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Paracrine signalling by pancreatic δ cells determines the glycaemic set point in mice

Nature Metabolism volume 6, pages 61–77 (2024)Cite this article

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Abstract

While pancreatic β and α cells are considered the main drivers of blood glucose homeostasis through insulin and glucagon secretion, the contribution of δ cells and somatostatin (SST) secretion to glucose homeostasis remains unresolved. Here we provide a quantitative assessment of the physiological contribution of δ cells to the glycaemic set point in mice. Employing three orthogonal mouse models to remove SST signalling within the pancreas or transplanted islets, we demonstrate that ablating δ cells or SST leads to a sustained decrease in the glycaemic set point. This reduction coincides with a decreased glucose threshold for insulin response from β cells, leading to increased insulin secretion to the same glucose challenge. Our data demonstrate that β cells are sufficient to maintain stable glycaemia and reveal that the physiological role of δ cells is to provide tonic feedback inhibition that reduces the β cell glucose threshold and consequently lowers the glycaemic set point in vivo.

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Fig. 1: Sst-CreTG/TG mice exhibit loss of Sst and a decreased glycaemic set point.
Fig. 2: Specific ablation of pancreatic δ cells in Sst-Cre × lsl-DTR mice.
Fig. 3: δ cell ablation decreases the glycaemic set point and increases glucose tolerance and insulin secretion.
Fig. 4: Inhibition of δ cell activity decreases glycaemia.
Fig. 5: Pancreatic δ cell ablation is sufficient to decrease the glycaemic set point.
Fig. 6: α Cell ablation does not affect basal glycaemia.
Fig. 7: β Cells exhibit calcium response at a lower glucose threshold in the absence of δ cells.
Fig. 8: Schematic of β cell glucose threshold and glycaemic set point in the presence and absence of δ cells.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files. Source data are available with this paper. Data for relevant images are available at Figshare at https://doi.org/10.6084/m9.figshare.24082434 (ref. 80). Source data are provided with this paper.

Code availability

The code used to perform glucose threshold analysis and neuron quantification is available on GitHub at github.com/Huising-Lab/Paracrine-signaling-by-pancreatic-mouse-cells-determines-the-glycemic-set-point.

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Acknowledgements

This work was supported by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK-110276; M.O.H.). J.L.H. was supported by a National Institute of General Medical Sciences-funded Pharmacology Training Program (T32 GM-099608). S.L. was supported by the NSF Graduate Research Fellowship (1650042), the UC Davis Training Program in Molecular and Cellular Biology (T32 GM-007377) and the UC Davis NSF Bridge to Doctorate Program (1612490). M.S.P. is supported by the UC Davis Training Program in Molecular and Cellular Biology (T32 GM-007377).

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Authors and Affiliations

  1. Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, CA, USA

    Jessica L. Huang, Mohammad S. Pourhosseinzadeh, Sharon Lee, Niels Krämer, Jaresley V. Guillen, Naomi H. Cinque, Paola Aniceto, Ariana T. Momen & Mark O. Huising

  2. Department of Animal Ecology and Physiology, Radboud Institute for Biological and Environmental Sciences, Radboud University, Nijmegen, The Netherlands

    Niels Krämer

  3. Department of Nutrition, University of California, Davis, CA, USA

    Shinichiro Koike

  4. Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, CA, USA

    Mark O. Huising

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Contributions

Conceptualization was the responsibility of J.L.H. and M.O.H. Methodology was the responsibility of J.L.H., S.L. and M.O.H. Software was the responsibility of M.S.P. Validation was carried out by J.L.H., S.L. and M.S.P. Formal analysis was conducted by J.L.H., S.L. and M.S.P. Investigation was the responsibility of J.L.H., M.S.P., S.L., N.K., J.V.G., N.C., P.A., A.T.M. and S.K. Writing of the original draft was carried out by J.L.H. and M.O.H. Review and editing was carried out by J.L.H., M.S.P. and M.O.H. Visualization was the responsibility of J.L.H., M.S.P. and M.O.H. Supervision was carried out by M.O.H.

Corresponding author

Correspondence to Mark O. Huising.

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Competing interests

M.O.H. received grant support from Crinetics to evaluate proprietary somatostatin-related compounds. None of this work is discussed in this paper. All other authors declare no competing interests.

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Nature Metabolism thanks Marcela Brissova and the other, anonymous, reviewers for their contribution to the peer review of this work. Primary Handling Editor: Christoph Schmitt, in collaboration with the Nature Metabolism team.

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Extended data

Extended Data Fig. 1 Body weight in Sst-Cre+/TG and Sst-Cre TG/TG males and females.

a) Body weight measurements of male Sst-Cre+/TG and Sst-CreTG/TG mice from Fig. 1d (n = 6 Sst-Cre+/TG, n = 9 Sst-CreTG/TG). b) Body weight measurements of female Sst-Cre+/TG and Sst-CreTG/TG mice from Fig. 1e (n = 7 Sst-Cre+/TG, n = 7 Sst-CreTG/TG). Significance was determined by two-way ANOVA or mixed modeling for genotype and age followed by Holm-Sidak’s correction for multiple comparisons. Error bars represent SEM.

Source data

Extended Data Fig. 2 Glucose measurements in SAL/DT-treated Sst-Cre only, DTR only, and Sst-Cre x lsl-DTR mice.

a) Blood glucose measurements of SAL and DT-treated male Sst-Cre only (n = 3 and n = 4, respectively) and SAL and DT-treated Sst-Cre x lsl-DTR (n = 5 and n = 6, respectively) male mice. Black arrows represent IP administration of DT. Significance was determined by three-way ANOVA for genotype and DT administration, followed by multiple comparisons of every mean to every other mean and Holm-Sidak’s correction. Error bars represent SEM. † represents statistically significant difference (p = 0.029) between DT-treated Sst-Cre only and Sst-Cre x lsl-DTR mice. b) Blood glucose measurements of male DT-treated lsl-DTR only (n = 6) and Sst-Cre x lsl-DTR (n = 5) mice. Black arrows represent IP administration of DT. Significance was determined by two-way ANOVA for ablation followed by Holm-Sidak’s correction for multiple comparisons (A; B, *p = 0.022, *p = 0.022, ****p < 0.0001). Error bars represent SEM.

Source data

Extended Data Fig. 3 Body weight and feeding measurements in Sst-Cre x lsl-DTR mice.

a) Body weight measurements of male CTRL and DT mice in Fig. 3a (n = 8 CTRL, n = 6 DT). Black arrows represent IP administration of SAL or DT. b) Body weight measurements of female CTRL and DT mice in Fig. 3b (n = 6 CTRL, n = 6 DT). Black arrows represent IP administration of SAL or DT. c) Feeding measurements in DT-treated Sst-Cre x lsl-DTR (n = 3) and Sst-Cre only (n = 3) mice. Black arrows represent IP administration of DT. d) Glucose tolerance test of male mice 3 months after ablation (n = 4 CTRL, n = 6 DT). e) Glucose tolerance test of female mice 3 months after ablation (n = 3 CTRL, n = 3 DT). Significance was determined by two-way ANOVA for ablation (A, B, C) or ablation and glucose (D, E) followed by Holm-Sidak’s correction for multiple comparisons (A: *p = 0.039; D: *p = 0.045, *p = 0.032) or two-tailed unpaired t-test (baseline-corrected AUC for D, *p = 0.040; baseline-corrected AUC for E, *p = 0.021). Error bars represent SEM.

Source data

Extended Data Fig. 4 Glucagon secretion in islets isolated from Sst-Cre x lsl-DTR mice.

a) Static glucagon secretion assay performed on islets isolated from SAL- or DT-treated Sst-Cre x lsl-DTR mice (n = 4 each). Islets were stimulated with 100 nM epinephrine to stimulate glucagon secretion. b) Static glucagon secretion assay performed on the same islets from Fig. 3m (n = 5 replicates per group, 10 islets each, pooled from 3 CTRL or 3 DT mice). c) Static glucagon secretion performed on the same islets from Fig. 3n (n = 5 replicates per group, 10 islets each, pooled from 3 CTRL or 3 DT mice). Significance was determined by two-way ANOVA followed by Holm-Sidak’s correction for multiple comparisons (A, *p = 0.015; B, *p = 0.042; C). Error bars represent SEM.

Source data

Extended Data Fig. 5 β and δ cell traces from Pair 1 of non-ablated and ablated mice.

a) Non-ablated and b) ablated islet calcium responses. Each box represents an islet. Each line represents calcium activity of a single β (green) or δ (red) cell. Dashed lines represent points at which glucose levels were changed. Ghrelin was used to functionally distinguish δ cells. 30 mM KCl was used to confirm viability of the cells. c and d) Traces from the same c) non-ablated and d) ablated mice in which islets were perfused with 5 mM glucose between each glucose step to confirm that the responses are not due to time or a delayed response to previous glucose levels.

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Extended Data Fig. 6 β and δ cell traces from Pair 2 of non-ablated and ablated mice.

a) Non-ablated and b) ablated islet calcium responses. Each box represents an islet. Each line represents calcium activity of a single β cell. Dashed lines represent points at which glucose levels were changed. 30 mM KCl was used to confirm viability of the cells. c and d) Traces from the same c) non-ablated and d) ablated mice in which islets were perfused with 5 mM glucose between each glucose step to confirm that the responses are not due to time or a delayed response to previous glucose levels. 30 mM KCl was used to confirm viability of the cells.

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Extended Data Fig. 7 β and δ cell traces from Pair 3 of non-ablated and ablated mice.

a) Non-ablated and b) ablated islet calcium responses. Each box represents an islet. Each line represents calcium activity of a single β cell. Dashed lines represent points at which glucose levels were changed. 30 mM KCl was used to confirm viability of the cells.

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Extended Data Fig. 8 Simultaneous collection of calcium dynamics in islets and insulin secretion.

The top graph shows insulin secretion over time from control (blue) and δ cell-ablated (green) islets as glucose is raised from 4 mM to 11 mM glucose. Below are the respective calcium traces of whole islets (n = 60 each) from the control (middle) and δ cell-ablated (bottom) mouse imaged at 4x. Each row represents the response of an individual islet.

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Huang, J.L., Pourhosseinzadeh, M.S., Lee, S. et al. Paracrine signalling by pancreatic δ cells determines the glycaemic set point in mice. Nat Metab 6, 61–77 (2024). https://doi.org/10.1038/s42255-023-00944-2

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