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β-cell adaptation in mice expressing exclusively lamin C counteracts glucose intolerance associated with aging, obesity and diabetes (LamineA-C_RNASeq)

ABSTRACT: Lamin A, lamin C and progerin, produced by alternative RNA processing of LMNA gene, are intermediate filaments involved in nuclear and chromatin architecture. We investigate the ability of LMNALCS/LCS mice to adapt insulin level to physiological and physiopathologic conditions. The metabolic status of young vs old mice shows that old LMNALCS/LCS mice are obese but glucose tolerant due to an increased β cell mass and insulin secretion. By combining RNAseq and RRBS analysis, we observed a transcriptional disregulation of genes related to translation and mitochondria, confirmed by functionnal analysis, suggesting that LMNALCS/LCS mice set up a transcriptional program to adapt β cell mass and function to insulin demand. To investigate this point, we challenged young mice by inducing T1DM and T2DM. In these contexts, we show that LMNALCS/LCS mice are able to normalize their fasting glycemia by both increasing insulin secretion and regenerating β cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE122359 | GEO | 2019/11/09

REPOSITORIES: GEO

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β-cell adaptation in mice expressing exclusively lamin C counteracts glucose intolerance associated with aging, obesity and diabetes (LamineA-C_RRBS)

Project description:Lamin A, lamin C and progerin, produced by alternative RNA processing of LMNA gene, are intermediate filaments involved in nuclear and chromatin architecture. We investigate the ability of LMNALCS/LCS mice to adapt insulin level to physiological and physiopathologic conditions. The metabolic status of young vs old mice shows that old LMNALCS/LCS mice are obese but glucose tolerant due to an increased β cell mass and insulin secretion. By combining RNAseq and RRBS analysis, we observed a transcriptional disregulation of genes related to translation and mitochondria, confirmed by functionnal analysis, suggesting that LMNALCS/LCS mice set up a transcriptional program to adapt β cell mass and function to insulin demand. To investigate this point, we challenged young mice by inducing T1DM and T2DM. In these contexts, we show that LMNALCS/LCS mice are able to normalize their fasting glycemia by both increasing insulin secretion and regenerating β cells.

2019-11-09 | GSE122360 | GEO

Expression data from pancreatic islets of prolactin receptor null pregnant mice

Project description:Pancreatic islets adapt to the increase in insulin demand during pregnancy by up-regulating beta cell proliferation, insulin synthesis, and lowering the threshold of glucose-stimulated insulin secretion. In vitro studies suggest that pregnancy hormones, such as placental lactogens and prolactin, both act through the prolactin receptor, are required for these adaptation. Furhtermore, we found that transgenic mice with heterogenous prolactin receptor null mutation are glucose intolerant, with a lower beta-cell mass and lower insulin levels. The goal here is to discover novel targets of prolactin receptor signaling in pancreatic beta cells during pregnancy.

2019-02-01 | GSE125350 | GEO

Transcription profiling of pancreatic islets in wild type and Tcf-1 knock-out mice to identify target genes Tcf-1 that may be responsible of mediating beta cell growth

Project description:Mutations in several transcription factors lead to a subtype of type 2 diabetes called maturity-onset diabetes of the young (MODY), which are characterized by autosomal dominant inheritance, an early age of disease onset, and development of marked hyperglycemia with a progressive impairment in insulin secretion (Shih and Stoffel, 2002). The most frequent form of MODY is caused by mutations in the gene encoding hepatocyte nuclear factor-1a (HNF-1a, TCF1). Mutant mice with loss of Tcf1 function as well as transgenic mice expressing a naturally occurring dominant-negative form of human TCF1(P291fsinsC) in pancreatic beta cells develop progressive hyperglycemia due to impaired glucose-stimulated insulin secretion (Hagenfeldt-Johansson et al., 2001; Yamagata et al., 2002). Importantly, these mice exhibit a progressive reduction in beta cell number, proliferation rate, and pancreatic insulin content. These data indicate that Tcf-1 target genes are also required for maintenance of normal beta cell mass. In this study we sought to identify target genes of Tcf-1 that may be responsible of mediating beta cell growth by comparing gene expression profiles of Tcf-1 knock-out and wild-type littermates in isolated pancreatic islets.

2007-02-27 | E-CBIL-21 | biostudies-arrayexpress

The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice

Project description:AIMS/HYPOTHESIS: Manoeuvres aimed at increasing beta cell mass have been proposed as regenerative medicine strategies for diabetes treatment. Raf-1 kinase inhibitor protein 1 (RKIP1) is a common regulatory node of the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and therefore may be involved in regulation of beta cell homeostasis. The aim of this study was to investigate the involvement of RKIP1 in the control of beta cell mass and function. METHODS: Rkip1 (also known as Pebp1) knockout (Rkip1 (-/-)) mice were characterised in terms of pancreatic and glucose homeostasis, including morphological and functional analysis. Glucose tolerance and insulin sensitivity were examined, followed by assessment of glucose-induced insulin secretion in isolated islets and beta cell mass quantification through morphometry. Further characterisation included determination of endocrine and exocrine proliferation, apoptosis, MAPK activation and whole genome gene expression assays. Capacity to reverse a diabetic phenotype was assessed in adult Rkip1 (-/-) mice after streptozotocin treatment. RESULTS: Rkip1 (-/-) mice exhibit a moderately larger pancreas and increased beta cell mass and pancreatic insulin content, which correlate with an overall improvement in whole body glucose tolerance. This phenotype is established in young postnatal stages and involves enhanced cellular proliferation without significant alterations in cell death. Importantly, adult Rkip1 (-/-) mice exhibit rapid reversal of streptozotocin-induced diabetes compared with control mice. CONCLUSIONS/INTERPRETATION: These data implicate RKIP1 in the regulation of pancreatic growth and beta cell expansion, thus revealing RKIP1 as a potential pharmacological target to promote beta cell regeneration. Pancreatic gene expression of Rkip-1 (Raf kinase inhibitor 1) knockout (KO) and wild type (WT) mice, including three biological replicates in each group.

2012-11-19 | E-GEOD-31150 | biostudies-arrayexpress

Regulation of islet function and gene expression by prolactin during pregnancy

Project description:Pancreatic islets adapt to insulin resistance of pregnancy by up regulating beta-cell proliferation and increase insulin secretion. Previously, we found that prolactin receptor (Prlr) signaling is important for this process, as heterozygous prolactin receptor-null (Prlr+/-) mice are glucose intolerant, had a lower number of beta cells and lower serum insulin levels than wild type mice during pregnancy. However, since Prlr expression is ubiquitous, to determine its beta-cell-specific effects, we generated a transgenic mouse with a floxed Prlr allele under the control of an inducible promoter, i.e. bPrlR-/- mice, allowing conditional deletion of Prlr from beta cells in adult mice. In this study, we found that beta-cell-specific Prlr reduction resulted in elevated blood glucose during pregnancy. Similar to our previous finding in mice with global Prlr reduction, beta-cell-specific Prlr loss led to a lower beta-cell mass and a lower in vivo insulin level during pregnancy. However, these islets do not have an intrinsic insulin secretion defect when tested in vitro. Interestingly, when we compared the islet gene expression profile, using islets isolated from mice with global versus beta-cell-specific Prlr reduction, we found differences in expression of genes that regulate apoptosis, synaptic vesicle function and neuronal development. Indeed, islets from pregnant Prlr+/- mice are more susceptible glucolipotoxicity than bPrlR+/- islets. These observations suggest that Prlr has both cell-autonomous and non-cell-autonomous effect on beta cells, beyond its regulation of pro-proliferative genes.

2020-08-25 | GSE156774 | GEO

Expression profiling of pancreatic beta-cells harboring a pancreatic-specific deletion of PPAR-beta

Project description:Peroxisome proliferator-activated receptor beta/delta protects against obesity by reducing dyslipidemia and insulin resistance via effects in various organs, including muscle, adipose tissue, liver, and heart. However, nothing is known about the function of PPAR-beta in pancreas, a prime organ in the control of glucose metabolism. To gain insight into so far hypothetical functions of this PPAR isotype in insulin production, we specifically ablated Ppar-beta in pancreas. The mutated mice developed a chronic hyperinsulinemia, due to an increase in both beta-cell mass and insulin secretion. Gene expression profiling indicated a broad repressive function of PPAR-beta impacting the vesicular compartment, actin cytoskeleton, and metabolism of glucose and fatty acids. Analyses of insulin release from the islets revealed an increased second-phase glucose-stimulated insulin secretion. Higher levels of PKD, PKC-delta and diacyglycerol in mutated animals lead to an enhanced formation of trans-Golgi network (TGN)-to-plasma-membrane transport carriers in concert with F-actin disassembly, which resulted in increased insulin secretion and its associated systemic effects. Taken together, these results provide evidence for PPAR-beta playing a repressive role on beta-cell growth and insulin exocytosis, which shed new light on its anti-obesity action. Pancreas-specific knock-out animals were generated by breeding mice harbouring a floxed Ppar-beta (PPARbetafl/fl) to mice expressing the Cre transgene under the control of the Pdx1 promoter (Pdx1Cre). Islets from 3 different animals from the knock-out group Pdx1Cre;PPARbetafl/fl and the control littermates group PPARbetafl/fl were compared.

2012-08-30 | E-GEOD-16048 | biostudies-arrayexpress

The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice

2012-11-19 | GSE31150 | GEO

Metabolic Inflexibility Impairs Insulin Secretion And Results In MODY-like Diabetes In Triple FoxO-deficient Mice

Project description:Pancreatic b-cell failure in type 2 diabetes is associated with functional abnormalities of insulin secretion and deficits of b-cell mass. It’s unclear how one begets the other. We have shown that loss of b-cell mass can be ascribed to impaired FoxO1 function in different models of diabetes. Here we show that ablation of the three FoxO genes (1, 3a, and 4) in mature b-cells results in early-onset, maturity onset diabetes of the young (MODY)-like diabetes, with signature abnormalities of the MODY networks of Hnf4a, Hnf1a, and Pdx1. Transcriptome and functional analyses reveal that FoxO-deficient b-cells are metabolically inflexible, i.e., they preferentially utilize lipids rather than carbohydrates as source of acetyl-CoA for mitochondrial oxidative phosphorylation. This results in impaired ATP generation, and reduced Ca2+-dependent insulin secretion. When viewed in the context of prior data illustrating a role of FoxO1 in b-cell dedifferentiation, the present findings define a seamless FoxO-dependent mechanism linking the twin abnormalities of b-cell function in diabetes. We used microarrays to detail the change of gene expression in pancreatic beta cells after knocking out FoxO1,3 and 4. Primary islets were isolated from pancretic beta cell- specific triple FoxO(1,3, and 4) KO and their littermates control (WT) mice. Gene expression was analyzed by microarray.

2014-08-20 | E-GEOD-60505 | biostudies-arrayexpress

Gene expression analysis of mouse pancreatic islets from Ggcxff; Pdx1-Cre and Ggcxff mice by RNA-sequencing.

Project description:Vitamin K-dependent carboxylation is necessary to the acquisition of an adequate beta-cell mass and for insulin secretion in mice. To better understand how this pathway affect pancreatic beta-cell function, we analysed the expression profile of pancreatic islets from Ggcxff; Pdx1-Cre and Ggcxff mice by RNA-sequencing.

2023-05-08 | GSE199319 | GEO

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. three replicates each of ps_ctrl_refed, ps_tamox_refed, ps_ctrl_fasted, ps_tamox_fasted

2013-01-18 | E-GEOD-43581 | biostudies-arrayexpress

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