Abstract
Homeostasis of blood glucose is maintained by hormone secretion from the pancreatic islets of Langerhans. Glucose stimulates insulin secretion from β-cells but suppresses the release of glucagon, a hormone that raises blood glucose, from α-cells1. The mechanism by which nutrients stimulate insulin secretion has been studied extensively: ATP has been identified as the main messenger and the ATP-sensitive potassium channel as an essential transducer in this process2. By contrast, much less is known about the mechanisms by which nutrients modulate glucagon secretion. Here we use conventional pancreas perfusion and a transcriptional targeting strategy to analyse cell-type-specific signal transduction and the relationship between islet α- and β-cells. We find that pyruvate, a glycolytic intermediate and principal substrate of mitochondria, stimulates glucagon secretion. Our analyses indicate that, although α-cells, like β-cells, possess the inherent capacity to respond to nutrients, secretion from α-cells is normally suppressed by the simultaneous activation of β-cells. Zinc released from β-cells may be implicated in this suppression. Our results define the fundamental mechanisms of differential responses to identical stimuli between cells in a microorgan.
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Acknowledgements
We thank O. Dupont for technical assistance. H.I. is a recipient of a fellowship from Manpei Suzuki Foundation for Diabetes Research and a fellowship from the Juvenile Diabetes Foundation International and P.M. is a fellow of the Professor Max Cloetta Foundation. This work was supported by grants from the Swiss National Science Foundation (to C.B.W., P.M. and P.L.H.) and the Juvenile Diabetes Research Foundation (to P.L.H.).
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Supplementary information
Figure S1
Strategy to study specific cell types in heterogeneous cell populations. (PPT 360 kb)
Figure S2
Cytosolic and mitochondrial Ca2+ concentrations in response to varying concentrations of KCl in islet α- and β-cells. (PPT 362 kb)
Figure S3
Recombinant adenovirus system for expressing diphtheria toxin A (DTA) chain. (PPT 18 kb)
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Ishihara, H., Maechler, P., Gjinovci, A. et al. Islet β-cell secretion determines glucagon release from neighbouring α-cells. Nat Cell Biol 5, 330–335 (2003). https://doi.org/10.1038/ncb951
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DOI: https://doi.org/10.1038/ncb951
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