Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE121539 | GEO | 2019/05/10

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

A Single-cell Transcriptomic Atlas of Primate Pancreatic Islet Aging

Project description:Aging-related degeneration of pancreatic islet cells contributes to impaired glucose tolerance and diabetes. Endocrine cells age heterogeneously, complicating the effort to unravel the molecular drives underlying endocrine aging. To overcome these obstacles, we undertook single-cell RNA sequencing of pancreatic islet cells obtained from young and aged non-diabetic cynomolgus monkeys. Despite sex differences and increased single-cell level transcriptional variations, aged β-cells showed increased unfolded protein response (UPR) along with the accumulation of protein aggregates. We observed transcriptomic dysregulation of UPR components linked to canonical ATF6 and IRE1 signaling, comprising adaptive UPR during pancreatic aging. Notably, we found age-related β-cell-specific upregulation of HSP90B1, an ER-located chaperone, impeded high glucose-induced insulin secretion. Our work decodes aging-associated transcriptomic changes that underlie pancreatic islet functional decay at the single-cell resolution and indicates that targeting UPR components may prevent loss of proteostasis, suggesting an avenue for therapies to delay β-cell aging and prevent aging-related diabetes.

2020-06-11 | GSE120180 | GEO

Microarray comparing gene expression changes between control, normoglycaemic mice, and mice expressing the human neonatal diabetes mutation Kir6.2-V59M in pancreatic beta-cells left diabetic for 2 weeks

Project description:Activating mutations in the KATP channel cause a rare genetic form of diabetes called neonatal diabetes. These mutations render the channel permanently open results in membrane hyperpolarisation of the pancreatic beta-cell. This prevents calcium influx and impairs insulin secretion. Mice expressing the human neonatal diabetes mutation Kir6.2-V59M specifically in pancreatic beta-cells are diabetic but do not display dyslipidaemia or insulin resistance. In this experiment, gene expression changes were analysed to explore the effect of high blood glucose per se on isolated pancreatic islets

2017-07-05 | E-MTAB-5086 | biostudies-arrayexpress

Phosphoproteomics reveals the GSK3-PDX1 axis as a key pathogenic signaling node in diabetic islets

Project description:Progressive decline of pancreatic beta cell function is central to the pathogenesis of type 2 diabetes. Protein phosphorylation regulates glucose-stimulated insulin secretion from beta cells, but how signaling networks are remodeled in diabetic islets in vivo remains unknown. Using high-sensitivity mass spectrometry-based proteomics we quantified 6,500 proteins and 13,000 phosphopeptides in islets of obese diabetic mice and matched controls, revealing drastic remodeling of key kinase hubs and signaling pathways. Integration with a literature-derived signaling network implicated GSK3 kinase in the control of the beta cell-specific transcription factor PDX1. Deep phosphoproteomic analysis of human islets chronically treated with high glucose demonstrated a conserved glucotoxicity-dependent role of GSK3 kinase in regulating insulin secretion. Remarkably, the ability of beta cells to secrete insulin in response to glucose was rescued almost completely by pharmacological inhibition of GSK3. Thus, our resource enables investigation of mechanisms and drug targets in type 2 diabetes.

2019-03-15 | PXD012671 | Pride

Male biased islet b cell dysfunction is caused by the MODY MAFA S64F variant by inducing premature aging and senescence

Project description:A heterozygous missense mutation producing a variant of the islet β-cell-enriched MAFA transcription factor (p.Ser64Phe (S64F)) was identified in patients who developed adult-onset, β-cell dysfunction (diabetes or insulinomatosis), with men more prone to diabetes than women. This mutation engenders increased stability to the normally unstable MAFA protein. To obtain insight into how this variant impacts β cell function, we developed a mouse model expressing S64F MafA and found sex-dependent phenotypes, with heterozygous mutant males (MafAS64F/+) displaying impaired glucose tolerance while females were slightly hypoglycemic with improved blood glucose clearance. Only MafAS64F/+ males showed transiently higher MafA protein levels preceding the onset of glucose intolerance and sex-dependent, differential expression of genes involved in Ca2+ signaling, DNA damage, aging, and senescence. Functional changes in islet Ca2+ handling and signs of islet aging and senescence processes were uniquely observed in male animals. In addition, MAFAS64F production in male human β cells accelerated cellular senescence and increased production of senescence-associated secretory proteins compared to cells expressing MAFAWT. Together, these results implicate a conserved mechanism of accelerated islet aging and senescence in promoting diabetes in MAFAS64F carriers in a sex-dependent manner.

2021-09-10 | GSE183561 | 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

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

Acinar to β-like cell conversion through inhibition of focal adhesion kinase

Project description:Insufficient functional β-cell mass causes diabetes; however, an effective cell replacement therapy for curing diabetes is currently not available. Reprogramming of acinar cells toward functional insulin-producing cells would offer an abundant and autologous source of insulin-producing cells. Our lineage tracing studies along with transcriptomic characterization demonstrate that treatment of adult mice with a small molecule that specifically inhibits kinase activity of focal adhesion kinase results in trans-differentiation of acinar cells into insulin producing β-like cells. The acinar-derived insulin-producing cells infiltrate the pre-existing endocrine islets, partially restore β-cell mass, and significantly improve glucose homeostasis in diabetic mice. Importantly, this treatment can substantially reduce the exogenous insulin requirements in streptozotocin-induced diabetic non-human primates. These findings provide evidence that inhibition of the kinase activity of focal adhesion kinase can convert acinar cells into insulin-producing cells and could offer a promising strategy for treating diabetes.

2024-03-12 | GSE251852 | GEO

Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells

Project description:Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 β-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.

2019-04-10 | PXD012979 | Pride

Transforming growth factor beta-like stimulated clone 22 D4 promotes diabetic hyperglycemia and insulin resistance [skeletal muscle]

Project description:Obesity-related insulin resistance represents the core component of the so-called Metabolic Syndrome, ultimately promoting glucose intolerance, pancreatic beta cell failure, and overt type 2 diabetes 1 2. Based on substantial side effects of existing pharmacological approaches, efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications. Here, we identify Transforming Growth Factor beta-like Stimulated Clone (TSC) 22 D4 as a critical molecular determinant of insulin signaling and glucose handling. Hepatocyte-specific inactivation of TSC22D4 enhanced insulin signaling in liver and skeletal muscle, while hepatic TSC22D4 overexpression blunted insulin tissue responses. Consequently, hepatic TSC22D4 inhibition both prevented and reversed hyperglycemia, glucose intolerance, and insulin resistance in various diabetes mouse models, respectively. TSC22D4 was found to exert its effects on systemic glucose homeostasis –in large parts- through the transcriptional regulation of the small secretory protein lipocalin (LCN) 13 as demonstrated by chromatin recruitment and genetic rescue experiments in vivo. As hepatic TSC22D4 levels were found to be elevated in human diabetic patients, correlating with decreased insulin sensitivity and hyperglycemia, our results establish the inhibition of TSC22D4 as an attractive insulin sensitizing option in diabetes therapy.

2014-10-15 | GSE53754 | GEO

Transforming growth factor beta-like stimulated clone 22 D4 promotes diabetic hyperglycemia and insulin resistance [abdominal fat]

Project description:Obesity-related insulin resistance represents the core component of the so-called Metabolic Syndrome, ultimately promoting glucose intolerance, pancreatic beta cell failure, and overt type 2 diabetes 1 2. Based on substantial side effects of existing pharmacological approaches, efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications 3. Here, we identify Transforming Growth Factor beta-like Stimulated Clone (TSC) 22 D4 as a critical molecular determinant of insulin signaling and glucose handling. Hepatocyte-specific inactivation of TSC22D4 enhanced insulin signaling in liver and skeletal muscle, while hepatic TSC22D4 overexpression blunted insulin tissue responses. Consequently, hepatic TSC22D4 inhibition both prevented and reversed hyperglycemia, glucose intolerance, and insulin resistance in various diabetes mouse models, respectively. TSC22D4 was found to exert its effects on systemic glucose homeostasis - in large parts - through the transcriptional regulation of the small secretory protein lipocalin (LCN) 13 as demonstrated by chromatin recruitment and genetic rescue experiments in vivo. As hepatic TSC22D4 levels were found to be elevated in human diabetic patients, correlating with decreased insulin sensitivity and hyperglycemia, our results establish the inhibition of TSC22D4 as an attractive insulin sensitizing option in diabetes therapy.

2014-10-15 | GSE53753 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data