β Cell mass expansion during puberty involves serotonin signaling and determines glucose homeostasis in adulthood

Castell, Anne-Laure; Goubault, Clara; Ethier, Mélanie; Fergusson, Grace; Tremblay, Caroline; Baltz, Marie; Soglio, Dorothée Dal; Ghislain, Julien; Poitout, Vincent

doi:10.1172/jci.insight.160854

Cited by 15 publications

(12 citation statements)

References 78 publications

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“…This may explain the inverse association between GHR and IGF-1 that we observed. Increased GHR signaling in pancreatic islets has been shown to regulate pubertal beta cell expansion in rats . However, little is known about the association of plasma GHR levels with systemic metabolism.…”

Section: Discussionsupporting

confidence: 62%

“…Increased GHR signaling in pancreatic islets has been shown to regulate pubertal beta cell expansion in rats. 35 However, little is known about the association of plasma GHR levels with systemic metabolism. Plasma GHR levels were recently reported to be associated with incident T2D in a large cohort study, 36 and reductions in GHR levels were identified as a causal mediator of improvements in glycemia after bariatric surgery in adults with T2D.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Growth Hormone Mediators and Glycemic Control in Youths With Type 2 Diabetes

Lu,

Wolfs,

El ghormli

et al. 2024

JAMA Netw Open

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ImportanceYouth-onset type 2 diabetes (T2D) has a more aggressive phenotype than adult-onset T2D, including rapid loss of glycemic control and increased complication risk.ObjectiveTo identify associations of growth hormone mediators with glycemic failure, beta cell function, and insulin sensitivity in youth-onset T2D.Design, Setting, and ParticipantsThis post hoc secondary analysis of the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) randomized clinical trial, which enrolled participants from July 2004 to February 2009, included 398 participants from 15 university-affiliated medical centers with available plasma samples from baseline and 36 months. Participants were youths aged 10 to 17 years with a duration of T2D of less than 2 years who were randomized to metformin, metformin plus lifestyle intervention, or metformin plus rosiglitazone. Participants were followed up for a mean (SD) of 3.9 (1.5) years during the trial, ending in 2011. Statistical analysis was performed from August 2022 to November 2023.ExposurePlasma insulin-like growth factor-1 (IGF-1), growth hormone receptor (GHR), and insulin-like growth factor binding protein 1 (IGFBP-1).Main Outcomes and MeasuresMain outcomes were (1) loss of glycemic control during the TODAY study, defined as hemoglobin A1c (HbA1c) level of 8% or more for 6 months or inability to wean from insulin therapy, and (2) baseline and 36-month measures of glycemia (fasting glucose, HbA1c), insulin sensitivity (1/fasting C-peptide), high-molecular-weight adiponectin, and beta cell function (C-peptide index, C-peptide oral disposition index).ResultsThis analysis included 398 participants (mean [SD] age, 13.9 [2.0] years; 248 girls [62%]; 166 Hispanic participants [42%]; 134 non-Hispanic Black participants [34%], and 84 non-Hispanic White participants [21%]). A greater increase in IGF-1 level between baseline and 36 months was associated with lower odds of glycemic failure (odds ratio [OR], 0.995 [95% CI, 0.991-0.997]; P &lt; .001) and higher C-peptide index per 100-ng/mL increase in IGF-1 (β [SE], 0.015 [0.003]; P &lt; .001). A greater increase in log2 GHR level between baseline and 36 months was associated with higher odds of glycemic failure (OR, 1.75 [95% CI, 1.05-2.99]; P = .04) and lower C-peptide index (β [SE], −0.02 [0.006]; P &lt; .001). A greater increase in log2 IGFBP-1 level between baseline and 36 months was associated with higher odds of glycemic failure (OR, 1.37 [95% CI, 1.09-1.74]; P = .007) and higher high-molecular-weight adiponectin (β [SE], 431 [156]; P = .007).Conclusions and RelevanceThis study suggests that changes in plasma growth hormone mediators are associated with loss of glycemic control in youth-onset T2D, with IGF-1 associated with lower risk and GHR and IGFBP-1 associated with increased risk.Trial RegistrationClinicalTrials.gov Identifier: NCT00081328

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Growth Hormone Mediators and Glycemic Control in Youths With Type 2 Diabetes

Lu,

Wolfs,

El ghormli

et al. 2024

JAMA Netw Open

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“…We show that CDX2 drives the expression of serotonin synthesis genes in these pre-β-cells. Serotonin production is a feature of neonatal and adolescent β-cells (Castell et al, 2022; Moon et al, 2020b), and adult β-cells can activate serotonin synthesis during pregnancy (Baeyens et al, 2016; Kim et al, 2010; Moon et al, 2020a; Ohara-Imaizumi et al, 2013). Based on this evidence, we posit that SC-ECs are not an erroneous intestinal cell type of SC-islet in vitro differentiation but rather represent a cell type characteristic of normal human β-cell development.…”

Section: Resultsmentioning

confidence: 99%

Improving stem cell-derived pancreatic islets using single-cell multiome-inferred regulomes

Zhu

Wang

Nguyen-Ngoc

et al. 2022

Preprint

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Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem cell-derived and primary islets remain, but molecular insights to inform improvements are limited. Here, we acquire single-cell transcriptomes and accessible chromatin profiles during in vitro islet differentiation and pancreas from childhood and adult donors for comparison. We delineate major cell types, define their regulomes, and describe spatiotemporal gene regulatory relationships between transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a transient, previously unrecognized, CDX2+ pre-β-cell population in fetal pancreas, arguing against a proposed non-pancreatic origin. Furthermore, we observe insufficient activation of signal-dependent transcriptional programs during in vitro β-cell maturation and identify sex hormones as drivers of β-cell proliferation in childhood. Altogether, our analysis provides a comprehensive understanding of cell fate acquisition in stem cell-derived islets and a framework for manipulating cell identities and maturity.

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“…Pancreatic β-cells adhere to this pattern, featuring a complex system for controlling cell mass ( Bouwens and Rooman, 2005 ). Consequently, this endocrine organ is distinguished by the determination of developmental trajectories, influencing various aspects of feeding behavior and adaptive physiological traits in adult life ( Kim et al, 2010 ; Castell et al, 2022 ). Our discovery reveals that in sea urchins, the post-oral neurons is a part of a complex neuroendocrine regulator, resembling its operation in vertebrates.…”

Section: Discussionmentioning

confidence: 99%

“…However, the regulation of cell mass in pancreatic β-cells is still intertwined with these ancient monoaminergic regulatory systems. β-cells express 5-HT receptors, and 5-HT increases their proliferation in pubertal islets ( Castell et al, 2022 ). DA synthesis is absent in β-cells in vertebrates.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous intersibling polymorphism in the development of dopaminergic neuroendocrine cells in sea urchin larvae: impacts on the expansion of marine benthic species

Obukhova,

Khabarova,

Semenova

et al. 2024

Front. Neurosci.

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IntroductionThe plasticity of the nervous system plays a crucial role in shaping adaptive neural circuits and corresponding animal behaviors. Understanding the mechanisms underlying neural plasticity during development and its implications for animal adaptation constitutes an intriguing area of research. Sea urchin larvae offer a fascinating subject for investigation due to their remarkable evolutionary and ecological diversity, as well as their diverse developmental forms and behavioral patterns.Materials and methodsWe conducted immunochemical and histochemical analyses of serotonin-containing (5-HT-neurons) and dopamine-containing (DA-positive) neurons to study their developmental dynamics in two sea urchin species: Mesocentrotus nudus and Paracentrotus lividus. Our approach involved detailed visualization of 5-HT- and DA-positive neurons at gastrula-pluteus stages, coupled with behavioral assays to assess larval upward and downward swimming in the water column, with a focus on correlating cell numbers with larval swimming ability.ResultsThe study reveals a heterochronic polymorphism in the appearance of post-oral DA-positive neuroendocrine cells and confirms the stable differentiation pattern of apical 5-HT neurons in larvae of both species. Notably, larvae of the same age exhibit a two- to four-fold difference in DA neurons. An increased number of DA neurons and application of dopamine positively correlate with larval downward swimming, whereas 5-HT-neurons and serotonin application induce upward swimming. The ratio of 5-HT/DA neurons determines the stage-dependent vertical distribution of larvae within the water column. Consequently, larvae from the same generation with a higher number of DA-positive neurons tend to remain at the bottom compared to those with fewer DA-positive neurons.DiscussionThe proportion of 5-HT and DA neurons within larvae of the same age underlies the different potentials of individuals for upward and downward swimming. A proposed model illustrates how coordination in humoral regulation, based on heterochrony in DA-positive neuroendocrine cell differentiation, influences larval behavior, mitigates competition between siblings, and ensures optimal population expansion. The study explores the evolutionary and ecological implications of these neuroendocrine adaptations in marine species.

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β Cell mass expansion during puberty involves serotonin signaling and determines glucose homeostasis in adulthood

Cited by 15 publications

References 78 publications

Growth Hormone Mediators and Glycemic Control in Youths With Type 2 Diabetes

Growth Hormone Mediators and Glycemic Control in Youths With Type 2 Diabetes

Improving stem cell-derived pancreatic islets using single-cell multiome-inferred regulomes

Spontaneous intersibling polymorphism in the development of dopaminergic neuroendocrine cells in sea urchin larvae: impacts on the expansion of marine benthic species

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