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Shuai, Hongyan
Publications (10 of 10) Show all publications
Yu, Q., Shuai, H., Ahooghalandari, P., Gylfe, E. & Tengholm, A. (2019). Glucose controls glucagon secretion by directly modulating cAMP in alpha cells. Diabetologia, 62(7), 1212-1224
Open this publication in new window or tab >>Glucose controls glucagon secretion by directly modulating cAMP in alpha cells
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2019 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, no 7, p. 1212-1224Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis

Glucagon is critical for normal glucose homeostasis and aberrant secretion of the hormone aggravates dysregulated glucose control in diabetes. However, the mechanisms by which glucose controls glucagon secretion from pancreatic alpha cells remain elusive. The aim of this study was to investigate the role of the intracellular messenger cAMP in alpha-cell-intrinsic glucose regulation of glucagon release.

Methods

Subplasmalemmal cAMP and Ca2+ concentrations were recorded in isolated and islet-located alpha cells using fluorescent reporters and total internal reflection microscopy. Glucagon secretion from mouse islets was measured using ELISA.

Results

Glucose induced Ca2+-independent alterations of the subplasmalemmal cAMP concentration in alpha cells that correlated with changes in glucagon release. Glucose-lowering-induced stimulation of glucagon secretion thus corresponded to an elevation in cAMP that was independent of paracrine signalling from insulin or somatostatin. Imposed cAMP elevations stimulated glucagon secretion and abolished inhibition by glucose elevation, while protein kinase A inhibition mimicked glucose suppression of glucagon release.

Conclusions/interpretation

Glucose concentrations in the hypoglycaemic range control glucagon secretion by directly modulating the cAMP concentration in alpha cells independently of paracrine influences. These findings define a novel mechanism for glucose regulation of glucagon release that underlies recovery from hypoglycaemia and may be disturbed in diabetes.

Keywords
Ca2+, Cyclic AMP, Glucagon release, Hypoglycaemia, Insulin, Pancreatic alpha cell, Protein kinase A, Somatostatin
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-388762 (URN)10.1007/s00125-019-4857-6 (DOI)000471176200012 ()30953108 (PubMedID)
Funder
Swedish Research CouncilErnfors FoundationNovo NordiskSwedish Diabetes AssociationEXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2019-08-13 Created: 2019-08-13 Last updated: 2019-08-14Bibliographically approved
Shuai, H. (2018). Studies of cAMP and Ca2+ signaling in pancreatic islet cells. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Studies of cAMP and Ca2+ signaling in pancreatic islet cells
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The blood glucose-lowering and -elevating hormones insulin and glucagon are released from the pancreatic islet β- and α-cells, respectively. The intracellular messengers Ca2+ and cAMP have central roles in controlling the secretion of both hormones, but the underlying mechanisms are incompletely understood. A powerful approach to gain further insight is to study the messengers in individual cells within pancreatic islets, provided that each cell can be identified. To facilitate such studies, adenoviral vectors were generated for expression of fluorescent proteins controlled by the insulin and preproglucagon promoters, as well as the somatostatin and pancreatic polypeptide promoters that identify the other two major islet cell types, δ- and PP-cells. Recordings of cAMP and Ca2+ concentration changes with fluorescent reporters demonstrated that cells expressing identification markers responded as expected to well-known stimuli and modulators of the two messengers. Glucose-induced Ca2+ oscillations in β-cells were found to be synchronized with those in δ-cells, and two subpopulations of α-cells with different Ca2+ regulation by glucose were identified. Mouse and human β-cells responded to the insulinotropic hormones glucagon, GIP and GLP-1 with elevations of cAMP. Most α-cells reacted similarly to GIP, whereas only a subpopulation – larger among human than mouse α-cells - responded to glucagon and GLP-1. The GLP-1-receptor antagonist exendin-(9-39) suppressed both GLP-1- and glucagon-induced cAMP elevations in β-cells. Since exendin-(9-39) did not antagonize glucagon receptors, glucagon apparently activates GLP-1 receptors in β-cells. Even in the absence of glucagon/GLP-1, exendin-(9-39) reduced cAMP increases obtained by glucose stimulation or elevation of Ca2+. This effect was attributable to constitutive GLP-1-receptor activity rather than paracrine effects. Exendin-(9-39) also inhibited glucose-induced insulin release, highlighting the importance of cAMP formation in nutrient-stimulated secretion. Simultaneous recordings of cAMP and Ca2+ showed a complex and variable interrelationship between the messengers and the cAMP precursor ATP in β-cells. Depolarization-induced Ca2+ increases inhibited forskolin-, IBMX- and GLP-1-induced cAMP elevations. This cAMP lowering in part reflected suppression of the Ca2+-sensitive activity of adenylyl cyclases AC5 and 6, but also autocrine signaling induced by Ca2+-triggered exocytosis of insulin and adenine nucleotides, whose receptors activate phosphodiesterases and inhibit adenylyl cyclases, respectively.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 53
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1521
Keywords
pancreatic islet, insulin, glucagon, somatostatin, pancreatic polypeptide, exendin-(9-39), GLP-1, GIP, ATP, adenosine, cAMP, Ca2+, β-cell, α-cell, δ-cell, PP-cell
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-368612 (URN)978-91-513-0526-4 (ISBN)
Public defence
2019-02-12, B41, Biomedical Centre, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Note

Ca2+ in the keywords is Ca2+, please help me to change it. Thanks!

Available from: 2019-01-16 Created: 2018-12-11 Last updated: 2019-01-21
Yu, Q., Shuai, H., Ahooghalandari, P., Gylfe, E. & Tengholm, A. (2016). Glucose lowers cAMP to inhibit glucagon secretion by a direct effect on alpha cells. Paper presented at 52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 12-16, 2016, Munich, GERMANY. Diabetologia, 59, S266-S267
Open this publication in new window or tab >>Glucose lowers cAMP to inhibit glucagon secretion by a direct effect on alpha cells
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2016 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, p. S266-S267Article in journal (Refereed) Published
Place, publisher, year, edition, pages
SPRINGER, 2016
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-322056 (URN)000398373701362 ()
Conference
52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 12-16, 2016, Munich, GERMANY
Available from: 2017-05-16 Created: 2017-05-16 Last updated: 2017-05-16Bibliographically approved
Tian, G., Sol, E. M., Xu, Y., Shuai, H. & Tengholm, A. (2015). Impaired cAMP generation contributes to defective glucose-stimulated insulin secretion after long-term exposure to palmitate. Diabetes, 64(3), 904-915
Open this publication in new window or tab >>Impaired cAMP generation contributes to defective glucose-stimulated insulin secretion after long-term exposure to palmitate
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2015 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 3, p. 904-915Article in journal (Refereed) Published
Abstract [en]

Chronic palmitate exposure impairs glucose-stimulated insulin secretion and other aspects of β-cell function but the underlying mechanisms are not known. Using various live-cell fluorescence imaging approaches we show here that long-term palmitate treatment influences cAMP signaling in pancreatic β-cells. Glucose stimulation of mouse and human β-cells induced oscillations of the sub-plasma-membrane cAMP concentration but after 48 h exposure to palmitate, most β-cells failed to increase cAMP in response to glucose. In contrast, GLP-1-triggered cAMP formation and glucose- and depolarization-induced increases in cytoplasmic Ca2+ concentration were unaffected by the fatty acid treatment. Insulin secretion from control β-cells was pulsatile but the response deteriorated after long-term palmitate exposure. Palmitate-treated mouse islets showed reduced expression of adenylyl cyclase 9 and knockdown of this protein in insulinoma cells reduced the glucose-stimulated cAMP response and insulin secretion. We conclude that impaired glucose-induced generation of cAMP is an important determinant of defective insulin secretion after chronic palmitate exposure.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-192309 (URN)10.2337/db14-1036 (DOI)000350235900031 ()25281428 (PubMedID)
Funder
Swedish Research Council
Available from: 2013-01-17 Created: 2013-01-17 Last updated: 2018-01-11Bibliographically approved
Li, J., Shuai, H., Gylfe, E. & Tengholm, A. (2013). Oscillations of sub-membrane ATP in glucose-stimulated beta cells depend on negative feedback from Ca2+. Diabetologia, 56(7), 1577-1586
Open this publication in new window or tab >>Oscillations of sub-membrane ATP in glucose-stimulated beta cells depend on negative feedback from Ca2+
2013 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, no 7, p. 1577-1586Article in journal (Refereed) Published
Abstract [en]

ATP links changes in glucose metabolism to electrical activity, Ca2+ signalling and insulin secretion in pancreatic beta cells. There is evidence that beta cell metabolism oscillates, but little is known about ATP dynamics at the plasma membrane, where regulation of ion channels and exocytosis occur. The sub-plasma-membrane ATP concentration ([ATP](pm)) was recorded in beta cells in intact mouse and human islets using total internal reflection microscopy and the fluorescent reporter Perceval. Glucose dose-dependently increased [ATP](pm) with half-maximal and maximal effects at 5.2 and 9 mmol/l, respectively. Additional elevations of glucose to 11 to 20 mmol/l promoted pronounced [ATP](pm) oscillations that were synchronised between neighbouring beta cells. [ATP](pm) increased further and the oscillations disappeared when voltage-dependent Ca2+ influx was prevented. In contrast, K+-depolarisation induced prompt lowering of [ATP](pm). Simultaneous recordings of [ATP](pm) and the sub-plasma-membrane Ca2+ concentration ([Ca2+](pm)) during the early glucose-induced response revealed that the initial [ATP](pm) elevation preceded, and was temporarily interrupted by the rise of [Ca2+](pm). During subsequent glucose-induced oscillations, the increases of [Ca2+](pm) correlated with lowering of [ATP](pm). In beta cells, glucose promotes pronounced oscillations of [ATP](pm), which depend on negative feedback from Ca2+ (.) The bidirectional interplay between these messengers in the sub-membrane space generates the metabolic and ionic oscillations that underlie pulsatile insulin secretion.

Keywords
ATP, Ca2+, Human islets, Mouse islets, Oscillations, Pancreatic beta cell, Perceval, Plasma membrane
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-203521 (URN)10.1007/s00125-013-2894-0 (DOI)000319881300015 ()
Available from: 2013-07-16 Created: 2013-07-15 Last updated: 2017-12-06Bibliographically approved
Tian, G., Sågetorp, J., Xu, Y., Shuai, H., Degerman, E. & Tengholm, A. (2012). Role of phosphodiesterases in the shaping of sub-plasma-membrane cAMP oscillations and pulsatile insulin secretion. Journal of Cell Science, 125(21), 5084-5095
Open this publication in new window or tab >>Role of phosphodiesterases in the shaping of sub-plasma-membrane cAMP oscillations and pulsatile insulin secretion
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2012 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 125, no 21, p. 5084-5095Article in journal (Refereed) Published
Abstract [en]

Specificity and versatility in cyclic AMP (cAMP) signalling are governed by the spatial localisation and temporal dynamics of the signal. Phosphodiesterases (PDEs) are important for shaping cAMP signals by hydrolyzing the nucleotide. In pancreatic β-cells, glucose triggers sub-plasma-membrane cAMP oscillations, which are important for insulin secretion, but the mechanisms underlying the oscillations are poorly understood. Here, we investigated the role of different PDEs in the generation of cAMP oscillations by monitoring the concentration of cAMP in the sub-plasma-membrane space ([cAMP](pm)) with ratiometric evanescent wave microscopy in MIN6 cells or mouse pancreatic β-cells expressing a fluorescent translocation biosensor. The general PDE inhibitor IBMX increased [cAMP](pm), and whereas oscillations were frequently observed at 50 µM IBMX, 300 µM-1 mM of the inhibitor caused a stable increase in [cAMP](pm). The [cAMP](pm) was nevertheless markedly suppressed by the adenylyl cyclase inhibitor 2',5'-dideoxyadenosine, indicating IBMX-insensitive cAMP degradation. Among IBMX-sensitive PDEs, PDE3 was most important for maintaining a low basal level of [cAMP](pm) in unstimulated cells. After glucose induction of [cAMP](pm) oscillations, inhibitors of PDE1, PDE3 and PDE4 inhibitors the average cAMP level, often without disturbing the [cAMP](pm) rhythmicity. Knockdown of the IBMX-insensitive PDE8B by shRNA in MIN6 cells increased the basal level of [cAMP](pm) and prevented the [cAMP](pm)-lowering effect of 2',5'-dideoxyadenosine after exposure to IBMX. Moreover, PDE8B-knockdown cells showed reduced glucose-induced [cAMP](pm) oscillations and loss of the normal pulsatile pattern of insulin secretion. It is concluded that [cAMP](pm) oscillations in β-cells are caused by periodic variations in cAMP generation, and that several PDEs, including PDE1, PDE3 and the IBMX-insensitive PDE8B, are required for shaping the sub-membrane cAMP signals and pulsatile insulin release.

Keywords
cAMP, PDE, palmitate, STIM1, insulin secretion, total internal reflection fluorescence microscopy, beta-cell, alpha-cell, glucagon secretion, oscillations
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-192307 (URN)10.1242/jcs.107201 (DOI)000312984300016 ()22946044 (PubMedID)
Available from: 2013-01-17 Created: 2013-01-17 Last updated: 2017-12-06Bibliographically approved
Shuai, H. Constitutive GLP-1-receptor signaling contributes to basal and glucose-stimulated cAMP formation in β-cells: Constitutive GLP-1 receptor signaling in β-cells.
Open this publication in new window or tab >>Constitutive GLP-1-receptor signaling contributes to basal and glucose-stimulated cAMP formation in β-cells: Constitutive GLP-1 receptor signaling in β-cells
(English)In: Article in journal (Other (popular science, discussion, etc.)) Submitted
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-368723 (URN)
Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2018-12-11
Shuai, H. & Tengholm, A.Effects of Ca2+ and autocrine signals on cAMP dynamics in β-cells.
Open this publication in new window or tab >>Effects of Ca2+ and autocrine signals on cAMP dynamics in β-cells
(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-368721 (URN)
Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2018-12-11
Shuai, H. & Tengholm, A.Glucagon and GLP-1 evoke cAMP elevations in sub-populations of mouse and human α-cells.
Open this publication in new window or tab >>Glucagon and GLP-1 evoke cAMP elevations in sub-populations of mouse and human α-cells
(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-368722 (URN)
Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2018-12-20
Yu, Q., Shuai, H., Ahooghalandari, P., Gylfe, E. & Tengholm, A. Glucose controls glucagon secretion by directly modulating cAMP in α‑cells.
Open this publication in new window or tab >>Glucose controls glucagon secretion by directly modulating cAMP in α‑cells
Show others...
(English)In: Article in journal (Other (popular science, discussion, etc.)) Submitted
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-356473 (URN)
Available from: 2018-07-29 Created: 2018-07-29 Last updated: 2018-07-31
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