Neonatal beta cells lack the specialized metabolic phenotype of mature beta cells
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE24790 | GEO | 2011/02/22
SECONDARY ACCESSION(S): PRJNA132245
REPOSITORIES: GEO
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Project description:Fetal and neonatal beta cells have poor glucose-induced insulin secretion and only gain robust glucose responsiveness several weeks after birth. This unresponsiveness may be due to a generalized immaturity of the metabolic pathways normally found in beta cells. Gene expression profile of neonatal (1 day old) and young adult (6 weeks old) Sprague-Dawley rat islets were evaluated and compared. Frozen sections were obtained from pancreases of neonatal (1 day old) and young adult (6 weeks old) Sprague-Dawley rats. The beta cell enriched cores of the islets were excised using laser capture microdissection. RNA was extracted, amplified and subjected to microarray analysis.
2011-02-22 | E-GEOD-24790 | biostudies-arrayexpress
Project description:The lower glucose-responsiveness of neonatal beta cells is generally considered a sign of endocrine immaturity. We compared mRNA profiles of neonatal and 10-weeks old rat beta cells to see how their gene expression changes with functional maturation. Neonatal beta cells showed a lower glucose-inducible increment in insulin production than adult cells. This was in part explained by basal protein synthetic hyperactivity of neonatal cells: while at 2.5mM glucose 80% of neonatal beta cells were recruited into active protein synthesis, 10 mM glucose was required to achieve a similar fraction of active adult beta cells. Besides this progressive recruitment, glucose exerted in both age groups an additional amplifying effect in the recruited cells, but clearly more so in adult beta cells that showed a higher maximal synthetic capacity/cell. Neonatal beta cells balanced an advanced endocrine differentiation as judged by their mRNA expression of conserved beta cell marker genes, with higher expression of genes involved in cell cycle and development. One example, Delta-like 1 homolog (DLK1) was used to investigate if neonatal beta cells with basal hyperactivity corresponded to a more immature subset, as marked by high DLK1. Neonatal pancreas contained distinct subsets of DLK1high and DLK1low insulin-expressing cells, but both showed equal hyperactivity. We conclude that neonatal beta cells combine advanced endocrine maturation with traits of residual developmental immaturity. If DLK1 is used as marker for the latter, the basal hyperactivity which proved to be a cardinal feature of neonatal beta cells is not a direct reflection of their residual immaturity. A genome-wide view on postnatal maturation/differentiation of the rat beta cells The study compares Affymetrix RG230.20 expression profiles of 3 cell subsets: (1) HSSC: a population of cells isolated from post natal day 2-3 rat pancreas that is enriched (65-70%) in insulin cells (n=3), (2) LSSC: a population of cells isolated from postnatal day 2-3 rat pancreas that is mostly devoid of endocrine cells, and selected by its low side scatter (n=3); and (3) adult beta: a reference population of FACS-purified adult rat beta cells (>90% insulin+) freshly isolated from pancreas of 10 weeks-old rats (n=5). RNA was extracted from the cells immediately after isolation, without further treatment or culture. Details of the isolation procedure and extensive microscopic characterization of the preps are described in the accompanying scientific paper by Martens GA et al.
2013-08-20 | E-GEOD-47174 | biostudies-arrayexpress
Project description:The lower glucose-responsiveness of neonatal beta cells is generally considered a sign of endocrine immaturity. We compared mRNA profiles of neonatal and 10-weeks old rat beta cells to see how their gene expression changes with functional maturation. Neonatal beta cells showed a lower glucose-inducible increment in insulin production than adult cells. This was in part explained by basal protein synthetic hyperactivity of neonatal cells: while at 2.5mM glucose 80% of neonatal beta cells were recruited into active protein synthesis, 10 mM glucose was required to achieve a similar fraction of active adult beta cells. Besides this progressive recruitment, glucose exerted in both age groups an additional amplifying effect in the recruited cells, but clearly more so in adult beta cells that showed a higher maximal synthetic capacity/cell. Neonatal beta cells balanced an advanced endocrine differentiation as judged by their mRNA expression of conserved beta cell marker genes, with higher expression of genes involved in cell cycle and development. One example, Delta-like 1 homolog (DLK1) was used to investigate if neonatal beta cells with basal hyperactivity corresponded to a more immature subset, as marked by high DLK1. Neonatal pancreas contained distinct subsets of DLK1high and DLK1low insulin-expressing cells, but both showed equal hyperactivity. We conclude that neonatal beta cells combine advanced endocrine maturation with traits of residual developmental immaturity. If DLK1 is used as marker for the latter, the basal hyperactivity which proved to be a cardinal feature of neonatal beta cells is not a direct reflection of their residual immaturity. A genome-wide view on postnatal maturation/differentiation of the rat beta cells
2013-08-20 | GSE47174 | GEO
Project description:Neonatal beta cells are considered developmentally immature and hence less glucose-responsive. To study the acquisition of mature glucose-responsiveness, we compared glucose-regulated redox state, insulin synthesis and secretion of beta cells purified from neonatal or 10-weeks old rats to their transcriptomes and proteomes measured by oligonucleotide and LC-MS/MS profiling. Lower glucose-responsiveness of neonatal beta cells was explained by two distinct properties: higher activity at low glucose and lower activity at high glucose. Basal hyperactivity was associated with higher NAD(P)H, a higher fraction of neonatal beta cells actively incorporating 3H-Tyrosine, and persistently increased insulin secretion below 5 mM glucose. Neonatal beta cells lacked the steep glucose-responsive NAD(P)H rise between 5-10 mM glucose characteristic for adult beta cells, and accumulated less NAD(P)H at high glucose. They had 2-fold lower expression of malate/aspartate-NADH shuttle and most glycolytic enzymes. Genome-wide profiling situated neonatal beta cells at a developmental crossroad: they showed advanced endocrine differentiation when specifically analyzed for their mRNA/protein level of classical neuroendocrine markers. On the other hand, discrete neonatal beta cell subpopulations still expressed mRNAs/proteins typical for developing/proliferating tissues. One example, Delta-like 1 homolog (DLK1) was used to investigate if neonatal beta cells with basal hyperactivity corresponded to a more immature subset with high DLK1, but no association was found. In conclusion, the current study supports the importance of glycolytic NADH-shuttling in stimulus-function coupling, presents basal hyperactivity as novel property of neonatal beta cells, and provides potential markers to recognize intercellular developmental differences in the endocrine pancreas.
2014-12-12 | PXD001577 | Pride
Project description:Neonatal beta-cells undergo a maturation process to acquire glucose responsiveness. We hypothesize that in later life, a partial reversal of this maturation might promote beta-cell dysfunction. We previously ascertained that fetuin-A, a fetal glycoprotein downregulated at birth but increasingly secreted when fatty liver develops, inhibits insulin secretion. Here, we evaluate fetuin-A’s impact on beta-cell maturation. In vitro maturation of neonatal porcine islet cell clusters (NICCs) promoted expression of beta-cell markers and TGFBR/SMAD signaling. Fetuin-A reduced both functional and proliferative gene expression and SMAD phosphorylation. Consequently, fetuin-A impaired glucose- and forskolin-dependent secretion, and reduced adaptive beta-cell proliferation. In adult human islets, fetuin-A abolished glucose responsiveness, diminished SMAD phosphorylation and downregulated functional and proliferative genes. Our findings suggest that perinatal decline of fetuin-A relieves TGFBR signaling in neonatal beta-cells, thereby facilitating the onset of postnatal maturation. However, this program remains revocable during adulthood, since fatty liver-derived fetuin-A reverses beta-cells’ maturity, conferring them a neonatal-like phenotype and contributing to their failure.
2020-12-07 | GSE144950 | GEO
Project description:Pregnancy poses significant metabolic challenges for women, yet the impact of repeated deliveries on overall glucose metabolism in females remains inadequately explored. In this study, we investigate alterations in female glucose metabolism following multiple deliveries using a comprehensive phenotyping mouse model that closely resembles humans. To establish a multiparty mouse model, a 9-week-old female mouse underwent three consecutive pregnancies. Three weeks post-pregnancy, multiparous mice exhibited improved glucose tolerance and enhanced glucose-stimulated insulin secretion (GSIS), without changes in insulin sensitivity compared to virgin mice. Histological analysis revealed an increased beta cell mass in multiparous mice at this stage of life. Intriguingly, 16 weeks after the last delivery, multiparous mice demonstrated impaired glucose tolerance, accompanied by compromised GSIS and increased basal insulin secretion both in vivo and ex vivo. These mice also developed insulin resistance at 16 weeks post-delivery, with no discernible difference in beta cell mass. To assess whether multiparous islets were impaired in their compensatory ability to meet increased insulin demand, multiparous and virgin islets (3 weeks after the last delivery) were transplanted to opposite sides of the kidney capsule in a single recipient mouse. Upon S-961 injection, multiparous mice were reduced in Ki-67 expressing cells compared with virgin mice. Bulk RNA sequencing (RNA-seq) analysis of S-961-injected multiparous islet genes revealed downregulation of cell cycle-related genes (Cenpi and Cenpf, Cdk1, Cdk2, and Cdkn2d). Single-cell RNA-seq analysis identified multiparous-specific beta cell clusters that displayed upregulation of stress-related genes (Ddit3, Fkbp11, Sdf2l1, Nupr1, Atf5, Atf3, Hspa1a, Hspa1b, and Dnajb1). Furthermore, multiparous mice beta cells exhibited shortened telomere lengths and increased expression of Cdkn2a, indicating an accelerated aging phenotype. In humans, women with higher parities (parity > 3 times) exhibited greater impairment in glucose tolerance and increased obesity compared to women with lower parities (parity < 3 times) at 2 months postpartum. Women with higher parity who experienced weight gain after delivery also demonstrated a greater decline in beta cell function (disposition index). Overall, our findings indicate that multiparty increases the risk of diabetes by impairing beta cells ability to compensate for the increased insulin demand.
2023-06-16 | GSE234741 | GEO
Project description:Pregnancy poses significant metabolic challenges for women, yet the impact of repeated deliveries on overall glucose metabolism in females remains inadequately explored. In this study, we investigate alterations in female glucose metabolism following multiple deliveries using a comprehensive phenotyping mouse model that closely resembles humans. To establish a multiparty mouse model, a 9-week-old female mouse underwent three consecutive pregnancies. Three weeks post-pregnancy, multiparous mice exhibited improved glucose tolerance and enhanced glucose-stimulated insulin secretion (GSIS), without changes in insulin sensitivity compared to virgin mice. Histological analysis revealed an increased beta cell mass in multiparous mice at this stage of life. Intriguingly, 16 weeks after the last delivery, multiparous mice demonstrated impaired glucose tolerance, accompanied by compromised GSIS and increased basal insulin secretion both in vivo and ex vivo. These mice also developed insulin resistance at 16 weeks post-delivery, with no discernible difference in beta cell mass. To assess whether multiparous islets were impaired in their compensatory ability to meet increased insulin demand, multiparous and virgin islets (3 weeks after the last delivery) were transplanted to opposite sides of the kidney capsule in a single recipient mouse. Upon S-961 injection, multiparous mice were reduced in Ki-67 expressing cells compared with virgin mice. Bulk RNA sequencing (RNA-seq) analysis of S-961-injected multiparous islet genes revealed downregulation of cell cycle-related genes (Cenpi and Cenpf, Cdk1, Cdk2, and Cdkn2d). Single-cell RNA-seq analysis identified multiparous-specific beta cell clusters that displayed upregulation of stress-related genes (Ddit3, Fkbp11, Sdf2l1, Nupr1, Atf5, Atf3, Hspa1a, Hspa1b, and Dnajb1). Furthermore, multiparous mice beta cells exhibited shortened telomere lengths and increased expression of Cdkn2a, indicating an accelerated aging phenotype. In humans, women with higher parities (parity > 3 times) exhibited greater impairment in glucose tolerance and increased obesity compared to women with lower parities (parity < 3 times) at 2 months postpartum. Women with higher parity who experienced weight gain after delivery also demonstrated a greater decline in beta cell function (disposition index). Overall, our findings indicate that multiparty increases the risk of diabetes by impairing beta cells ability to compensate for the increased insulin demand.
2023-06-16 | GSE234740 | GEO
Project description:We found that in rodents, postnatal beta-cell maturation is associated with changes in the expression of several islet microRNAs and discovered that these modifications are driven by changes in the nutrient supply. Mimicking the microRNA changes observed during β-cell maturation in newborn rat islet cells was sufficient to promote glucose-induced insulin release and to achieve a mature β-cell secretory phenotype. Moreover, the modifications in the level of some of these microRNAs reduced the proliferation of newborn β-cells, suggesting that they contribute to the limited proliferative capacity of adult β-cells. These findings demonstrated that miRNAs contribute to postnatal beta-cell maturation and development. Their role is likely to promote beta-cell adaptation to fuel supply and to maintain glucose homeostasis by regulating insulin release and proliferation. Islets from 10-day-old rats (P10) (n=4) or 3-month-old male rat (n=4) were taken. Total RNA was extracted and microRNA profiling was performed with miRNA Agilent arrays.
2014-09-04 | E-GEOD-61090 | biostudies-arrayexpress
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
Project description:Immature β-cells are present in adult islets. However, their contribution to insulin release is not fully understood. Here we show that specific loss of immature β-cells induces failure throughout the β-cell complement. Functional mapping of the β-cell population in rodent and human loss-of-immaturity islets revealed defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, loss of immature β-cells led to dysregulation of gene pathways involved in glucose and carbohydrate-derivative metabolic processes. Using a chemogenetic disruption strategy, immature β-cells were found to depend on the islet signaling network for their phenotype. During metabolic stress, islet function could be restored by redressing the balance between immature and mature β-cells. We thus unveil immature β-cells as a critical component in islet operation. Preserving immature β-cells might be important for islet engineering efforts and more broadly the treatment of type 1 and type 2 diabetes.
2020-10-15 | GSE133798 | GEO