Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet

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Standard

Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet. / Kellard, Joely A.; Rorsman, Nils J. G.; Hill, Thomas G.; Armour, Sarah L.; van de Bunt, Martijn; Rorsman, Patrik; Knudsen, Jakob G.; Briant, Linford J. B.

I: Molecular Metabolism, Bind 40, 101021, 2020.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Kellard, JA, Rorsman, NJG, Hill, TG, Armour, SL, van de Bunt, M, Rorsman, P, Knudsen, JG & Briant, LJB 2020, 'Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet', Molecular Metabolism, bind 40, 101021. https://doi.org/10.1016/j.molmet.2020.101021

APA

Kellard, J. A., Rorsman, N. J. G., Hill, T. G., Armour, S. L., van de Bunt, M., Rorsman, P., Knudsen, J. G., & Briant, L. J. B. (2020). Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet. Molecular Metabolism, 40, [101021]. https://doi.org/10.1016/j.molmet.2020.101021

Vancouver

Kellard JA, Rorsman NJG, Hill TG, Armour SL, van de Bunt M, Rorsman P o.a. Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet. Molecular Metabolism. 2020;40. 101021. https://doi.org/10.1016/j.molmet.2020.101021

Author

Kellard, Joely A. ; Rorsman, Nils J. G. ; Hill, Thomas G. ; Armour, Sarah L. ; van de Bunt, Martijn ; Rorsman, Patrik ; Knudsen, Jakob G. ; Briant, Linford J. B. / Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet. I: Molecular Metabolism. 2020 ; Bind 40.

Bibtex

@article{a11d29c5fc774806b21a9acd04835a3c,
title = "Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet",
abstract = "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.",
keywords = "Alpha cell, Calcium, Delta cell, Diabetes, High fat diet, Hyperglucagonemia, Insulin tolerance, Islet of Langerhans, Paracrine, Somatostatin",
author = "Kellard, {Joely A.} and Rorsman, {Nils J. G.} and Hill, {Thomas G.} and Armour, {Sarah L.} and {van de Bunt}, Martijn and Patrik Rorsman and Knudsen, {Jakob G.} and Briant, {Linford J. B.}",
year = "2020",
doi = "10.1016/j.molmet.2020.101021",
language = "English",
volume = "40",
journal = "Molecular Metabolism",
issn = "2212-8778",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet

AU - Kellard, Joely A.

AU - Rorsman, Nils J. G.

AU - Hill, Thomas G.

AU - Armour, Sarah L.

AU - van de Bunt, Martijn

AU - Rorsman, Patrik

AU - Knudsen, Jakob G.

AU - Briant, Linford J. B.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - Alpha cell

KW - Calcium

KW - Delta cell

KW - Diabetes

KW - High fat diet

KW - Hyperglucagonemia

KW - Insulin tolerance

KW - Islet of Langerhans

KW - Paracrine

KW - Somatostatin

U2 - 10.1016/j.molmet.2020.101021

DO - 10.1016/j.molmet.2020.101021

M3 - Journal article

C2 - 32446876

AN - SCOPUS:85086844911

VL - 40

JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

M1 - 101021

ER -

ID: 244277592