Transcriptome landmarks of the functional maturity of rat beta-cells, from lactation to adulthood

Larqué, Carlos; Velasco, Manuel; Barajas‐Olmos, Francisco; García-Delgado, Neyvis; Chávez-Maldonado, Juan Pablo; García-Morales, Jazmín; Hiriart, Marcia

doi:10.1530/jme-16-0052

Cited by 8 publications

(11 citation statements)

References 33 publications

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“…Our results showed that, distinct to other isoforms, Cav3.2 expression progressively increased from one stage of maturation to the other. This confirms the validation approach of our group, whose microarray analysis revealed a higher expression of different calcium channel isoforms, like α1H subunit (Cav3.2), in adult beta cells compared with P20 cells ( 20 ). Neurons and myocytes also exhibit a variable pattern of calcium channel expression during different stages of development ( 42 – 44 ).…”

Section: Discussionsupporting

confidence: 86%

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Calcium Channels in Postnatal Development of Rat Pancreatic Beta Cells and Their Role in Insulin Secretion

et al. 2018

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Pancreatic beta cells during the first month of development acquire functional maturity, allowing them to respond to variations in extracellular glucose concentration by secreting insulin. Changes in ionic channel activity are important for this maturation. Within the voltage-gated calcium channels (VGCC), the most studied channels are high-voltage-activated (HVA), principally L-type; while low-voltage-activated (LVA) channels have been poorly studied in native beta cells. We analyzed the changes in the expression and activity of VGCC during the postnatal development in rat beta cells. We observed that the percentage of detection of T-type current increased with the stage of development. T-type calcium current density in adult cells was higher than in neonatal and P20 beta cells. Mean HVA current density also increased with age. Calcium current behavior in P20 beta cells was heterogeneous; almost half of the cells had HVA current densities higher than the adult cells, and this was independent of the presence of T-type current. We detected the presence of α1G, α1H, and α1I subunits of LVA channels at all ages. The Cav 3.1 subunit (α1G) was the most expressed. T-type channel blockers mibefradil and TTA-A2 significantly inhibited insulin secretion at 5.6 mM glucose, which suggests a physiological role for T-type channels at basal glucose conditions. Both, nifedipine and TTA-A2, drastically decreased the beta-cell subpopulation that secretes more insulin, in both basal and stimulating glucose conditions. We conclude that changes in expression and activity of VGCC during the development play an important role in physiological maturation of beta cells.

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Section: Discussionsupporting

confidence: 86%

“…Furthermore, a recent work of our group revealed that transcriptome changes are involved in the beta-cell maturation, by microarray analysis ( 20 ). We showed a differential expression in P20 and adult cells in a variety of gene sets including those involved in excitability.…”

Section: Introductionmentioning

confidence: 99%

Calcium Channels in Postnatal Development of Rat Pancreatic Beta Cells and Their Role in Insulin Secretion

et al. 2018

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“…Immediately after birth, β-cells are not fully functional and have to undergo a major gene reprogramming to acquire the ability to secrete adequate amounts of insulin in response to glucose (1). Our group and others (2,5,24) have shown a large-scale rewiring of transcriptional programs occurring during the neonatal period. However, little is known on cis-regulation of gene expression at the chromatin level before and after weaning.…”

Section: Discussionmentioning

confidence: 82%

“…Cells that generate and secrete insulin can be produced in vitro using various methods (3,4) and are similar to β-cells in many aspects. However, these cells show lower glucose-stimulated insulin secretion (GSIS) and transcriptome differences compared with normal β-cells (5). Consequently, there is a need to better understand the regulation of the maturation process to enable the engineering of fully functional surrogate insulin-producing cells.…”

Section: Introductionmentioning

confidence: 99%

Chromatin accessibility variations across pancreatic islet maturation

Sobel

Guay

Rodríguez-Trejo

et al. 2019

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Glucose-induced insulin secretion, a peculiar property of fully mature β-cells, is only achieved after birth and is preceded by a phase of intense proliferation. These events occurring in the neonatal period are decisive for the establishment of an appropriate functional β-cell mass that provides the required insulin throughout life. However, key regulators of gene expression involved in cellular reprogramming along pancreatic islet maturation remain to be elucidated. The present study addressed this issue by mapping open chromatin regions in newborn versus adult rat islets using the ATAC-seq assay. Accessible regions were then correlated with the expression profiles of mRNAs to unveil the regulatory networks governing functional islet maturation. This led to the identification of Scrt1, a novel transcriptional repressor controlling β-cell proliferation. ATAC-seq | Scrt1 | Pancreatic Islet maturation | β-cellCorrespondence: Romano.Regazzi@unil.ch Sobel et al. | bioRχiv | September 25, 2019 | 1-17

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“…We are interested in the physiological changes during early postnatal development, specifically around weaning in Wistar rats (that under laboratory conditions occurs at postnatal day 20 (p20)). During this critical developmental window, which lasts approximately eight days, previous works by Hiriart and collaborators identified changes related to the functional maturation of pancreatic beta cells [ 22 , 24 – 26 ] and observed systemic IR in male p20 rats [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Sexual dimorphism in the molecular mechanisms of insulin resistance during a critical developmental window in Wistar rats

et al. 2022

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Background Insulin resistance (IR) is a condition in which the response of organs to insulin is impaired. IR is an early marker of metabolic dysfunction. However, IR also appears in physiological contexts during critical developmental windows. The molecular mechanisms of physiological IR are largely unknown in both sexes. Sexual dimorphism in insulin sensitivity is observed since early stages of development. We propose that during periods of accelerated growth, such as around weaning, at postnatal day 20 (p20) in rats, the kinase S6K1 is overactivated and induces impairment of insulin signaling in its target organs. This work aimed to characterize IR at p20, determine its underlying mechanisms, and identify whether sexual dimorphism in physiological IR occurs during this stage. Methods We determined systemic insulin sensitivity through insulin tolerance tests, glucose tolerance tests, and blood glucose and insulin levels under fasting and fed conditions at p20 and adult male and female Wistar rats. Furthermore, we quantified levels of S6K1 phosphorylated at threonine 389 (T389) (active form) and its target IRS1 phosphorylated at serine 1101 (S1101) (inhibited form). In addition, we assessed insulin signal transduction by measuring levels of Akt phosphorylated at serine 473 (S473) (active form) in white adipose tissue and skeletal muscle through western blot. Finally, we determined the presence and function of GLUT4 in the plasma membrane by measuring the glucose uptake of adipocytes. Results were compared using two-way ANOVA (With age and sex as factors) and one-way ANOVA with post hoc Tukey’s tests or t-student test in each corresponding case. Statistical significance was considered for P values < 0.05. Results We found that both male and female p20 rats have elevated levels of glucose and insulin, low systemic insulin sensitivity, and glucose intolerance. We identified sex- and tissue-related differences in the activation of insulin signaling proteins in p20 rats compared to adult rats. Conclusions Male and female p20 rats present physiological insulin resistance with differences in the protein activation of insulin signaling. This suggests that S6K1 overactivation and the resulting IRS1 inhibition by phosphorylation at S1101 may modulate to insulin sensitivity in a sex- and tissue-specific manner.

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Transcriptome landmarks of the functional maturity of rat beta-cells, from lactation to adulthood

Cited by 8 publications

References 33 publications

Calcium Channels in Postnatal Development of Rat Pancreatic Beta Cells and Their Role in Insulin Secretion

Calcium Channels in Postnatal Development of Rat Pancreatic Beta Cells and Their Role in Insulin Secretion

Chromatin accessibility variations across pancreatic islet maturation

Sexual dimorphism in the molecular mechanisms of insulin resistance during a critical developmental window in Wistar rats

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