The physiological role of β-cell heterogeneity in pancreatic islet function

It is becoming increasingly apparent that not all insulin-secreting beta cells are equal. Subtle differences exist at the transcriptomic and protein expression levels, with repercussions for beta cell survival/proliferation, calcium signalling and insulin release. Notably, beta cell heterogeneity displays plasticity during development, metabolic stress and type 2 diabetes mellitus (T2DM). Thus, heterogeneity or lack thereof may be an important contributor to beta cell failure during T2DM in both rodents and humans. The present review will discuss the molecular and cellular features of beta cell heterogeneity at both the single-cell and islet level, explore how this influences islet function and insulin release and look into the alterations that may occur during obesity and T2DM.

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New insights into the role of connexins in pancreatic islet function and diabetes

FEBS Letters ◽

10.1016/j.febslet.2014.02.035 ◽

2014 ◽

Vol 588 (8) ◽

pp. 1278-1287 ◽

Cited By ~ 38

Author(s):

Nikki L. Farnsworth ◽

Richard K.P. Benninger

Keyword(s):

Pancreatic Islet ◽

Islet Function

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Chromomycin A2 potently inhibits glucose-stimulated insulin secretion from pancreatic β cells

10.1101/337113 ◽

2018 ◽

Author(s):

Michael A Kalwat ◽

In Hyun Hwang ◽

Jocelyn Macho ◽

Magdalena G Grzemska ◽

Jonathan Z Yang ◽

...

Keyword(s):

Insulin Secretion ◽

Natural Product ◽

Pancreatic Islet ◽

Islet Function ◽

Gene Promoters ◽

Β Cells ◽

Β Cell ◽

Regulatory Pathways ◽

Glucose Stimulated Insulin Secretion ◽

Cell Gene

ABSTRACTEnhancers or inhibitors of insulin secretion could become therapeutics as well as lead to the identification of requisite β-cell regulatory pathways and increase our understanding of pancreatic islet function. Toward this goal, we previously used an insulin-linked luciferase that is co-secreted with insulin in MIN6 β-cells to perform a high-throughput natural product screen for chronic effects on glucose-stimulated insulin secretion. Using multiple phenotypic analyses, we identified that one of the top natural product hits, chromomycin A2 (CMA2), potently inhibited insulin secretion through at least three mechanisms: disruption of Wnt signaling, interfering with β-cell gene expression, and suppression of triggering calcium (Ca2+) influx. Chronic treatment with CMA2 largely ablated glucose-stimulated insulin secretion even post-washout, but did not inhibit glucose-stimulated generation of ATP or Ca2+ influx. However, by using the KATP channel-opener diazoxide, we uncovered defects in depolarization-induced Ca2+ influx which may contribute to the suppressed secretory response. Glucose-responsive ERK1/2 and S6 phosphorylation were also disrupted by chronic CMA2 treatment. The FUSION bioinformatic database indicated that the phenotypic effects of CMA2 clustered with a number of Wnt/GSK3 pathway-related genes. Consistently, CMA2 decreased GSK3 phosphorylation and suppressed activation of a β-catenin activity reporter. CMA2 and a related compound mithramycin are described to have DNA-interaction properties, possibly abrogating transcription factor binding to critical β-cell gene promoters. We observed that CMA2, but not mithramycin, suppressed expression of PDX1 and UCN3. However, neither expression of INSI/II nor insulin content was affected by chronic CMA2. The mechanisms of CMA2-induced insulin secretion defects may involve components both proximal and distal to Ca2+ influx. Therefore, CMA2 is an example of a chemical that can simultaneously disrupt β-cell function through both non-cytotoxic and cytotoxic mechanisms. Future applications of CMA2 and similar aureolic acid analogs for disease therapies should consider the potential impacts on pancreatic islet function.

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Functional architecture of the pancreatic islets: First responder cells drive the first-phase [Ca2+] response

10.1101/2020.12.22.424082 ◽

2020 ◽

Author(s):

Vira Kravets ◽

JaeAnn M. Dwulet ◽

Wolfgang E. Schleicher ◽

David J. Hodson ◽

Anna M. Davis ◽

...

Keyword(s):

Response Time ◽

Phase Response ◽

Cell Subpopulation ◽

Islet Function ◽

Β Cells ◽

Β Cell ◽

First Responder ◽

Intact Mouse ◽

Responder Cell

AbstractInsulin-secreting β-cells are functionally heterogeneous. Subpopulations of β-cells can control islet function and the regulation of hormone release, such as driving the second (oscillatory) phase of free-calcium ([Ca2+]) following glucose elevation. Whether there exists a subpopulation that drives the first-phase response, critical for effective insulin secretion and disrupted early in diabetes, has not been examined. Here, we examine a ‘first responder’ cell population, defined by the earliest [Ca2+] response during first-phase [Ca2+] elevation. We record [Ca2+] dynamics in intact mouse islets, via β-cell specific expression of the [Ca2+] indicator GCamP6s. We identify multiple β-cell subpopulations based on signatures of their [Ca2+] dynamics and investigate the role of ‘first responder’ cells in islet function by means of 2-photon laser ablation. We further characterize the functional properties of ‘first responder’ cells by NAD(P)H autofluorescence, fluorescent recovery after photobleaching, glibenclamide stimulation, and network analysis. We also investigate which functional characteristics of these cells are critical by a computational model of islet electrophysiology. Based on the dynamics of [Ca2+] responses, first responder cells are distinct from previously identified functional subpopulations. The first-phase response time of β-cells is spatially organized, dependent on the cell’s distance to the first responder cells, and consistent over time up to ~24 h. First responder cells showed characteristics of high membrane excitability and slightly lower than average coupling to their neighbors. When first responder cells were ablated, the first-phase [Ca2+] diminished, compared to ablating a random cell. We also observed a hierarchy of the first-phase response time, where cells that were next earliest to respond often take over the role of the first responder cell upon ablation. In summary, we discover and characterize a distinct first responder β-cell subpopulation, based on [Ca2+] response timing, which is critical for the islet first-phase response to glucose.

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Nuclear Factor Y in Male Mouse pancreatic β-cells Plays a Crucial Role in Glucose Homeostasis by Regulating β-Cell Mass and Insulin Secretion

10.2337/figshare.14547255 ◽

2021 ◽

Author(s):

Yin Liu ◽

Siyuan He ◽

Ruixue Zhou ◽

Xueping Zhang ◽

Shanshan Yang ◽

...

Keyword(s):

Cell Proliferation ◽

Insulin Secretion ◽

Cell Mass ◽

Physiological Role ◽

Nuclear Factor ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Nuclear Factor Y

Pancreatic β-cell mass and insulin secretion are determined by the dynamic change of transcription factor expression levels in response to altered metabolic demand. Nuclear factor-Y (NF-Y) is an evolutionarily conserved transcription factor playing critical roles in multiple cellular processes. However, the physiological role of NF-Y in pancreatic β-cells is poorly understood. The present study was undertaken in a conditional knockout of Nf-ya specifically in pancreatic β-cells (Nf-ya βKO) to define the essential physiological role of NF-Y in β-cells. Nf-ya βKO mice exhibited glucose intolerance without changes in insulin sensitivity. Reduced β-cell proliferation resulting in decreased β-cell mass was observed in these mice, which was associated with disturbed actin cytoskeleton. NF-Y-deficient β-cells also exhibited impaired insulin secretion with a reduced Ca2+ influx in response to glucose, which was associated an inefficient glucose uptake into β-cells due to a decreased expression of glucose transporter 2 and a reduction in ATP production resulting from the disruption of mitochondrial integrity. This study is the first to show that NF-Y is critical for pancreatic islets homeostasis and function through regulation in β-cell proliferation, glucose uptake into β-cells, and mitochondrial energy metabolism. Modulating NF-Y expression in β-cells may therefore offer an attractive approach for therapeutic intervention.

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Lysosomes and pancreatic islet function: Adaptation of β-cell lysosomes to various metabolic demands

Metabolism ◽

10.1016/0026-0495(91)90151-l ◽

1991 ◽

Vol 40 (4) ◽

pp. 399-405 ◽

Cited By ~ 17

Author(s):

A.H. Schnell Landström ◽

A. Andersson ◽

L.A.H. Borg

Keyword(s):

Pancreatic Islet ◽

Islet Function ◽

Β Cell

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Chromomycin A2 potently inhibits glucose-stimulated insulin secretion from pancreatic β cells

The Journal of General Physiology ◽

10.1085/jgp.201812177 ◽

2018 ◽

Vol 150 (12) ◽

pp. 1747-1757 ◽

Cited By ~ 1

Author(s):

Michael A. Kalwat ◽

In Hyun Hwang ◽

Jocelyn Macho ◽

Magdalena G. Grzemska ◽

Jonathan Z. Yang ◽

...

Keyword(s):

Insulin Secretion ◽

Pancreatic Islet ◽

Cell Function ◽

Islet Function ◽

Gene Promoters ◽

Β Cells ◽

Β Cell ◽

Regulatory Pathways ◽

Glucose Stimulated Insulin Secretion ◽

Cell Gene

Modulators of insulin secretion could be used to treat diabetes and as tools to investigate β cell regulatory pathways in order to increase our understanding of pancreatic islet function. Toward this goal, we previously used an insulin-linked luciferase that is cosecreted with insulin in MIN6 β cells to perform a high-throughput screen of natural products for chronic effects on glucose-stimulated insulin secretion. In this study, using multiple phenotypic analyses, we found that one of the top natural product hits, chromomycin A2 (CMA2), potently inhibited insulin secretion by at least three potential mechanisms: disruption of Wnt signaling, interference of β cell gene expression, and partial suppression of Ca2+ influx. Chronic treatment with CMA2 largely ablated glucose-stimulated insulin secretion even after washout, but it did not inhibit glucose-stimulated generation of ATP or Ca2+ influx. However, by using the KATP channel opener diazoxide, we uncovered defects in depolarization-induced Ca2+ influx that may contribute to the suppressed secretory response. Glucose-responsive ERK1/2 and S6 phosphorylation were also disrupted by chronic CMA2 treatment. By querying the FUSION bioinformatic database, we revealed that the phenotypic effects of CMA2 cluster with a number of Wnt–GSK3 pathway-related genes. Furthermore, CMA2 consistently decreased GSK3β phosphorylation and suppressed activation of a β-catenin activity reporter. CMA2 and a related compound, mithramycin, are known to have DNA interaction properties, possibly abrogating transcription factor binding to critical β cell gene promoters. We observed that CMA2 but not mithramycin suppressed expression of PDX1 and UCN3. However, neither expression of INSI/II nor insulin content was affected by chronic CMA2. The mechanisms of CMA2-induced insulin secretion defects may involve components both proximal and distal to Ca2+ influx. Therefore, CMA2 is an example of a chemical that can simultaneously disrupt β cell function through both noncytotoxic and cytotoxic mechanisms. Future therapeutic applications of CMA2 and similar aureolic acid analogues should consider their potential effects on pancreatic islet function.

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Role of nucleolar protein NOM1 in pancreatic islet β cell apoptosis in diabetes

Experimental and Therapeutic Medicine ◽

10.3892/etm.2016.3576 ◽

2016 ◽

Vol 12 (4) ◽

pp. 2275-2280 ◽

Cited By ~ 1

Author(s):

Leilei Yu ◽

Huifeng Wang ◽

Zhongxiu Guo ◽

Fenghua Li ◽

Hong Cui

Keyword(s):

Pancreatic Islet ◽

Cell Apoptosis ◽

Nucleolar Protein ◽

Β Cell

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SUN-640 Sex-Specific Difference in REG3G Expression Directs the Maintenance of Islet Function in Offspring of Obese Mice

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1918 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Jose Casasnovas ◽

James C Jarrell ◽

Kok Lim Kua

Keyword(s):

Insulin Secretion ◽

Pancreatic Islet ◽

Glucose Intolerance ◽

Maternal Obesity ◽

Fat Body ◽

Cell Mass ◽

Protective Role ◽

Islet Function ◽

Β Cell ◽

The Impact

Abstract Offspring exposed to maternal obesity are more likely to develop pancreatic islet dysfunction, but the underlying mechanistic pathway is unclear. We previously reported that fetal rats exposed to in-utero hyperglycemia had decreased fetal β-cell REG3G, and then developed lower β-cell mass and insulin secretion at adulthood. REG3G is reported to bind EXTL3 which initiates heparan sulfate (HS) synthesize important for pancreatic islet integrity. In this study, we sought the delineate the impact of maternal obesity exposure in altering offspring islet Reg3g and HS, and determine how changes in Reg3g and HS alters offspring islet insulin secretion. We hypothesize that exposure to maternal obesity (MatOb) suppresses offspring β-cell REG3G leading to decreased HS affecting β-cell health/function. We induced maternal obesity by feeding female mice western style diet for 4 weeks, while control mice were fed with regular chow. Offspring were evaluated for fat body mass, glucose intolerance, insulin secretion at postnatal day 21 and at 2-month-old. MatOb mouse offspring had increased fat-to-lean ratio and glucose intolerance but no insulin resistance at postnatal day 21, indicating decreased islet function. We performed islet perifusion to measure insulin induced secretion in postnatal day 21 offsprings. We found that male offspring but not female had impaired insulin secretion. In 2-month old offspring fat-to-lean ratio persisted but only males presented glucose intolerance. We found that pancreatic islet Reg3g expression was higher in MatOb females than males. This was accompanied increased HS in pancreatic islets of MatOb females compared to males. All together our data indicates a sex-specific protective role of Reg3g/HS in pancreatic islet function.

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