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