Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet
Objectives: Elevated plasma glucagon is an early symptom of diabetes, occurring in subjects with impaired glucose regulation. Here, we explored alpha-cell function in female mice fed a high-fat diet (HFD). Methods: Female mice expressing the Ca2+ indicator GCaMP3 specifically in alpha-cells were fed...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-10-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877820300958 |
| _version_ | 1818034289747427328 |
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| author | Joely A. Kellard Nils J.G. Rorsman Thomas G. Hill Sarah L. Armour Martijn van de Bunt Patrik Rorsman Jakob G. Knudsen Linford J.B. Briant |
| author_facet | Joely A. Kellard Nils J.G. Rorsman Thomas G. Hill Sarah L. Armour Martijn van de Bunt Patrik Rorsman Jakob G. Knudsen Linford J.B. Briant |
| author_sort | Joely A. Kellard |
| collection | DOAJ |
| description | Objectives: Elevated plasma glucagon is an early symptom of diabetes, occurring in subjects with impaired glucose regulation. Here, we explored alpha-cell function in female mice fed a high-fat diet (HFD). Methods: Female mice expressing the Ca2+ indicator GCaMP3 specifically in alpha-cells were fed a high-fat or control (CTL) diet. We then conducted in vivo phenotyping of these mice, as well as experiments on isolated (ex vivo) islets and in the in situ perfused pancreas. Results: In HFD-fed mice, fed plasma glucagon levels were increased and glucagon secretion from isolated islets and in the perfused mouse pancreas was also elevated. In mice fed a CTL diet, increasing glucose reduced intracellular Ca2+ ([Ca2+]i) oscillation frequency and amplitude. This effect was also observed in HFD mice; however, both the frequency and amplitude of the [Ca2+]i oscillations were higher than those in CTL alpha-cells. Given that alpha-cells are under strong paracrine control from neighbouring somatostatin-secreting delta-cells, we hypothesised that this elevation of alpha-cell output was due to a lack of somatostatin (SST) secretion. Indeed, SST secretion in isolated islets from HFD-fed mice was reduced but exogenous SST also failed to suppress glucagon secretion and [Ca2+]i activity from HFD alpha-cells, in contrast to observations in CTL mice. Conclusions: These findings suggest that reduced delta-cell function, combined with intrinsic changes in alpha-cells including sensitivity to somatostatin, accounts for the hyperglucagonaemia in mice fed a HFD. |
| first_indexed | 2024-12-10T06:36:48Z |
| format | Article |
| id | doaj.art-ad9a94c5162e4167af86f21b28811f7f |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-10T06:36:48Z |
| publishDate | 2020-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-ad9a94c5162e4167af86f21b28811f7f2022-12-22T01:58:54ZengElsevierMolecular Metabolism2212-87782020-10-0140101021Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat dietJoely A. Kellard0Nils J.G. Rorsman1Thomas G. Hill2Sarah L. Armour3Martijn van de Bunt4Patrik Rorsman5Jakob G. Knudsen6Linford J.B. Briant7Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, Churchill Hospital, Oxford OX3 7LE, UKOxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, Churchill Hospital, Oxford OX3 7LE, UKOxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, Churchill Hospital, Oxford OX3 7LE, UKSection for Cell Biology and Physiology, Department of Biology, University of Copenhagen, DenmarkDepartment of Bioinformatics and Data Mining, Novo Nordisk A/S, Maaloev, DenmarkOxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, Churchill Hospital, Oxford OX3 7LE, UK; Department of Neuroscience and Physiology, University of Göteborg, Box 430, SE40530 Göteborg, Sweden; Oxford National Institute for Health Research, Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LE, UKOxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, Churchill Hospital, Oxford OX3 7LE, UK; Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Denmark; Corresponding author. Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, Churchill Hospital, Oxford OX3 7LE, UK.Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, Churchill Hospital, Oxford OX3 7LE, UK; Department of Computer Science, University of Oxford, Oxford OX1 3QD, UK; Corresponding author. Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, Churchill Hospital, Oxford OX3 7LE, UK.Objectives: Elevated plasma glucagon is an early symptom of diabetes, occurring in subjects with impaired glucose regulation. Here, we explored alpha-cell function in female mice fed a high-fat diet (HFD). Methods: Female mice expressing the Ca2+ indicator GCaMP3 specifically in alpha-cells were fed a high-fat or control (CTL) diet. We then conducted in vivo phenotyping of these mice, as well as experiments on isolated (ex vivo) islets and in the in situ perfused pancreas. Results: In HFD-fed mice, fed plasma glucagon levels were increased and glucagon secretion from isolated islets and in the perfused mouse pancreas was also elevated. In mice fed a CTL diet, increasing glucose reduced intracellular Ca2+ ([Ca2+]i) oscillation frequency and amplitude. This effect was also observed in HFD mice; however, both the frequency and amplitude of the [Ca2+]i oscillations were higher than those in CTL alpha-cells. Given that alpha-cells are under strong paracrine control from neighbouring somatostatin-secreting delta-cells, we hypothesised that this elevation of alpha-cell output was due to a lack of somatostatin (SST) secretion. Indeed, SST secretion in isolated islets from HFD-fed mice was reduced but exogenous SST also failed to suppress glucagon secretion and [Ca2+]i activity from HFD alpha-cells, in contrast to observations in CTL mice. Conclusions: These findings suggest that reduced delta-cell function, combined with intrinsic changes in alpha-cells including sensitivity to somatostatin, accounts for the hyperglucagonaemia in mice fed a HFD.http://www.sciencedirect.com/science/article/pii/S2212877820300958DiabetesHigh fat dietIslet of LangerhansAlpha cellInsulin toleranceHyperglucagonemia |
| spellingShingle | Joely A. Kellard Nils J.G. Rorsman Thomas G. Hill Sarah L. Armour Martijn van de Bunt Patrik Rorsman Jakob G. Knudsen Linford J.B. Briant Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet Molecular Metabolism Diabetes High fat diet Islet of Langerhans Alpha cell Insulin tolerance Hyperglucagonemia |
| title | Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet |
| title_full | Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet |
| title_fullStr | Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet |
| title_full_unstemmed | Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet |
| title_short | Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet |
| title_sort | reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high fat diet |
| topic | Diabetes High fat diet Islet of Langerhans Alpha cell Insulin tolerance Hyperglucagonemia |
| url | http://www.sciencedirect.com/science/article/pii/S2212877820300958 |
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