Glucose‐induced oscillations of intracellular Ca<sup>2+</sup> concentration resembling bursting electrical activity in single mouse islets of Langerhans

Valdeolmillos, Miguel; Santos, Rosa M.; Contreras, Diego; Soria, Bernat; Rosário, Luı́s M.

doi:10.1016/0014-5793(89)81484-x

Cited by 211 publications

(179 citation statements)

References 15 publications

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“…Our [Ca 2ϩ ] i recordings from whole human islets did not show the typical oscillatory patterns described for rodent islets (13,14). In rodent islets, ␤ cells are clustered, and their oscillations in membrane potential and [Ca 2ϩ ] i in response to high glucose concentrations are coordinated.…”

Section: Discussionmentioning

confidence: 56%

The unique cytoarchitecture of human pancreatic islets has implications for islet cell function

Cabrera

Berman

Kenyon

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

1,107

967

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The cytoarchitecture of human islets has been examined, focusing on cellular associations that provide the anatomical framework for paracrine interactions. By using confocal microscopy and multiple immunofluorescence, we found that, contrary to descriptions of prototypical islets in textbooks and in the literature, human islets did not show anatomical subdivisions. Insulin-immunoreactive ␤ cells, glucagon-immunoreactive ␣ cells, and somatostatin-containing ␦ cells were found scattered throughout the human islet. Human ␤ cells were not clustered, and most (71%) showed associations with other endocrine cells, suggesting unique paracrine interactions in human islets. Human islets contained proportionally fewer ␤ cells and more ␣ cells than did mouse islets. In human islets, most ␤, ␣, and ␦ cells were aligned along blood vessels with no particular order or arrangement, indicating that islet microcirculation likely does not determine the order of paracrine interactions. We further investigated whether the unique human islet cytoarchitecture had functional implications. Applying imaging of cytoplasmic free Ca 2؉ concentration, [Ca 2؉ ]i, we found that ␤ cell oscillatory activity was not coordinated throughout the human islet as it was in mouse islets. Furthermore, human islets responded with an increase in [Ca 2؉ ]i when lowering the glucose concentration to 1 mM, which can be attributed to the large contribution of ␣ cells to the islet composition. We conclude that the unique cellular arrangement of human islets has functional implications for islet cell function.␣ cell ͉ ␤ cell ͉ cytoplasmic free Ca 2ϩ concentration ͉ insulin ͉ glucagon I n the last three decades, hundreds of individuals with type 1 diabetes mellitus have received allogeneic transplants of endocrine pancreas, the islets of Langerhans, to cure their chronic condition. In these patients, diabetes is reversed by transplanting cells capable of physiologically regulating insulin secretion. Determining the quality of islets obtained from cadaveric pancreata should be indispensable in this context. However, it is not known which physiological parameters correlate best with a fully functional islet capable of reversing diabetes after transplantation. There is a wealth of information about the physiology of rodent islets, but the biology of human islets remains poorly understood. As assays for determining islet quality are being developed by many laboratories in the field of islet transplantation, a reassessment of the structure and function of human islets is warranted.The islets of Langerhans are small organs located in the pancreas that are crucial for glucose homeostasis. Islets typically consist of four types of secretory endocrine cells, namely, the insulin-containing ␤ cells, the glucagon-containing ␣ cells, the somatostatin-containing ␦ cells, and the pancreatic polypeptideproducing (PP) cells. In rodent islets, the vastly predominating ␤ cells are clustered in the core of a generally round islet, surrounded by a mantle of ␣, ␦, and PP cells. Thus, ...

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Section: Discussionmentioning

confidence: 56%

The unique cytoarchitecture of human pancreatic islets has implications for islet cell function

Cabrera

Berman

Kenyon

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

1,107

967

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“…The ability to assess cell function in vivo at the cellular level would allow investigations of 21 (Fig. 4c,d).…”

Section: In Vivo Imaging Of Beta Cell Cytoplasmic Free Ca 2+ Concentrmentioning

confidence: 99%

Noninvasive in vivo imaging of pancreatic islet cell biology

Speier

Nyqvist

Cabrera

et al. 2008

Nat Med

241

331

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Advanced imaging techniques have become a valuable tool in the study of complex biological processes at the cellular level in biomedical research. Here, we introduce a new technical platform for noninvasive in vivo fluorescence imaging of pancreatic islets using the anterior chamber of the eye as a natural body window. Islets transplanted into the mouse eye engrafted on the iris, became vascularized, retained cellular composition, responded to stimulation and reverted diabetes. Laserscanning microscopy allowed repetitive in vivo imaging of islet vascularization, beta cell function and death at cellular resolution. Our results thus establish the basis for noninvasive in vivo investigations of complex cellular processes, like beta cell stimulus-response coupling, which can be performed longitudinally under both physiological and pathological conditions. Adequate release of insulin by pancreatic beta cells in response to changing blood glucose levels is a vital requirement for maintaining glucose homeostasis. Failure to do so is one of the major causes of type 2 diabetes mellitus, the most common metabolic disorder in humans 1 . Under physiological conditions, insulin release is regulated by the complex interplay between glucose and a plethora of additional factors-for example, nutrients, autocrine-paracrine signaling and the continuous input from hormones and neurotransmitters 2 . Beta cells, together with other pancreatic endocrine cell types, are situated within the endocrine pancreas, that is, the islets of Langerhans, which are densely vascularized 3 and abundantly innervated 4 . Pancreatic islets, constituting 1%-2% of the pancreatic volume, are difficult to access for in vivo monitoring because they are deeply embedded and scattered in the exocrine tissue of the pancreas 5 . As a consequence, the majority of functional beta cell studies have so far been conducted in vitro on isolated islets or beta cells. Isolated islets 6 , and especially pancreatic slices 7 , allow functional studies of Author Contributions: S.S., D.N. and A.C. developed the experimental transplantation platform. S.S., D.N., O.C., J.Y., R.D.M., A.P., T.M., M.K., B.L. and A.C. did the experiments. J.W. was responsible for generating the transgenic mice. C.R. was involved in designing the transplantation protocols and writing the manuscript. S.S., D.N., I.B.L. and P.-O.B. were responsible for designing the overall experimental plan and writing the manuscript. P.-O.B. was the originator of the idea of using the anterior chamber of the eye for noninvasive in vivo imaging of pancreatic islet cell biology Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions Note: Supplementary information is available on the Nature Medicine website. Laser-scanning microscopy (LSM) of isolated islets and cell preparations has been successfully applied for imaging multiple signaling pathways in the beta cell 6 . However, intravital applications of LSM for studies of beta cell physiology have not been repo...

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“…The classical stimulus-secretion coupling that drives insulin release involves the closure of K ATP channels by increasing the intracellular ATP/ADP ratio (Ashcroft et al, 1984) and diadenosine polyphosphates concentration (DPs) (Ripoll et al, 1996) oscillatory pattern is originated (Nadal et al, 1999;Santos et al, 1991;Valdeolmillos et al, 1989), which triggers a pulsatile insulin secretion (Barbosa et al, 1998;Gilon et al, 1993;Dyachok et al, 2008).…”

Section: The Pancreatic -Cell As a Target Of Estrogens And Xenoestromentioning

confidence: 99%

“…The K ATP channels closure induces membrane depolarization that activates voltage-operated Ca 2+ channels and Ca 2+ influx (Valdeolmillos et al, 1992). Therefore, as a consequence of the oscillations in the membrane potential, a [Ca 2+ ] i oscillatory pattern is originated (Nadal et al, 1999;Santos et al, 1991;Valdeolmillos et al, 1989), which triggers a pulsatile insulin secretion (Barbosa et al, 1998;Gilon et al, 1993;Dyachok et al, 2008).…”

Section: The Role Of the Endocrine Pancreas In Blood Glucose Homeostasismentioning

confidence: 99%

The pancreatic β-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes

Nadal

Alonso-Magdalena

Soriano

et al. 2009

Molecular and Cellular Endocrinology

263

187

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. The pancreatic β-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes. Molecular and Cellular Endocrinology, Elsevier, 2009, 304 (1-2) Please cite this article as: Nadal, A., Alonso-Magdalena, P., Soriano, S., Quesada, I., Ropero, A.B., The pancreatic ␤-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes, Molecular and Cellular Endocrinology (2008), doi:10.1016/j.mce.2009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. THE PANCREATIC -CELL AS A TARGET OF ESTROGENS AND XENOESTROGENS: IMPLICATIONS FOR BLOOD GLUCOSE HOMEOSTASIS AND DIABETESAngel Rosen & Spiegelman, 2006;Fritsche et al., 2008). During the fasting state, insulin remains at low levels because plasma glucose concentration is low. In this situation, the levels of the counter-regulatory hormones, glucagon, adrenaline and corticosteroids are increased to promote hepatic glucose production. In contrast, insulin, the only hormone in the body able to decrease blood glucose levels, is increased during the fed state. Insulin decreases blood glucose by promoting adipocyte and muscle glucose uptake, as well as by preventing the liver from producing glucose by suppressing glycogenolysis and gluconeogenesis (Fritsche et al., 2008). neurotransmitters, hormones and nutrients, among which glucose is the most important.Normally, in response to short glucose stimulation, insulin biosynthesis is regulated by the increased translation of the preproinsulin transcript. After a prolonged glucose exposure, however, it is regulated via the insulin gene transcription (Orland et al., 1985;Permutt & Rotwein, 1983;Poitout et al., 2006). Both transcriptional and translational regulation of insulin biosynthesis is essential to maintain the intracellular stores of insulin on a long term basis.The secretory response of -cells depends on their electrical activity. This consists of oscillations of the membrane potential that range from electrically silent periods to depolarised plateaus on which Ca 2+ -action potentials originate (Rorsman et al., 2000).The classical stimulus-secretion coupling that drives insulin release involves the closure of K ATP channels by increasing the intracellular ATP/ADP ratio (Ashcroft et al., 1984) and diadenosine polyphosphates concentration (DPs) (Ripoll et al., 1996) oscillatory pattern is originated (Nadal et al., 1999;Santos et al., 1991;Valdeolmillos et al., 1989), which triggers a pulsatile insulin secretion (Barbosa et al., 1998;Gilon et al., 1993;Dyachok et al., 2008). Estrogens, estrogen receptors and blood glucose homeostasisT...

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Glucose‐induced oscillations of intracellular Ca²⁺ concentration resembling bursting electrical activity in single mouse islets of Langerhans

Cited by 211 publications

References 15 publications

The unique cytoarchitecture of human pancreatic islets has implications for islet cell function

The unique cytoarchitecture of human pancreatic islets has implications for islet cell function

Noninvasive in vivo imaging of pancreatic islet cell biology

The pancreatic β-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes

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Glucose‐induced oscillations of intracellular Ca2+ concentration resembling bursting electrical activity in single mouse islets of Langerhans

Cited by 211 publications

References 15 publications

The unique cytoarchitecture of human pancreatic islets has implications for islet cell function

The unique cytoarchitecture of human pancreatic islets has implications for islet cell function

Noninvasive in vivo imaging of pancreatic islet cell biology

The pancreatic β-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes

Contact Info

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Glucose‐induced oscillations of intracellular Ca²⁺ concentration resembling bursting electrical activity in single mouse islets of Langerhans