β‐Cells are not uniform after all—Novel insights into molecular heterogeneity of insulin‐secreting cells

Avrahami, Dana; Wang, Yue J.; Klochendler, Agnes; Dor, Yuval; Gläser, Benjamin; Kaestner, Klaus H.

doi:10.1111/dom.13019

Cited by 26 publications

(23 citation statements)

References 42 publications

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“…Accumulating evidence on distinct functional sub‐populations of β‐cells prompted the search for molecular insights of such diversity using single‐cell large‐scale transcriptome analyses, allowing for the identification and characterization of new sub‐populations among human and mouse islet cells. Interestingly, a sub‐population of proliferating β‐cells was discovered in adult mice based on their transcriptome signature .…”

Section: Zooming Into the Pancreatic Islet Clock: Molecular Oscillatomentioning

confidence: 99%

“…Interestingly, a sub-population of proliferating β-cells was discovered in adult mice based on their transcriptome signature. 101,103,104 This sub-population seems to be the source of newly generated β-cells in the model of β-cell regeneration after partial ablation. 105 Interestingly, while most single-cell studies in human islets failed to detect proliferating β-cell sub-populations, a sub-population of proliferating α-cells was recently described.…”

Section: Islet Cell Heterogeneity: Do Molecular Clock Properties DImentioning

confidence: 99%

“…106 Although most islet cells possess a narrow functional specialization in the adult organism, single-cell RNA sequencing analyses identified the presence of infrequent bi-or multi-hormonal cells that were often excluded from the final analysis. 106,109 At the same time, the presence of bi-hormonal cells is common in foetal islets and upon T2D development, likely representing an inter-lineage plasticity during cellular development, or dedifferentiation resulting from β-cell failure (reviewed in 101,102 ). Indeed, following a nearly total β-cell ablation in mice, αand δ-cells were reported to acquire β-cell identity.…”

Section: Islet Cell Heterogeneity: Do Molecular Clock Properties DImentioning

confidence: 99%

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Time zones of pancreatic islet metabolism

Petrenko

Philippe

Dibner

2018

Diabetes Obesity Metabolism

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Most living beings possess an intrinsic system of circadian oscillators, allowing anticipation of the Earth's rotation around its own axis. The mammalian circadian timing system orchestrates nearly all aspects of physiology and behaviour. Together with systemic signals originating from the central clock that resides in the hypothalamic suprachiasmatic nucleus, peripheral oscillators orchestrate tissue-specific fluctuations in gene transcription and translation, and posttranslational modifications, driving overt rhythms in physiology and behaviour. There is accumulating evidence of a reciprocal connection between the circadian oscillator and most aspects of physiology and metabolism, in particular as the circadian system plays a critical role in orchestrating body glucose homeostasis. Recent reports imply that circadian clocks operative in the endocrine pancreas regulate insulin secretion, and that islet clock perturbation in rodents leads to the development of overt type 2 diabetes. While whole islet clocks have been extensively studied during the last years, the heterogeneity of islet cell oscillators and the interplay between α- and β-cellular clocks for orchestrating glucagon and insulin secretion have only recently gained attention. Here, we review recent findings on the molecular makeup of the circadian clocks operative in pancreatic islet cells in rodents and in humans, and focus on the physiologically relevant synchronizers that are resetting these time-keepers. Moreover, the implication of islet clock functional outputs in the temporal coordination of metabolism in health and disease will be highlighted.

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Section: Zooming Into the Pancreatic Islet Clock: Molecular Oscillatomentioning

confidence: 99%

Section: Islet Cell Heterogeneity: Do Molecular Clock Properties DImentioning

confidence: 99%

Section: Islet Cell Heterogeneity: Do Molecular Clock Properties DImentioning

confidence: 99%

See 1 more Smart Citation

Time zones of pancreatic islet metabolism

Petrenko

Philippe

Dibner

2018

Diabetes Obesity Metabolism

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“…Single-cell RNA-seq is no exception, and over the past 3 years over a dozen publication have reported results from its application to pancreatic islet (Baron et al, 2016;Enge et al, 2017;Lawlor et al, 2017;Li et al, 2016;Muraro et al, 2016;Qiu et al, 2018;Segerstolpe et al, 2016;Wang et al, 2016b;Xin et al, 2016aXin et al, , 2016bXin et al, , 2016cXin et al, , 2018Zeng et al, 2017). There are several recent reviews that collate the individual findings (Avrahami et al, 2017;Carrano et al, 2017). Here, we will attempt to summarize the development of single-cell RNA methodologies, give an overview of the discoveries made in the islet biology field using these approaches, and discuss their limitations and potentials for future improvements.…”

Section: Introductionmentioning

confidence: 99%

Single-Cell RNA-Seq of the Pancreatic Islets––a Promise Not yet Fulfilled?

2019

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In the past 3 years, we have seen a flurry of publications on single-cell RNA sequencing (RNA-seq) analyses of pancreatic islets from mouse and human. This technology holds the promise to refine cell-type signatures and discover cellular heterogeneity among the canonical endocrine cell types such as the glucagon-producing a and insulin-producing b cells, going as far as suggesting new subtypes. In addition, single-cell RNA-seq has the ability to characterize rare endocrine cell types that are not captured by prior bulk analysis. With transcriptomics data from individual endocrine cells, cellular states can be profiled both along developmental processes and during the emergence of metabolic diseases. However, the promises of this new technology have not yet been met in full. While the methodology for the first time enabled the transcriptional definition of rare endocrine cell types such as ghrelin-producing 3 cells, some of the conclusions regarding cell-type-specific gene expression changes in type 2 diabetes might need to be revisited once larger sample sizes become available. Data generation and analysis are continuously improving single-cell RNA-seq approaches and are helping us to understand the (mal)adaptations of the islet cells during development, metabolic challenge, and disease. ''Dropouts,'' i.e., cells with zero reads for the genes in question, are indicated in dark blue. Note that even key marker genes such as PCSK1 and MAFB, which are likely expressed in all human b cells, are not detected in a significant fraction of the cells analyzed, illustrating the limitations of the current technology.

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“…28,29 A child unable to achieve this growth in β-cell mass would develop a relative deficiency of insulin if this was not compensated for by increased insulin secretion from the already present β cells; however, hyperactive β cells enhance expression of islet autoantigens 30 as well as post-transcriptional modifications of various proteins. [31][32][33][34][35][36][37] Increased β-cell stress also induces enhanced mitochondrial activity and endoplasmic reticulum stress responses that can eventually lead to β-cell death. 38,39 Enhanced expression of islet antigens and altered post-transcriptional modifications probably favour the formation of autoantibodies and autoreactive T cells that then can be regarded as circulating markers of ongoing β-cell stress, rather than part of an established β-cell cytotoxic immune response.…”

Section: Insulin Requirements During Childhood and Adolescencementioning

confidence: 99%

Aetiology of type 1 diabetes: Physiological growth in children affects disease progression

Skog

Korsgren

2017

Diabetes Obesity Metabolism

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The prevailing view is that type 1 diabetes (T1D) develops as a consequence of a severe decline in β-cell mass resulting from T-cell-mediated autoimmunity; however, progression from islet autoantibody seroconversion to overt diabetes and finally to total loss of C-peptide production occurs in most affected individuals only slowly over many years or even decades. This slow disease progression should be viewed in relation to the total β-cell mass of only 0.2 to 1.5 g in adults without diabetes. Focal lesions of acute pancreatitis with accumulation of leukocytes, often located around the ducts, are frequently observed in people with recent-onset T1D, and most patients display extensive periductal fibrosis, the end stage of inflammation. An injurious inflammatory adverse event, occurring within the periductal area, may have negative implications for islet neogenesis, dependent on stem cells residing within or adjacent to the ductal epithelium. This could in part prevent the 30-fold increase in β-cell mass that would normally occur during the first 20 years of life. This increase occurs in order to maintain glucose metabolism during the physiological increases in insulin production that are required to balance the 20-fold increase in body weight during childhood and increased insulin resistance during puberty. Failure to expand β-cell mass during childhood would lead to clinically overt T1D and could help to explain the apparently more aggressive form of T1D occurring in growing children when compared with that observed in affected adults.

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β‐Cells are not uniform after all—Novel insights into molecular heterogeneity of insulin‐secreting cells

Cited by 26 publications

References 42 publications

Time zones of pancreatic islet metabolism

Time zones of pancreatic islet metabolism

Single-Cell RNA-Seq of the Pancreatic Islets––a Promise Not yet Fulfilled?

Aetiology of type 1 diabetes: Physiological growth in children affects disease progression

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