Stimulation of the hepatoportal nerve plexus with focused ultrasound restores glucose homoeostasis in diabetic mice, rats and swine
Peripheral neurons that sense glucose relay signals of glucose availability to integrative clusters of neurons in the brain. However, the roles of such signalling pathways in the maintenance of glucose homoeostasis and their contribution to disease are unknown. Here we show that the selective activa...
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| Published in: | Nature biomedical engineering Vol. 6; no. 6; pp. 683 - 705 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
London
Nature Publishing Group UK
01-06-2022
Nature Publishing Group |
| Subjects: | |
| Online Access: | Get full text |
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| Summary: | Peripheral neurons that sense glucose relay signals of glucose availability to integrative clusters of neurons in the brain. However, the roles of such signalling pathways in the maintenance of glucose homoeostasis and their contribution to disease are unknown. Here we show that the selective activation of the nerve plexus of the hepatic portal system via peripheral focused ultrasound stimulation (pFUS) improves glucose homoeostasis in mice and rats with insulin-resistant diabetes and in swine subject to hyperinsulinemic-euglycaemic clamps. pFUS modulated the activity of sensory projections to the hypothalamus, altered the concentrations of metabolism-regulating neurotransmitters, and enhanced glucose tolerance and utilization in the three species, whereas physical transection or chemical blocking of the liver–brain nerve pathway abolished the effect of pFUS on glucose tolerance. Longitudinal multi-omic profiling of metabolic tissues from the treated animals confirmed pFUS-induced modifications of key metabolic functions in liver, pancreas, muscle, adipose, kidney and intestinal tissues. Non-invasive ultrasound activation of afferent autonomic nerves may represent a non-pharmacologic therapy for the restoration of glucose homoeostasis in type-2 diabetes and other metabolic diseases.
Selective activation of the hepatoportal nerve plexus via peripheral focused ultrasound stimulation improves glucose homoeostasis and enhances glucose tolerance and utilization in rodent models of diabetes and in swine. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 V.C. performed chronic stimulation experiments in ZDF and DIO models, data analysis and short-term stimulation experiments involving chemical lesioning and in vivo blocking; H.M. performed the in vitro stimulation experiments and data analysis; Z.H., K.A., M.D., L.B. and T.M. performed in vivo electrical recording experiments and contributed to data analysis; K.Q., J.N.T. and W.S. performed swine model experiments and data analysis; T.S.H., A.D. and T.T. performed western diet model experiments; N.T., Y.D. and K.J.-C. performed rodent H/E clamp experiments; J.G. performed transcriptomic and metabolomic analyses, data presentation and statistical analysis across manuscript data; R.M. performed analysis of electrical nerve recording data; K.W., T.-J.K. and Y.F. installed, set-up and calibrated ultrasound equipment and contributed experimental results from the mechanical piston stimulation data; E.L. and C.M. assisted in sample collection, storage and analysis of DIO and ZDF biological samples; J.A., K.J.T., T.R.C., D.D.C., D.S., S.Z., S.S.C., R.I.H. and C.P. designed the research and experiments, performed data analysis, edited and co-wrote sections of the manuscript; C.P. wrote the manuscript, including the assembly of sections from the collaborating institutions. Author contributions |
| ISSN: | 2157-846X 2157-846X |
| DOI: | 10.1038/s41551-022-00870-w |