its physiological role we used a gene-deficient (KO) mouse strain expressing the bacterial LacZ reporter gene to monitor the physiological expression pattern of P2Y14. We found that P2Y14 is mainly expressed in pancreas and salivary glands and in subpopulations of smooth muscle cells of the gastrointestinal tract, blood vessels, lung and uterus. Among other phenotypical differences KO mice showed a significantly impaired glucose tolerance following oral and intraperitoneal glucose application. An unchanged insulin tolerance suggested altered pancreatic islet function. Transcriptome analysis of pancreatic islets showed that P2Y14 deficiency significantly changed expression of components involved in insulin secretion. Insulin secretion tests revealed a reduced insulin release from P2Y14-deficient islets highlighting P2Y14 as a new modulator of proper insulin secretion. 10 samples from pancreatic islets isolated from wildtype mice; 10 samples from pancreatic islets isolated from P2Y14-knockout mice

2014-07-11 | E-GEOD-59285 | biostudies-arrayexpress

Sustained hyperglycemia specifically targets translation of mRNAs for insulin secretion

Project description:Pancreatic beta-cells are specialized for coupling glucose metabolism to insulin peptide production and secretion. Acute glucose exposure robustly and coordinately increases translation of proinsulin and proteins required for secretion of mature insulin peptide. By contrast, chronically elevated glucose levels that occur during diabetes impair beta-cell insulin secretion and have been shown experimentally to suppress insulin translation. Whether translation of other genes critical for insulin secretion are similarly downregulated by chronic high glucose is unknown. Here, we used high-throughput ribosome profiling and nascent proteomics in MIN6 insulinoma cells to elucidate the genome-wide impact of sustained high glucose on -cell mRNA translation. Prior to induction of ER stress or suppression of global translation, sustained high glucose suppressed glucose-stimulated insulin secretion and downregulated translation of not only insulin, but also of mRNAs related to insulin secretory granule formation, exocytosis, and metabolism-coupled insulin secretion. Translation of these mRNAs was also downregulated in primary rat and human islets following ex-vivo incubation with sustained high glucose and in an in vivo model of chronic mild hyperglycemia. Furthermore, translational downregulation decreased cellular abundance of these proteins. Our study uncovered a translational regulatory circuit during beta-cell glucose toxicity that impairs expression of proteins with critical roles in beta-cell function.

2023-12-03 | PXD047140 | Pride

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

RNA seq of pancreatic islets isolated from free fatty acid receptor 3 knockout (Ffar3 KO) and wildtype (Ffar3 WT) male mice

Project description:The short chain fatty acid (SCFA) receptor (free fatty acid receptor-3; FFAR3) is expressed in pancreatic beta cells; however, its role in insulin secretion is not clearly defined. Here, we examined the role of FFAR3 in insulin secretion. Using islets from global knockout FFAR3 (Ffar3-/-) mice, we explored the role of FFAR3 and ligand-induced FFAR3 signaling on glucose stimulated insulin secretion. RNA sequencing was also performed to gain greater insight into the impact of FFAR3 deletion on the islet transcriptome. First exploring insulin secretion, it was determined that Ffar3-/- islets secrete more insulin in a glucose-dependent manner as compared to wildtype (WT) islets. Next, exploring its primary endogenous ligand, propionate, and a specific agonist for FFAR3, signaling by FFAR3 inhibited glucose-dependent insulin secretion, which occurred through a GÎ±i/o pathway. To help understand these results, transcriptome analyses by RNA-sequencing of Ffar3-/- and WT islets observed multiple genes with well known roles in islet biology to be altered by genetic knockout of FFAR3. Our data shows that FFAR3 signaling mediates glucose stimulated insulin secretion through GÎ±i/o sensitive pathway. Future studies are needed to more rigorously define the role of FFAR3 by in vivo approaches. Analysis of total RNA from 3 biological replicates of pancreatic islets isolated from free fatty acid receptor 3 knockout (Ffar3 KO) and wildtype (Ffar3 WT) male mice

2016-07-03 | E-GEOD-67991 | biostudies-arrayexpress

Next Generation Sequencing Facilitates Quantitative Analysis of Transcriptomes in fetal and 2 weeks old rat islets

Project description:Unlike adult β-cells, fetal and neonatal islets are functional immature and have blunted glucose responsiveness and decreased insulin secretion in response to stimuli. Pancreatic islets are a mixture of different cell types. Study of transcriptomes from intact islets would identify novel molecular mechanisms controlling islet functional development. At e19 and 2 weeks of age, pancreatic islets were isolated and total RNA were extracted for RNA-Seq study. Gene expression profiles were compared in the study.

2020-07-02 | GSE153604 | GEO

Reduced insulin secretion in WFS1-deficient mice may be related to downregulation of Trpm5

Project description:Wolfram syndrome, an autosomal recessive disorder characterized by juvenile-onset diabetes mellitus and optic atrophy, is caused by mutations in the WFS1 gene. WFS1 encodes an endoplasmic reticulum resident transmembrane protein. The Wfs1-null mice exhibit progressive insulin deficiency and diabetes. The aim of the present study was to describe the insulin secretion and transcriptome of pancreatic islets in WFS1-deficient mice. WFS1-deficient (Wfs1KO) mice had considerably less pancreatic islets than heterozygous (Wfs1HZ) or wild-type (WT) mice. Wfs1KO pancreatic islets secreted less insulin after stimulation with 2 and 10 mM glucose and with tolbutamide solution compared to WT and Wfs1HZ islets, but not after stimulation with 20 mM glucose. Differences in proinsulin amount were not statistically significant although there was a trend that Wfs1KO had an increased level of proinsulin. After stimulation with 2 mM glucose solution the proinsulin/insulin ratio in Wfs1KO was significantly higher than that of WT and Wfs1HZ. RNA-seq from pancreatic islets found melastatin-related transient receptor potential subfamily member 5 protein gene (Trpm5) to be downregulated in WFS1-deficient mice. Functional annotation of RNA sequencing results showed that WFS1 deficiency influenced significantly the pathways related to tissue morphology, endocrine system development and function, molecular transport network. These findings suggest an interactive role of WFS1 and TRPM5 in insulin secretion. 12 samples: three genotypes, 4 individuals in each genotype

2015-02-14 | E-GEOD-65929 | biostudies-arrayexpress

Mapping of INS promoter interactions reveals its role in long-range regulation of SYT8 transcription

Project description:Insulin (INS) synthesis and secretion from pancreatic M-NM-2 cells are tightly regulated; their deregulation causes diabetes. Here we map INS-associated loci in human pancreatic islets by 4C and 3C techniques and show that the INS gene physically interacts with the SYT8 gene, located over 300 kb away. This interaction is elevated by glucose and accompanied by increases in SYT8 expression. Inactivation of the INS promoter by promoter-targeting siRNA reduces SYT8 gene expression. SYT8-INS interaction and SYT8 transcription are attenuated by CTCF depletion. Furthermore, SYT8 knockdown decreases insulin secretion in islets. These results reveal a non-redundant role for SYT8 in insulin secretion and indicate that the INS promoter acts from a distance to stimulate SYT8 transcription. This suggests a function for the INS promoter in coordinating insulin transcription and secretion through long-range regulation of SYT8 expression in human islets. Circular Chromosome Conformation Capture (4C)-Seq experiments to profile interactions of INS promoter in human pancreatic islets isolated from two donors: donor 1 and donor 2.

2011-02-22 | E-GEOD-25862 | biostudies-arrayexpress

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