Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men

Rorsman, Patrik; Ashcroft, Frances M.

doi:10.1152/physrev.00008.2017

Cited by 611 publications

(629 citation statements)

References 781 publications

(1,398 reference statements)

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“…Loss of nuclear Pdx1 and reduced binding of MafA to cis -elements with the promoters of respective target genes may, in addition to impaired insulin signaling, explain the loss of glucose responsiveness indicated by βFLUOMETRI under glucotoxic/lipotoxic conditions (57). Moreover, we identified reduced expression of the soluble N -ethylmaleimide attachment receptor protein syntaxin-1A, a key protein in insulin exocytosis (58, 59), in islets from mice fed an HFHSD for 8 wk. This is in agreement with earlier observations showing that impaired insulin signaling in β cells results in reduced expression of syntaxin-1A (8, 60).…”

Section: Discussionmentioning

confidence: 99%

Diet‐induced β‐cell insulin resistance results in reversible loss of functional β‐cell mass

et al. 2018

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Although convincing in genetic models, the relevance of β-cell insulin resistance in diet-induced type 2 diabetes (T2DM) remains unclear. Exemplified by diabetes-prone, male, C57B1/6J mice being fed different combinations of Western-style diet, we show that β-cell insulin resistance occurs early during T2DM progression and is due to a combination of lipotoxicity and increased β-cell workload. Within 8 wk of being fed a high-fat, high-sucrose diet, mice became obese, developed impaired insulin and glucose tolerances, and displayed noncompensatory insulin release, due, at least in part, to reduced expression of syntaxin-1A. Through reporter islets transplanted to the anterior chamber of the eye, we demonstrated a concomitant loss of functional β-cell mass. When mice were changed from diabetogenic diet to normal chow diet, the diabetes phenotype was reversed, suggesting a remarkable plasticity of functional β-cell mass in the early phase of T2DM development. Our data reinforce the relevance of diet composition as an environmental factor determining different routes of diabetes progression in a given genetic background. Employing the in vivo reporter islet-monitoring approach will allow researchers to define key times in the dynamics of reversible loss of functional β-cell mass and, thus, to investigate the underlying, molecular mechanisms involved in the progression toward T2DM manifestation.-Paschen, M., Moede, T., Valladolid-Acebes, I., Leibiger, B., Moruzzi, N., Jacob, S., García-Prieto, C. F., Brismar, K., Leibiger, I. B., Berggren, P.-O. Diet-induced β-cell insulin resistance results in reversible loss of functional β-cell mass.

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Section: Discussionmentioning

confidence: 99%

Diet‐induced β‐cell insulin resistance results in reversible loss of functional β‐cell mass

et al. 2018

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“…1,2 These islet cells are responsible for secreting insulin in response to rising plasma glucose concentrations. Robust, islet-wide oscillations in intracellular Ca 2+ are required for glucose-stimulated insulin secretion.…”

Section: Introductionmentioning

confidence: 99%

Beta-cell hubs maintain Ca²⁺ oscillations in human and mouse islet simulations

Lei

Kellard

Hara

et al. 2018

Islets

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Islet β-cells are responsible for secreting all circulating insulin in response to rising plasma glucose concentrations. These cells are a phenotypically diverse population that express great functional heterogeneity. In mice, certain β-cells (termed ‘hubs’) have been shown to be crucial for dictating the islet response to high glucose, with inhibition of these hub cells abolishing the coordinated Ca2+ oscillations necessary for driving insulin secretion. These β-cell hubs were found to be highly metabolic and susceptible to pro-inflammatory and glucolipotoxic insults. In this study, we explored the importance of hub cells in human by constructing mathematical models of Ca2+ activity in human islets. Our simulations revealed that hubs dictate the coordinated Ca2+ response in both mouse and human islets; silencing a small proportion of hubs abolished whole-islet Ca2+ activity. We also observed that if hubs are assumed to be preferentially gap junction coupled, then the simulations better adhere to the available experimental data. Our simulations of 16 size-matched mouse and human islet architectures revealed that there are species differences in the role of hubs; Ca2+ activity in human islets was more vulnerable to hub inhibition than mouse islets. These simulation results not only substantiate the existence of β-cell hubs, but also suggest that hubs may be favorably coupled in the electrical and metabolic network of the islet, and that targeted destruction of these cells would greatly impair human islet function.

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“…Elevated blood‐glucose level triggers the release of insulin from the pancreatic β‐cells through regulation of components of the β‐cell stimulus‐secretion coupling leading to Ca 2+ ‐dependent exocytosis of insulin‐containing granules. Molecular T2D islet defects of proteins important in ion channel regulation, metabolism and exocytosis display this pathway to be essential in the development of impaired insulin secretion and hyperglycaemia . Since 2004, when overexpression of the first islet miRNA was performed, several miRNAs were shown to influence primarily glucose uptake and metabolism as well as the exocytotic process (Figure ).…”

Section: Role Of Mirnas In the Insulin Secretion Processmentioning

confidence: 99%

“…The glucose transporters, GLUT1 and GLUT2, are responsible for glucose uptake. Once inside, glucose is phosphorylated to glucose‐6‐phosphate by glucokinase (GCK) . This is the rate‐limiting step in insulin secretion and mutations in the GCK gene lead to impaired insulin secretion .…”

Section: Role Of Mirnas In the Insulin Secretion Processmentioning

confidence: 99%

“…ATP has several functions in the β‐cell including closure of the ATP‐dependent K + channels. This initiates depolarization of the plasma membrane leading to the opening of voltage‐dependent Ca 2+ channels and exocytosis of insulin granules . In addition, ATP promotes insulin granule priming prior to exocytosis and regulates insulin content through stimulation of the intragranule conversion of proinsulin to insulin…”

Section: Role Of Mirnas In the Insulin Secretion Processmentioning

confidence: 99%

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MicroRNAs in islet hormone secretion

Esguerra

Nagao

Ofori

et al. 2018

Diabetes Obesity Metabolism

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Pancreatic islet hormone secretion is central in the maintenance of blood glucose homeostasis. During development of hyperglycaemia, the β-cell is under pressure to release more insulin to compensate for increased insulin resistance. Failure of the β-cells to secrete enough insulin results in type 2 diabetes (T2D). MicroRNAs (miRNAs) are short non-coding RNA molecules suitable for rapid regulation of the changes in target gene expression needed in β-cell adaptations. Moreover, miRNAs are involved in the maintenance of α-cell and β-cell phenotypic identities via cell-specific, or cell-enriched expression. Although many of the abundant miRNAs are highly expressed in both cell types, recent research has focused on the role of miRNAs in β-cells. It has been shown that highly abundant miRNAs, such as miR-375, are involved in several cellular functions indispensable in maintaining β-cell phenotypic identity, almost acting as "housekeeping genes" in the context of hormone secretion. Despite the abundance and importance of miR-375, it has not been shown to be differentially expressed in T2D islets. On the contrary, the less abundant miRNAs such as miR-212/miR-132, miR-335, miR-130a/b and miR-152 are deregulated in T2D islets, wherein the latter three miRNAs were shown to play key roles in regulating β-cell metabolism. In this review, we focus on β-cell function and describe miRNAs involved in insulin biosynthesis and processing, glucose uptake and metabolism, electrical activity and Ca -influx and exocytosis of the insulin granules. We present current status on miRNA regulation in α-cells, and finally we discuss the involvement of miRNAs in β-cell dysfunction underlying T2D pathogenesis.

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Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men

Cited by 611 publications

References 781 publications

Diet‐induced β‐cell insulin resistance results in reversible loss of functional β‐cell mass

Diet‐induced β‐cell insulin resistance results in reversible loss of functional β‐cell mass

Beta-cell hubs maintain Ca²⁺ oscillations in human and mouse islet simulations

MicroRNAs in islet hormone secretion

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Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men

Cited by 611 publications

References 781 publications

Diet‐induced β‐cell insulin resistance results in reversible loss of functional β‐cell mass

Diet‐induced β‐cell insulin resistance results in reversible loss of functional β‐cell mass

Beta-cell hubs maintain Ca2+ oscillations in human and mouse islet simulations

MicroRNAs in islet hormone secretion

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Beta-cell hubs maintain Ca²⁺ oscillations in human and mouse islet simulations