Exploring pancreatic beta-cell subgroups and their connectivity

Nature Metabolism, Journal Year: 2024, Volume and Issue: 6(11), P. 2039 - 2053

Published: Aug. 8, 2024

Language: Английский

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Mitochondrial metabolism and dynamics in pancreatic beta cell glucose sensing

Biochemical Journal, Journal Year: 2023, Volume and Issue: 480(11), P. 773 - 789

Published: June 7, 2023

Glucose-regulated insulin secretion becomes defective in all forms of diabetes. The signaling mechanisms through which the sugar acts on ensemble beta cells within islet remain a vigorous area research after more than 60 years. Here, we focus firstly role that privileged oxidative metabolism glucose plays detection, discussing importance 'disallowing' cell expression genes including Lactate dehydrogenase (Ldha) and lactate transporter Mct1/Slc16a1 to restrict other metabolic fates for glucose. We next explore regulation mitochondrial by Ca2+ its possible sustaining towards secretion. Finally, discuss depth structure dynamics cell, their potential therapeutic targeting incretin hormones or direct regulators fusion. This review, 2023 Sir Philip Randle Lecture GAR will give at Islet Study Group meeting Vancouver, Canada June 2023, honor foundational, sometimes under-appreciated, contributions made Professor his colleagues our understanding

Language: Английский

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Intra-islet glucagon signalling regulates beta-cell connectivity, first-phase insulin secretion and glucose homoeostasis

Molecular Metabolism, Journal Year: 2024, Volume and Issue: 85, P. 101947 - 101947

Published: April 26, 2024

Type 2 diabetes (T2D) is characterised by the loss of first-phase insulin secretion. We studied mice with β-cell selective glucagon receptor (Gcgrfl/fl X Ins-1Cre), to investigate role intra-islet signalling on pan-islet calcium activity and Metabolic profiling was conducted Gcgrβ-cell−/− littermate controls. Crossing GCaMP6f (STOP flox) animals further allowed for specific expression a fluorescent indicator. These islets were functionally imaged in vitro vivo. Wild-type transplanted expressing β-cells into anterior eye chamber placed high fat diet. Part cohort received analogue (GCG-analogue) 40 days control group fed achieve weight matching. Calcium imaging performed regularly during development hyperglycaemia response GCG-analogue treatment. exhibited higher glucose levels following intraperitoneal challenge (control 12.7 mmol/L ± 0.6 vs. 15.4 0.0 at 15 min, p = 0.002); fasting glycaemia not different In vitro, showed profound [Ca2+]I waves which only partially rescued Diet induced obesity also resulted co-ordinated islets. This reversed treatment, independently weight-loss (n 8). data provide novel evidence GCGR sustaining synchronised support possible therapeutic glucagonergic agents restore secretory capacity lost T2D.

Language: Английский

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Network representation of multicellular activity in pancreatic islets: Technical considerations for functional connectivity analysis

PLoS Computational Biology, Journal Year: 2024, Volume and Issue: 20(5), P. e1012130 - e1012130

Published: May 13, 2024

Within the islets of Langerhans, beta cells orchestrate synchronized insulin secretion, a pivotal aspect metabolic homeostasis. Despite inherent heterogeneity and multimodal activity individual cells, intercellular coupling acts as homogenizing force, enabling coordinated responses through propagation waves. Disruptions in this coordination are implicated irregular hallmark diabetes. Recently, innovative approaches, such integrating multicellular calcium imaging with network analysis, have emerged for quantitative assessment cellular islets. However, different groups use distinct experimental preparations, microscopic techniques, apply methods to process measured signals various derive functional connectivity patterns. This makes comparisons between findings their integration into bigger picture difficult has led disputes interpretations. To address these issues, we present here systematic analysis how approaches influence representation islet activity. Our show that choice used construct networks is not crucial, although care needed when combining data from Conversely, conclusions drawn can be heavily affected by pre-processing time series, type oscillatory component signals, preparation. tutorial-like investigation aims resolve interpretational reconcile conflicting views, advance implications, encourage researchers adopt analysis. As conclude, outline challenges future research, emphasizing broader applicability our other tissues exhibiting complex dynamics.

Language: Английский

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Optogenetic β cell interrogation in vivo reveals a functional hierarchy directing the Ca ²⁺ response to glucose supported by vitamin B6

Science Advances, Journal Year: 2024, Volume and Issue: 10(26)

Published: June 26, 2024

Coordination of cellular activity through Ca

Language: Английский

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Beta-cell intrinsic dynamics rather than gap junction structure dictates subpopulations in the islet functional network

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Nov. 29, 2023

Diabetes is caused by the inability of electrically coupled, functionally heterogeneous β-cells within pancreatic islet to provide adequate insulin secretion. Functional networks have been used represent synchronized oscillatory [Ca2+] dynamics and study β-cell subpopulations, which play an important role in driving function. The mechanism highly subpopulations drive function unclear. We experimental computational techniques investigate relationship between functional networks, structural (gap junction) intrinsic slow fast oscillating islets. Highly network were differentiated dynamics, including metabolic activity KATP channel conductance, more than coupling. Consistent with this, predictive high synchronization as compared levels Finally, dysfunction gap junctions, can occur diabetes, decreases efficiency clustering network. These results indicate that rather structure connections but junctions are still essential for overall efficiency. findings deepen our interpretation formation dynamic tissues such islet.

Language: Английский

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Both electrical and metabolic coupling shape the collective multimodal activity and functional connectivity patterns in beta cell collectives: A computational model perspective

Physical review. E, Journal Year: 2023, Volume and Issue: 108(5)

Published: Nov. 22, 2023

Pancreatic beta cells are coupled excitable oscillators that synchronize their activity via different communication pathways. Their oscillatory manifests itself on multiple timescales and consists of bursting electrical activity, subsequent oscillations in the intracellular ${\mathrm{Ca}}^{2+}$, as well metabolism exocytosis. The coordination intricate multicellular level plays a key role regulation physiological pulsatile insulin secretion is incompletely understood. In this paper, we investigate theoretically principles give rise to synchronized cell populations by building up phenomenological model incorporates basic features dynamics. Specifically, composed slow fast units reflect metabolic processes respectively. Using realistic description intercellular interactions, study how combination coupling generates collective rhythmicity shapes functional networks. It turns out while solely can responses, addition interactions further enhances coordination, spatial range increases number connections networks, ensures better consistency with experimental findings. Moreover, our computational results provide additional insights into relationship between heterogeneity, profiles, connectivity, supplementing thereby recent endocrine

Language: Английский

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Exendin-4 affects calcium signalling predominantly during activation and activity of beta cell networks in acute mouse pancreas tissue slices

Frontiers in Endocrinology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 16, 2024

Tight control of beta cell stimulus-secretion coupling is crucial for maintaining homeostasis energy-rich nutrients. While glucose serves as a primary regulator this process, incretins augment function, partly by enhancing cytosolic [Ca 2+ ] dynamics. However, the details how precisely they affect recruitment during activation, their active time, and functional connectivity plateau activity, influence deactivation remain to be described. Performing multicellular Ca imaging in acute mouse pancreas tissue slices enabled us systematically assess effects GLP-1 receptor agonist exendin-4 (Ex-4) simultaneously many coupled cells with high resolution. In otherwise substimulatory glucose, Ex-4 was able recruit approximately quarter into an state. Costimulation stimulatory shortened activation delays accelerated More specifically, time increased faster, required reach half-maximal effectively halved presence Ex-4. Moreover, regularity IC oscillations increased, especially first part response. contrast, subsequent addition already did not significantly enhance activity. Network analyses further confirmed activity Ex-4, hub roles remaining rather stable both experiments Interestingly, demonstrated biphasic effect on deactivation, slightly prolonging at physiological concentrations shortening supraphysiological concentrations. sum, costimulation increases indicating that may, important extent, explained enhanced signals. During previous incretin stimulation does critically prolong cellular which corroborates low risk hypoglycemia.

Language: Английский

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Development, regeneration, and physiological expansion of functional β-cells: Cellular sources and regulators

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: July 9, 2024

Pancreatic regeneration is a complex process observed in both normal and pathological conditions. The aim of this review to provide comprehensive understanding the emergence functionally active population insulin-secreting β-cells adult pancreas. renewal governed by multifaceted interaction between cellular sources genetic epigenetic factors. Understanding development heterogeneity β-cell populations crucial for functional regeneration. mass pancreatic increases situations such as pregnancy obesity. However, specific markers mature postnatal progenitors capable increasing self-reproduction these conditions remain be elucidated. capacity regenerate through various pathways, including proliferation pre-existing β-cells, neogenesis, differentiation from progenitor cells, transdifferentiation non-β-cells into reveals molecular mechanisms identifying inducers cell renewal. This provides an opportunity identify regeneration, which could have clinical applications treating pathologies, vitro cell-based technologies, deepen our different physiological

Language: Английский

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Integrating single-cell transcriptomics with cellular phenotypes: cell morphology, Ca2+ imaging and electrophysiology

Biophysical Reviews, Journal Year: 2023, Volume and Issue: 16(1), P. 89 - 107

Published: Dec. 18, 2023

Abstract I review recent technological advancements in coupling single-cell transcriptomics with cellular phenotypes including morphology, calcium signaling, and electrophysiology. Single-cell RNA sequencing (scRNAseq) has revolutionized cell type classifications by capturing the transcriptional diversity of cells. A new wave methods to integrate scRNAseq biophysical measurements is facilitating linkage transcriptomic data function, which provides physiological insight into states. briefly discuss critical factors these phenotypical characterizations such as timescales, information content, analytical tools. Dedicated sections focus on integration imaging, electrophysiology (patch-seq), emphasizing their complementary roles. application elucidating states, refining classifications, uncovering functional differences subtypes. To illustrate practical applications benefits methods, highlight use tissues excitable cell-types brain, pancreatic islets, retina. The potential combining phenotyping spatial for a detailed mapping situ explored. Finally, open questions future perspectives, need shift towards broader accessibility through increased throughput.

Language: Английский

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