Cx36-Mediated Coupling Reduces β-Cell Heterogeneity, Confines the Stimulating Glucose Concentration Range, and Affects Insulin Release Kinetics

Speier, Stephan; Gjinovci, Asllan; Charollais, Anne; Meda, Paolo; Rupnik, Marjan Slak

doi:10.2337/db06-0232

Cited by 163 publications

(243 citation statements)

References 49 publications

Supporting

Mentioning

219

Contrasting

Order By: Relevance

“…Similar observations were made in islets isolated from homozygous Cx36-null transgenic mice (Fig. 6), which lack gap junctions and are uncoupled (Ravier et al 2005;Speier et al 2007). These data show 152 E. SCEMES ET AL.…”

Section: Membrane Depolarization Does Not Induce Carbenoxolone-sensitsupporting

confidence: 64%

“…Thus, no functional "hemichannels" could be detected in freshly isolated islets of Langerhans, which, ex vivo, retain most of the normal features of primary β-cells in situ, notably with regard to insulin secretion and Cx36 channels (Ravier et al 2005;Speier et al 2007). The data provide evidence that, even if Cx36 were to form "hemichannels" in situ, these channels are unlikely to play a major physiological role.…”

Section: Discussionmentioning

confidence: 73%

“…The data provide evidence that, even if Cx36 were to form "hemichannels" in situ, these channels are unlikely to play a major physiological role. Thus, "hemichannels" are unlikely to account for the secretory alterations that have been observed in null and conditionally deleted transgenic mice that had lost β-cell Cx36 and gap junctions (Ravier et al 2005;Speier et al 2007, Wellershaus et al 2007). …”

Section: Discussionmentioning

confidence: 99%

“…Control C57/Bl6 (Charles River Laboratories, Lyon, France) and Cx36-null mice back-crossed with C57Bl6 partners for at least four generations at the animal facility of the University of Geneva (Ravier et al 2005;Speier et al 2007) were anesthetized (5% isoflurane) and sacrificed as per the regulations of our institutional and state committees on animal welfare. Islets of Langerhans were isolated from the mice pancreas, as previously reported (Ravier et al 2005).…”

Section: Cells and Pancreatic Isletsmentioning

confidence: 99%

See 3 more Smart Citations

Lack of “Hemichannel” Activity in Insulin-Producing Cells

Scemes

Bavamian

Charollais

et al. 2008

Cell Communication & Adhesion

Self Cite

View full text Add to dashboard Cite

Connexins and pannexins have been implicated in the formation of "hemichannels," which may account for the uptake and release of membrane-impermeant molecules in single cells. The in vivo existence of "hemichannels" and their protein composition is still debated. Investigations on these matters are complicated by the lack of adequate negative controls. In search for such essential controls, the authors have investigated transformed (MIN6 line) and primary insulin-producing cells. Here, the authors report that these cells, which express Cx36 and pannexin1, cannot be shown to display functional "hemichannels," as evaluated by (1) uptake of the membrane-impermeant tracer ethidium bromide, whether in the presence or absence of extracellular Ca 2+ , following stimulation of P2X 7 receptors, and after exposure to hypotonic medium; and (2) lack of exocytosis-independent release of endogenous ATP. Moreover, electrophysiological recordings indicated the absence of carbenoxolone-sensitive pannexin1 currents evoked by membrane potentials above +30 mV. Thus, insulin-producing cells are expected to provide a useful tool in the further characterization of hemichannel composition, properties, and physiological relevance.

show abstract

Section: Membrane Depolarization Does Not Induce Carbenoxolone-sensitsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Cells and Pancreatic Isletsmentioning

confidence: 99%

See 2 more Smart Citations

Lack of “Hemichannel” Activity in Insulin-Producing Cells

Scemes

Bavamian

Charollais

et al. 2008

Cell Communication & Adhesion

Self Cite

View full text Add to dashboard Cite

show abstract

“…GJ coupling between β-cells is essential for islet function. 6,86 The strength of this coupling decreases with age 87,88 and in animal models of diabetes. 89,90 Therefore, our simulations predict that a reduction in GJ coupling would reduce the ability of hubs to generate whole-islet Ca 2+ oscillations, greatly impairing insulin output.…”

Section: Discussionmentioning

confidence: 99%

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

Lei

Kellard

Hara

et al. 2018

Islets

View full text Add to dashboard Cite

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.

show abstract