Islet Function and Insulin Secretion

Jones, Peter M.; Persaud, Shanta J.

doi:10.1002/9781118924853.ch6

Cited by 9 publications

(11 citation statements)

References 148 publications

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“…Our observations that MSCs derived from four different tissues had similar qualitative effects to enhance insulin glucose‐induced secretion without affecting basal secretion suggest that this is a general property of MSCs. Our measurements showed that the MSC‐dependent enhancement of insulin secretion was not secondary to increased insulin content, confirming previous observations in mouse and human islets, consistent with an upregulation of the β‐cell secretory response to elevated glucose, the most physiologically important initiator of insulin secretion in mammals . Importantly, our experiments using human islets confirm and extend previous studies to demonstrate that human MSCs from a variety of tissues have the ability to enhance human β‐cell function.…”

Section: Discussionsupporting

confidence: 90%

“…Glucose‐induced insulin secretion shows a distinctive temporal pattern, with a rapidly rising initial peak (first phase), followed by a maintained plateau (second phase), with both phases being regulated by different β‐cell intracellular mechanisms . Dynamic measurements of insulin secretion from mouse islets demonstrated that preculture with maMSCs enhanced both phases of the secretory response to glucose (20 mM), as shown in Figure A.…”

Section: Resultsmentioning

confidence: 94%

“…We demonstrate here that MSC pretreatment also enhances insulin secretion in response to non‐nutrient and receptor‐mediated agonists. The mechanisms of glucose recognition by β‐cells are well understood: glucose and other nutrients initiate insulin secretion by increasing metabolic fluxes and ATP generation, leading to β‐cell depolarization and Ca 2+ influx through voltage‐dependent Ca2+ channels, which triggers the exocytotic release of insulin . In contrast, carbachol and other receptor‐mediated agonists do not initiate insulin secretion but potentiate responses to nutrients via well‐characterized intracellular pathways , whereas the cationic amino acid arginine is thought to stimulate insulin secretion primarily by inducing depolarization upon its transport into the β cell .…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms of glucose recognition by β‐cells are well understood: glucose and other nutrients initiate insulin secretion by increasing metabolic fluxes and ATP generation, leading to β‐cell depolarization and Ca 2+ influx through voltage‐dependent Ca2+ channels, which triggers the exocytotic release of insulin . In contrast, carbachol and other receptor‐mediated agonists do not initiate insulin secretion but potentiate responses to nutrients via well‐characterized intracellular pathways , whereas the cationic amino acid arginine is thought to stimulate insulin secretion primarily by inducing depolarization upon its transport into the β cell . Our observation that MSC coculture enhanced β‐cell responses to all these stimuli suggests an overall upregulation of the exocytotic process rather than specific effects on signal recognition and intracellular transduction cascades.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of the Effects of Mesenchymal Stromal Cells on Mouse and Human Islet Function

Arzouni

Vargas-Seymour

Dhadda

et al. 2019

Stem Cells Translational Medicine

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Islet transplantation has the potential to cure type 1 diabetes, but current transplantation protocols are not optimal and there is extensive loss of islet β‐cell insulin secretory function during the immediate post‐transplantation period. Studies using experimental models of diabetes have shown that the coculture of islets with mesenchymal stromal cells (MSCs) prior to transplantation improves graft function, but several variables differed among research groups (e.g., type of MSCs used and the treatment conditions). We have therefore assessed the effects of MSCs on mouse and human islets by investigating the importance of tissue source for MSCs, the coculture protocol configuration and length, the effect of activated MSCs, and different β‐cell secretory stimuli. MSCs derived from adipose tissue (aMSCs) were the most effective at supporting β‐cell insulin secretion in both mouse and human islets, in a direct contact coculture configuration. Preculture with aMSCs enhanced both phases of glucose‐induced insulin secretion and further enhanced secretory responses to the non‐nutrients carbachol and arginine. These effects required a coculture period of 48–72 hours and were not dependent on activation of the MSCs. Thus, direct contact coculture with autologous, adipose‐derived MSCs for a minimum of 48 hours before implantation is likely to be an effective addition to human islet transplantation protocols. stem cells translational medicine 2019;8:935&944

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Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Characterization of the Effects of Mesenchymal Stromal Cells on Mouse and Human Islet Function

Arzouni

Vargas-Seymour

Dhadda

et al. 2019

Stem Cells Translational Medicine

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“…Many proteins and peptides that act as ligands of islet GPCRs are expressed by the islet cells themselves [ 1 ], while others are secreted from non-islet cell types and transported to the islet microenvironment by the systemic circulation. Examples of locally produced peptide ligands of islet GPCRs include glucagon and somatostatin, which act in a paracrine function to regulate secretion of islet hormones from neighbouring cells [ 2 ]. In addition, collagen III and IV, which are components of the extracellular matrix that supports islet cells, interact with the islet-expressed GPCRs, GPR56 and GPR126 [ 3 – 5 ].…”

Section: Introductionmentioning

confidence: 99%

Defining G protein-coupled receptor peptide ligand expressomes and signalomes in human and mouse islets

Atanes

Ruz‐Maldonado

Hawkes

et al. 2018

Cell. Mol. Life Sci.

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IntroductionIslets synthesise and secrete numerous peptides, some of which are known to be important regulators of islet function and glucose homeostasis. In this study, we quantified mRNAs encoding all peptide ligands of islet G protein-coupled receptors (GPCRs) in isolated human and mouse islets and carried out in vitro islet hormone secretion studies to provide functional confirmation for the species-specific role of peptide YY (PYY) in mouse islets.Materials and methodsGPCR peptide ligand mRNAs in human and mouse islets were quantified by quantitative real-time PCR relative to the reference genes ACTB, GAPDH, PPIA, TBP and TFRC. The pathways connecting GPCR peptide ligands with their receptors were identified by manual searches in the PubMed, IUPHAR and Ingenuity databases. Distribution of PYY protein in mouse and human islets was determined by immunohistochemistry. Insulin, glucagon and somatostatin secretion from islets was measured by radioimmunoassay.ResultsWe have quantified GPCR peptide ligand mRNA expression in human and mouse islets and created specific signalomes mapping the pathways by which islet peptide ligands regulate human and mouse GPCR signalling. We also identified species-specific islet expression of several GPCR ligands. In particular, PYY mRNA levels were ~ 40,000-fold higher in mouse than human islets, suggesting a more important role of locally secreted Pyy in mouse islets. This was confirmed by IHC and functional experiments measuring insulin, glucagon and somatostatin secretion.DiscussionThe detailed human and mouse islet GPCR peptide ligand atlases will allow accurate translation of mouse islet functional studies for the identification of GPCR/peptide signalling pathways relevant for human physiology, which may lead to novel treatment modalities of diabetes and metabolic disease.Electronic supplementary materialThe online version of this article (10.1007/s00018-018-2778-z) contains supplementary material, which is available to authorized users.

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Optimizing beta cell function through mesenchymal stromal cell-mediated mitochondria transfer

et al. 2020

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Pretransplant islet culture is associated with the loss of islet cell mass and insulin secretory function. Insulin secretion from islet β‐cells is primarily controlled by mitochondrial ATP generation in response to elevations in extracellular glucose. Coculture of islets with mesenchymal stromal cells (MSCs) improves islet insulin secretory function in vitro, which correlates with superior islet graft function in vivo. This study aimed to determine whether the improved islet function is associated with mitochondrial transfer from MSCs to cocultured islets. We have demonstrated mitochondrial transfer from human adipose MSCs to human islet β‐cells in coculture. Fluorescence imaging showed that mitochondrial transfer occurs, at least partially, through tunneling nanotube (TNT)‐like structures. The extent of mitochondrial transfer to clinically relevant human islets was greater than that to experimental mouse islets. Human islets are subjected to more extreme cellular stressors than mouse islets, which may induce “danger signals” for MSCs, initiating the donation of MSC‐derived mitochondria to human islet β‐cells. Our observations of increased MSC‐mediated mitochondria transfer to hypoxia‐exposed mouse islets are consistent with this and suggest that MSCs are most effective in supporting the secretory function of compromised β‐cells. Ensuring optimal MSC‐derived mitochondria transfer in preculture and/or cotransplantation strategies could be used to maximize the therapeutic efficacy of MSCs, thus enabling the more widespread application of clinical islet transplantation.

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Islet Function and Insulin Secretion

Cited by 9 publications

References 148 publications

Characterization of the Effects of Mesenchymal Stromal Cells on Mouse and Human Islet Function

Characterization of the Effects of Mesenchymal Stromal Cells on Mouse and Human Islet Function

Defining G protein-coupled receptor peptide ligand expressomes and signalomes in human and mouse islets

Optimizing beta cell function through mesenchymal stromal cell-mediated mitochondria transfer

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